Imaging-based feedback cooling of a levitated nanoparticle.

Imaging-based detection of the motion of levitated nanoparticles complements a widely used interferometric detection method, providing a precise and robust way to estimate the position of the particle. Here, we demonstrate a camera-based feedback cooling scheme for a charged nanoparticle levitated in a linear Paul trap. The nanoparticle levitated in vacuum was imaged using a complementary metal-oxide semiconductor (CMOS) camera system. The images were processed in real-time with a microcontroller integrated with a CMOS image sensor. The phase-delayed position signal was fed back to one of the trap electrodes, resulting in cooling by velocity damping. Our study provides a simple and versatile approach applicable for the control of low-frequency mechanical oscillators.

Shift-and-add image processing incorporated with the unsharp masking method.

Shift-and-add (SAA) is a simple image processing procedure. SAA was devised to reconstruct a diffraction-limited image from atmospherically degraded stellar images. Recently SAA has been applied to biological imaging. There are several variants of SAA. Here proposed is an SAA procedure incorporated with unsharp masking (USM). The SAA procedure proposed here encompasses an extended version of USM. The proposed SAA method retains the simplicity and easiness, and the basic features of SAA. The effectiveness of the proposed method is examined by restoring atmospherically degraded solar images. It is shown that the USM SAA reconstructed image exhibits high contrast and reveals fine structures blurred by atmospheric turbulence. It is also shown that the USM SAA performs better with a data frame selection scheme.

Safety profile of vonoprazan compared with proton pump inhibitors: insight from a pharmacovigilance study.

Proton pump inhibitors (PPIs) are used to treat acid-related disorders such as peptic ulcer and gastroesophageal reflux disease. Recently, vonoprazan, a novel potassium-competitive acid blocker (P-CAB), has been introduced as more effective treatment option. The purpose of this study was to clarify the adverse events associated with vonoprazan compared to PPIs using a spontaneous reporting system database. We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between 2004 and 2017 were analyzed, and the reporting odds ratio (ROR) and 95% confidence interval (CI) for each adverse event were calculated. The database comprised 11,433 reports associated with PPIs, and 636 reports with vonoprazan. Hepatic and skin disorders were commonly detected in both PPIs and vonoprazan. There was a significant association of interstitial lung disease with PPIs as a class (ROR: 1.61, 95%CI: 1.47-1.77), but not with vonoprazan. Vonoprazan was strongly associated with haemorrhagic enterocolitis (ROR, 86.5; 95%CI, 59.7125). Among the PPIs, the signal score of microscopic colitis was noteworthy in the case of lansoprazole (ROR, 405; 95%CI, 348-472). It is suggested that there is a diversity in the strength of the association between PPIs and vonoprazan with adverse events. Our results may provide useful information for the treatment of acid-related disorders, but further research with more data is needed to finally clarify this.

Myositis with sarcoplasmic inclusions in Nakajo-Nishimura syndrome: a genetic inflammatory myopathy.

AIMS: Nakajo-Nishimura syndrome (NNS) is an autosomal recessive disease caused by biallelic mutations in the PSMB8 gene that encodes the immunoproteasome subunit ß5i. There have been only a limited number of reports on the clinicopathological features of the disease in genetically confirmed cases. METHODS: We studied clinical and pathological features of three NNS patients who all carry the homozygous p.G201V mutations in PSMB8. Patients' muscle specimens were analysed with histology and immunohistochemistry. RESULTS: All patients had episodes of typical periodic fever and skin rash, and later developed progressive muscle weakness and atrophy, similar to previous reports. Oral corticosteroid was used for treatment but showed no obvious efficacy. On muscle pathology, lymphocytes were present in the endomysium surrounding non-necrotic fibres, as well as in the perimysium perivascular area. Nearly all fibres strongly expressed MHC-I in the sarcolemma. In the eldest patient, there were abnormal protein aggregates in the sarcoplasm, immunoreactive to p62, TDP-43 and ubiquitin antibodies. CONCLUSIONS: These results suggest that inflammation, inclusion pathology and aggregation of abnormal proteins underlie the progressive clinical course of the NNS pathomechanism.

The Space Physics Environment Data Analysis System (SPEDAS).

With the advent of the Heliophysics/Geospace System Observatory (H/GSO), a complement of multi-spacecraft missions and ground-based observatories to study the space environment, data retrieval, analysis, and visualization of space physics data can be daunting. The Space Physics Environment Data Analysis System (SPEDAS), a grass-roots software development platform (www.spedas.org), is now officially supported by NASA Heliophysics as part of its data environment infrastructure. It serves more than a dozen space missions and ground observatories and can integrate the full complement of past and upcoming space physics missions with minimal resources, following clear, simple, and well-proven guidelines. Free, modular and configurable to the needs of individual missions, it works in both command-line (ideal for experienced users) and Graphical User Interface (GUI) mode (reducing the learning curve for first-time users). Both options have "crib-sheets," user-command sequences in ASCII format that can facilitate record-and-repeat actions, especially for complex operations and plotting. Crib-sheets enhance scientific interactions, as users can move rapidly and accurately from exchanges of technical information on data processing to efficient discussions regarding data interpretation and science. SPEDAS can readily query and ingest all International Solar Terrestrial Physics (ISTP)-compatible products from the Space Physics Data Facility (SPDF), enabling access to a vast collection of historic and current mission data. The planned incorporation of Heliophysics Application Programmer's Interface (HAPI) standards will facilitate data ingestion from distributed datasets that adhere to these standards. Although SPEDAS is currently Interactive Data Language (IDL)-based (and interfaces to Java-based tools such as Autoplot), efforts are under-way to expand it further to work with python (first as an interface tool and potentially even receiving an under-the-hood replacement). We review the SPEDAS development history, goals, and current implementation. We explain its "modes of use" with examples geared for users and outline its technical implementation and requirements with software developers in mind. We also describe SPEDAS personnel and software management, interfaces with other organizations, resources and support structure available to the community, and future development plans. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11214-018-0576-4) contains supplementary material, which is available to authorized users.

Approximate Bayesian computation analysis of EST-associated microsatellites indicates that the broadleaved evergreen tree Castanopsis sieboldii survived the Last Glacial Maximum in multiple refugia in Japan.

Climatic changes have played major roles in plants' evolutionary history. Glacial oscillations have been particularly important, but some of their effects on plants' populations are poorly understood, including the numbers and locations of refugia in Asian warm temperate zones. In the present study, we investigated the demographic history of the broadleaved evergreen tree species Castanopsis sieboldii (Fagaceae) during the last glacial period in Japan. We used approximate Bayesian computation (ABC) for model comparison and parameter estimation for the demographic modeling using 27 EST-associated microsatellites. We also performed the species distribution modeling (SDM). The results strongly support a demographic scenario that the Ryukyu Islands and the western parts in the main islands (Kyushu and western Shikoku) were derived from separate refugia and the eastern parts in the main islands and the Japan Sea groups were diverged from the western parts prior to the coldest stage of the Last Glacial Maximum (LGM). Our data indicate that multiple refugia survived at least one in the Ryukyu Islands, and the other three regions of the western and eastern parts and around the Japan Sea of the main islands of Japan during the LGM. The SDM analysis also suggests the potential habitats under LGM climate conditions were mainly located along the Pacific Ocean side of the coastal region. Our ABC-based study helps efforts resolve the demographic history of a dominant species in warm temperate broadleaved forests during and after the last glacial period, which provides a basic model for future phylogeographical studies using this approach.

Comparison of pregnancy outcomes following fresh and electively frozen single blastocyst transfer in natural cycle and clomiphene-stimulated IVF cycles.

STUDY QUESTION: Are there any differences in live birth rates (LBR) following fresh blastocyst transfer in natural or clomiphene-stimulated cycles, or after elective blastocyst freezing in clomiphene-stimulated cycles followed by thawing and transfer at different time-points? SUMMARY ANSWER: Clomiphene citrate (CC) administration adversely affected the LBR after single fresh blastocyst transfer (SBT) in CC cycles compared with that in natural cycles, while this adverse effect of CC is not present when a single vitrified-warmed blastocyst transfer (SVBT) is performed in subsequent natural ovulatory cycles, regardless of the duration between CC administration and the day of SVBT. WHAT IS KNOWN ALREADY: CC affects uterine receptivity associated with a thinning of the uterine endometrium through an antioestrogenic effect. However, the duration that this adverse effect of CC on uterine endometrium persists after initial use is still unknown. STUDY DESIGN SIZE DURATION: A retrospective cohort study of 157 natural cycle IVFs followed by SBT and 1496 minimal ovarian stimulation with CC IVF cycles followed by SBT (n = 24) or SVBT (n = 1472) from January 2010 to December 2014 was conducted. SVBT cycles were classified into two groups according to the period between the last day of CC administration and the day of SVBT (A: ≤60 d and B: ≥61 d). All groups were then compared based on pregnancy outcomes (natural-SBT group: n = 157, CC-SBT group: n = 24, SVBT-A: n = 1143, SVBT-B: n = 329). PARTICIPANTS/MATERIALS SETTING METHODS: Women were aged 30-39 years at oocyte retrieval. In SVBT cycles, blastocysts were vitrified and warmed using a Cryotop safety kit. SVBT was performed in subsequent natural ovulatory cycles. The main outcomes were LBR and neonatal outcome, and both were compared among the groups. MAIN RESULTS AND THE ROLE OF CHANCE: The LBR in the CC-SBT group (29.2%, 7/24) was significantly lower compared with the natural-SBT (56.1%, 88/157) (P = 0.01) and SVBT-A (50.0%, 572/1143) (P = 0.04), but not SVBT-B (47.4%, 156/329), groups. Furthermore, multivariate logistic regression analysis revealed that the LBR was comparable among the natural-SBT and SVBT groups, but was significantly lower in the CC-SBT group (adjusted odds ratio: 0.324, 95% CI: 0.119-0.800, P = 0.01). No significant differences among all groups were observed for gestational age (P = 0.19), birthweight (P = 0.41) and incidence of malformation (P = 0.53). LIMITATIONS REASONS FOR CAUTION: In this study we analysed a biased sample, based on clinical judgement regarding endometrial thickness, and the study was limited by its retrospective nature. The low statistical power caused by the group size disparity was also a limitation, especially in the CC-SBT group. Although the outcome showing inferiority of CC-SBT compared to natural-SBT is consistent with general findings in the literature, further large-scale clinical studies, ideally RCTs, are necessary to validate our results and clarify the prolonged effect of CC in SVBT cycles on pregnancy and neonatal outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Our observation suggests that CC administered in minimal ovarian stimulation cycles affects adversely the pregnancy outcomes when SBT is performed. Therefore, for a CC-based minimal stimulation IVF cycle, we suggest that frozen embryo transfer should be performed in a subsequent natural ovulatory cycle to avoid the possibility of implantation failure associated with CC administration. STUDY FUNDING/COMPETING INTERESTS: The authors have no conflicts of interest to declare. No external funding was either sought or obtained.

From Trioleoyl glycerol to extra virgin olive oil through multicomponent triacylglycerol mixtures: Crystallization and polymorphic transformation examined with differential scanning calorimetry and X-ray diffration techniques.

The polymorphic crystallization and transformation behavior of extra virgin olive oil (EVOO) was examined by using differential scanning calorimetry (DSC) and X-ray diffraction with both laboratory-scale (XRD) and synchrotron radiation source (SR-XRD). The complex behavior observed was studied by previously analyzing mixtures composed by its main 2 to 6 triacylglycerol (TAG) components. Thus, component TAGs were successively added to simulate EVOO composition, until reaching a 6 TAGs mixture, composed by trioleoyl glycerol (OOO), 1-palmitoyl-2,3-dioleoyl glycerol (POO), 1,2-dioleoyl-3-linoleoyl glycerol (OOL), 1-palmitoyl-2-oleoyl-3-linoleoyl glycerol (POL), 1,2-dipalmitoyl-3-oleoyl glycerol (PPO) and 1-stearoyl-2,3-dioleoyl glycerol (SOO). Molten samples were cooled from 25°C to -80°C at a controlled rate of 2°C/min and subsequently heated at the same rate. The polymorphic behavior observed in multicomponent TAG mixtures was interpreted by considering three main groups of TAGs with different molecular structures: triunsaturated OOO and OOL, saturated-unsaturated-unsaturated POO, POL and SOO, and saturated-saturated-unsaturated PPO. As confirmed by our previous work, TAGs belonging to the same structural group displayed a highly similar polymorphic behavior. EVOO exhibited two different ß'-2L polymorphic forms (ß'2-2L and ß'1-2L), which transformed into ß'-3L when heated. Equivalent polymorphic pathways were detected when the same experimental conditions were applied to the 6 TAG components mixture. Hence, minor components may not exert a strong influence in this case.

PU.1 acts as tumor suppressor for myeloma cells through direct transcriptional repression of IRF4.

We previously reported that PU.1 is downregulated in the majority of myeloma cell lines and primary myeloma cells of certain myeloma patients, and conditional expression of PU.1 in such myeloma cell lines induced cell cycle arrest and apoptosis. We found downregulation of IRF4 protein in the U266 myeloma cell line following induction of PU.1. Previous studies reported that knockdown of IRF4 in myeloma cell lines induces apoptosis, prompting us to further investigate the role of IRF4 downregulation in PU.1-induced cell cycle arrest and apoptosis in myeloma cells. PU.1 induced downregulation of IRF4 at the protein level, cell cycle arrest and apoptosis in six myeloma cell lines. Chromatin immunoprecipitation (ChIP) revealed that PU.1 directly binds to the IRF4 promoter, whereas a reporter assay showed that PU.1 may suppress IRF4 promoter activity. Stable expression of IRF4 in myeloma cells expressing PU.1 partially rescued the cells from apoptosis induced by PU.1. As it was reported that IRF4 directly binds to the IRF7 promoter and downregulates its expression in activated B cell-like subtype of diffuse large B cell lymphoma cells, we performed ChIP assays and found that IRF4 directly binds the IRF7 promoter in myeloma cells. It is known that IRF7 positively upregulates interferon-ß (IFNß) and induces apoptosis in many cell types. Binding of IRF4 to the IRF7 promoter decreased following PU.1 induction, accompanied by downregulation of IRF4 protein expression. Knockdown of IRF7 protected PU.1-expressing myeloma cells from apoptosis. Furthermore, IFNß, which is a downstream target of IRF7, was upregulated in myeloma cells along with IRF7 after PU.1 induction. Finally, we evaluated the mRNA expression levels of PU.1, IRF4 and IRF7 in primary myeloma cells from patients and found that PU.1 and IRF7 were strongly downregulated in contrast to the high expression levels of IRF4. These data strongly suggest that PU.1-induced apoptosis in myeloma cells is associated with IRF4 downregulation and subsequent IRF7 upregulation.

Effect of Antihypertensive Drugs on Uric Acid Metabolism in Patients with Hypertension: Cross-Sectional Cohort Study.

Background: Hypertension is a common complication in patients with gout and/or hyperuricemia. Besides, hyperuricemia is a risk factor of gout as well as ischemic heart disease in hypertensive patients. Moreover, the risk of gout is modified by antihypertensive drugs. However, it remains unclear how antihypertensive agents affect uric acid metabolism. Purpose: In the present study, we investigated the uric acid metabolism in treated hypertensive patients to find out whether any of them would influence serum levels of uric acid. Patients and methods: 751 hypertensive patients (313 men and 438 women) under antihypertensive treatment were selected. Blood pressure (BP), serum uric acid (SUA) and serum creatinine (Scr) were measured and evaluated statistically. Results: In patients treated with diuretics, beta-blockers and/or alpha-1 blockers SUA levels were significantly higher than in patients who were not taking these drugs. Besides, the estimated glomerular filtration rate (eGFR) in patients treated with diuretics, beta-blockers and/or alpha-1 blockers was negatively correlated with SUA level. There were gender differences in the effects of beta-blockers and alpha-1 blockers. Multiple regression analysis indicated that both diuretics and beta-blockers significantly contributed to hyperuricemia in patients with medication for hypertension. Conclusion: Diuretics, beta-blockers and alpha-1 blockers reduced glomerular filtration rate and raised SUA levels. Calcium channel blockers, ACE inhibitors and angiotensin receptor blockers, including losartan, did not increase SUA levels.

ENERGY AND ANGULAR DEPENDENCE OF RADIOPHOTOLUMINESCENT GLASS DOSEMETERS FOR EYE LENS DOSIMETRY.

Recent studies demonstrated that lens opacities can occur at lower radiation doses than previously accepted. In view of these studies, the International Commission of Radiological Protection recommended in 2011 to reduce the eye lens dose limit from 150 mSv/y to 20 mSv/y. This implies in the need of monitoring doses received by the eye lenses. In this study, small rod radiophotoluminescent glass dosemeters (GD-300 series; AGC, Japan) were characterized in terms of their energy (ISO 4037 X-rays narrow spectrum series, S-Cs and S-Co) and angular dependence (0  up to 90 degrees, with 2 ISO energies: N-60 and S-Cs). All acquisitions were performed at SCK•CEN-Belgium, using the ORAMED proposed cylindrical phantom. For selected energies (N-60, N-80, N-100, N-120 and N-250), the response of dosemeters irradiated on the ISO water slab phantom, at the Ruder Boskovic Institute-Croatia, was compared to those irradiated on the cylindrical phantom. GD-300 series showed good energy dependence, relative to S-Cs, on the cylindrical phantom. From 0 up to 45 degrees, the dosemeters showed no significant angular dependence, regardless whether they were tested when placed vertically or horizontally on the cylindrical phantom. However, at higher angles, some angular dependence was observed, mainly when the dosemeters were irradiated with low-energy photons (N-60). Results showed that GD-300 series have good properties related to Hp(3), although some improvements may be necessary.

In situ crystallization and transformation kinetics of polymorphic forms of saturated-unsaturated-unsaturated triacylglycerols: 1-palmitoyl-2,3-dioleoyl glycerol, 1-stearoyl-2,3-dioleoyl glycerol, and 1-palmitoyl-2-oleoyl-3-linoleoyl glycerol.

We examined the influence of dynamic thermal treatment (variation of cooling/heating rates) on the polymorphic crystallization and transformation pathways of 1-palmitoyl-2,3-dioleoyl glycerol (POO), 1-stearoyl-2,3-dioleoyl glycerol (SOO), and 1-palmitoyl-2-oleoyl-3-linoleoyl glycerol (POL), which are major saturated-unsaturated-unsaturated (SUU) triacylglycerols (TAGs) of vegetable oils and animal fats (e.g., palm oil, olive oil, and Iberian ham fat). Using mainly a combination of differential scanning calorimetry (DSC) and synchrotron radiation X-ray diffraction (SR-XRD), we analyzed the polymorphic behavior of TAGs when high (15°Cmin-1), intermediate (2°Cmin-1), and low (0.5°Cmin-1) cooling and heating rates were applied. Multiple polymorphic forms were detected in POO, SOO, and POL (sub-α, α, ß'2, and ß'1). Transient disordered phases, defined as kinetic liquid crystal (KLC) phases, were determined in POO and SOO for the first time. The results demonstrated that more stable forms were directly obtained from the melt by decreasing the cooling rates, whereas less stable forms predominated at high cooling rates, as confirmed in our previous work. Regarding heating rate variation, we confirmed that the nature of the polymorphic transformations observed (solid-state, transformation through KLC phase, or melt-mediation) depended largely on the heating rate. These results were discussed considering the activation energies involved in each process and compared with previous studies on TAGs with different saturated-unsaturated structures (1,3-dioleoyl-2-palmitoylglycerol, 1,3-dipalmitoyl-2-oleoyl-glycerol, trioleoyl glycerol, and 1,2-dioleoyl-3-linoleoyl glycerol).

Influence of morphology and polymorphic transformation of fat crystals on the freeze-thaw stability of mayonnaise-type oil-in-water emulsions.

This study examined the destabilization of an oil-in-water (O/W) emulsion by freeze-thawing with a focus on the influence of the morphology and polymorph of fat crystals. For a model of food emulsion, this study used a mayonnaise-type O/W emulsion containing 70wt% canola oil (canola emulsion) or soybean oil (soybean emulsion) stored at -15, -20, and -30°C. The freeze-thaw stabilities of the emulsions were evaluated by measuring the upper oil layer after freeze-thawing. The soybean emulsion kept at -20°C had the highest stability; the other emulsions were destabilized during 6h of storage. Crystallization in the emulsions was determined using differential scanning calorimetry (DSC), time variation of temperature, X-ray diffraction measurement, and polarized light microscopy. DSC thermograms indicated that crystallization in emulsions occurred first in the high-melting fraction of oil, followed by water and, last, in the low-melting fraction of oil during cooling to -40°C. In the canola emulsion, the amount of fat crystals derived from the low-melting fraction of oil increased during storage at all temperatures, resulting in partial coalescence. The soybean emulsion was expected to be destabilized by polymorphic transformation (sub-α to ß' and ß) of fat crystals derived from the high-melting fraction during storage at -15 and -20°C. However, the soybean emulsion did not exhibit polymorphic transformation stored at -30°C, and the amount of fat crystals did not increase during freezing; thus, it was destabilized via a different mechanism.

Evaluation of resectability after neoadjuvant chemotherapy for primary non-resectable colorectal liver metastases: A multicenter study.

BACKGROUND/AIM: The Kyushu Study Group of Clinical Cancer (KSCC) previously reported the safety and efficacy of neoadjuvant chemotherapy with mFOLFOX6 + bevacizumab for H2/H3 liver metastases of colorectal cancer. The aim of the current study was to evaluate the resectability of these metastases before and after chemotherapy as determined by independent liver surgeons. METHODS: Between May 2008 and April 2010, 40 patients were registered in a multicenter phase 2 trial of neoadjuvant chemotherapy (KSCC 0802). In Study 1, 5 independent liver surgeons from five different KSCC centers evaluated the resectability of liver metastases of colorectal cancer based on imaging studies performed before and after chemotherapy. Each surgeon was blinded to the other surgeons' evaluations. In addition, no information about the patients' characteristics was provided. In Study 2, 3 surgeons evaluated the resectability of these lesions based on imaging studies with discussion with each other, with the surgeons being provided with information on the patients' characteristics. RESULTS: In Study 1, 13 patients (36.1%) were evaluated to be resectable at baseline, whereas 17 patients (47.2%) were evaluated to be resectable after chemotherapy. In Study 2, 4 patients (11.1%) were evaluated to be resectable at baseline, compared to 23 patients (63.9%) after chemotherapy. CONCLUSION: Neoadjuvant chemotherapy with mFOLFOX6 + bevacizumab was confirmed to increase the resectability of non-resectable liver metastases of colorectal cancer according to the independent assessments of surgeons.

Long-term advanced therapy with bosentan improves symptoms and prevents deterioration of inoperable chronic thromboembolic pulmonary hypertension.

AIMS: Chronic thromboembolic pulmonary hypertension (CTEPH) is a devastating disease, and treating patients with CTEPH who are not eligible for pulmonary endarterectomy is particularly challenging. Short-term bosentan or phosphodiesterase type-5-inhibitor treatment can greatly improve symptoms and hemodynamics in these patients; however, the long-term benefits of advanced pulmonary vasodilators are not known. We retrospectively investigated the long-term effects of advanced pharmacological therapy in Japanese patients with inoperable CTEPH. MAIN METHODS: Seven consecutive patients with inoperable CTEPH (five women; mean age, 62.6±6.9 years) treated with bosentan were included. World Health Organization functional class (WHO-FC), hemodynamics, exercise capacity, and plasma B-type natriuretic peptide (BNP) concentration were evaluated at baseline and for more than 2 years. Time to clinical worsening was also examined during long-term follow-up. KEY FINDINGS: WHO-FC improved significantly, from 3.1±0.4 to 2.1±0.4 (p=0.005). Significant improvement was also seen in pulmonary vascular resistance, which decreased from 786.9±300.0 to 352.2±210.7 dynes s cm(-5) (p<0.05). Plasma BNP concentration decreased significantly from 1160.0±971.4 to 305.1±285.9 pg/mL (p<0.05). No patient required hospitalization during the follow-up period (mean, 896±564 days). SIGNIFICANCE: Long-term advanced therapy with bosentan significantly improves symptoms, pulmonary vascular resistance, plasma BNP concentration, and time to clinical worsening in Japanese patients with inoperable CTEPH. We consider bosentan to be an essential treatment for these patients.

Missense variants of the alanine: glyoxylate aminotransferase 2 gene correlated with carotid atherosclerosis in the Japanese population.

Alanine:glyoxylate aminotransferase 2 (AGXT2; EC 2.6.1.44) degrades asymmetric dimethylarginine (ADMA), a competitive inhibitor of nitric oxide (NO) synthase. Increased ADMA, reduced NO, and hypertension are shown in Agxt2 knockout mice. There are four single nucleotide polymorphisms (rs37370, rs37369, rs180749, and rs16899974) with which AGXT2 activity changes in humans and may be related to vulnerability of vascular sclerosis. To examine the relationship between them, we studied the functional haplotypes of the AGXT2 gene and decided their relationship with arteriosclerotic changes via carotid intima-media thickness (carotid IMT) in Japanese subjects. Genotyping of those polymorphisms and the carotid IMT in 1,426 Japanese subjects were then evaluated. Subjects with C-A-A-A haplotype (rs37370, rs37369, rs180749, rs16899974) showed low AGXT2 activity (P<0.0001; Pearson’s correlation coefficients: 0.497). The C-A-A-A haplotype was significantly associated with mean carotid IMT (P=0.049) and max carotid IMT (P=0.004). Subjects with two C-A-A-A haplotypes exhibited thicker mean carotid IMT (P=0.022) and maximum carotid IMT (P=0.001). In multiple regression analysis, subjects with two C-A-A-A haplotypes were independently and positively associated with mean carotid IMT (P=0.02) and maximum IMT (P=0.005) after correction. There was a significant correlation between the functional variants in the AGXT2 gene and carotid IMT in Japanese. The AGXT2 genotype may be an important factor underlying atherosclerosis.

Axonal protection by Nmnat3 overexpression with involvement of autophagy in optic nerve degeneration.

Axonal degeneration often leads to the death of neuronal cell bodies. Previous studies demonstrated the crucial role of nicotinamide mononucleotide adenylyltransferase (Nmnat) 1, 2, and 3 in axonal protection. In this study, Nmnat3 immunoreactivity was observed inside axons in the optic nerve. Overexpression of Nmnat3 exerts axonal protection against tumor necrosis factor-induced and intraocular pressure (IOP) elevation-induced optic nerve degeneration. Immunoblot analysis showed that both p62 and microtubule-associated protein light chain 3 (LC3)-II were upregulated in the optic nerve after IOP elevation. Nmnat3 transfection decreased p62 and increased LC3-II in the optic nerve both with and without experimental glaucoma. Electron microscopy showed the existence of autophagic vacuoles in optic nerve axons in the glaucoma, glaucoma+Nmnat3 transfection, and glaucoma+rapamycin groups, although preserved myelin and microtubule structures were noted in the glaucoma+Nmnat3 transfection and glaucoma+rapamycin groups. The axonal-protective effect of Nmnat3 was inhibited by 3-methyladenine, whereas rapamycin exerted axonal protection after IOP elevation. We found that p62 was present in the mitochondria and confirmed substantial colocalization of mitochondrial Nmnat3 and p62 in starved retinal ganglion cell (RGC)-5 cells. Nmnat3 transfection decreased p62 and increased autophagic flux in RGC-5 cells. These results suggest that the axonal-protective effect of Nmnat3 may be involved in autophagy machinery, and that modulation of Nmnat3 and autophagy may lead to potential strategies against degenerative optic nerve disease.

Displacement of foveal area toward optic disc after macular hole surgery with internal limiting membrane peeling.

PURPOSE: To determine whether there is a displacement of the fovea toward the optic disc after successful macular hole (MH) surgery with internal limiting membrane (ILM) peeling. METHODS: The medical records of 54 eyes of 53 patients that had undergone pars plana vitrectomy with ILM peeling and gas or air tamponade for an idiopathic MH were evaluated. Spectral-domain optical coherence tomography (OCT) had been performed before and >6 months after the surgery. The preoperative distances between the center of the MH and the optic disc (MH-OD), center of the MH and the bifurcation or crossing of retinal vessels (MH-RV) were measured in the OCT images. In addition, the postoperative distance between the center of the fovea and optic disc (F-OD) and the center of the fovea and the same bifurcation or crossing of retinal vessels (F-RV) were measured in the OCT images. RESULTS: The F-OD was 2.67±0.33 disc diameters (DD), which was significantly shorter than that of the MH-OD of 2.77±0.33 DD (P<0.001). The F-RV was also significantly shorter than the MH-RV on the inner nasal area (from 0.85±0.16DD to 0.79±0.15DD; P<0.001), the inner temporal area (from 0.82±0.15DD to 0.77±0.14DD; P<0.001), and outer nasal area (from 1.70±0.31DD to 1.65±0.32DD; P<0.001), but it was significantly longer than the MH-RV in the outer temporal area (from 1.65±0.29DD to 1.68±0.29DD; P<0.001). CONCLUSION: Our results showed that successful closure of a MH by vitrectomy with ILM peeling and gas tamponade leads to a displacement of the center of the macula toward the optic disc.