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Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): the research grant D2 from Kansai Medical University Objectives Angiopoietin-like protein 2 (ANGPTL2) is a protein, whose structure is similar to that of angiopoietin, but binds to a different receptor. Overexpression of ANGPTL2 promotes chronic inflammation and relates to the development of aging-related diseases. ANGPTL2 has been reported to be mainly secreted by adipose tissue. Although ANGPTL2 has been implicated in the pathogenesis of heart failure, there are no studies about serum ANGPTL2 levels in patients with heart failure participating in cardiac rehabilitation program. The aim of this study was to investigate the characteristics, related factors and changes of ANGPTL2 in patients with chronic heart failure during phase III of cardiac rehabilitation program. Methods The subjects included 57 patients (70.1 ± 10.2 years old; 46 men) with chronic heart failure whose serum ANGPTL2 levels were measured during the maintenance phase of cardiac rehabilitation program. Furthermore, we classified 25 patients (70.6 ± 7.5 years old; 23 men) from the 6-month course into a reduced group and an unchanged group to characterize change in ANGPTL2. We excluded patients who were admitted or discharged within 3 months of the evaluation of serum ANGPTL2. We evaluated exercise tolerance using the cardiopulmonary exercise test, grip strength, body composition using a body composition analyzer, blood examinations, and echocardiography. Serum ANGPTL2 was measured by solid-phase sandwich enzyme-linked immunosorbent assay (ELISA). Results The median value of ANGPTL2 was 4.05 ng/ml. ANGPTL2 was positively correlated with body weight, body mass index, body fat mass, body fat percentage, C-reactive protein (CRP) and total protein (TP) levels, and negatively correlated with skeletal muscle mass percentage and anaerobic threshold (AT). From the result of the logistic regression analysis, AT (OR=0.68, 95% CI:0.47-0.97and TP (OR=20.1, 95% CI:2.52-160.63) were extracted as independent factors related to the level of ANGPTL2. In addition, overall serum ANGPTL2 levels decreased significantly after 6 months. Changes in ANGPTL2 in the reduced group showed a positive correlation between baseline peak VO2, left ventricular ejection fraction and skeletal muscle rate, and a negative correlation with baseline ANGPTL2, CRP, body fat mass. In an unchanged group, HbA1c increased, but no significant change was observed in other factors. Conclusions Exercise tolerance in patients with chronic heart failure during maintenance phase might be related to the inflammation marker ANGPTL2. Serum ANGPTL2 levels with stable chronic heart failure patients decreased significantly 6 months after continued cardiac rehabilitation.

A 39-year-old male presented with bilateral hearing loss and progressive left eye vision loss over a 14-month period. The development of systemic symptoms including arthralgias, enlarged lymph nodes, and profound leg weakness, prompted a workup for lymphoproliferative disease, infection, and autoimmune inflammatory conditions which was unrevealing. Subsequently, the right visual acuity declined from 20/25 to 20/70 and the left to hand motions due to corneal interstitial keratitis. There was limitation of left infraduction. Neuroimaging revealed dural thickening of the internal auditory canals, cavernous sinuses, cerebellum, and along the optic nerves. There was fusiform enhancing enlargement of the left inferior and medial rectus muscles and pathologic enlargement of the left lacrimal gland. Biopsy of the left lacrimal gland and left inferior rectus revealed fibrosis and lymphocytic infiltration. The patient was diagnosed with atypical Cogan syndrome and treated with oral prednisone, with improvement in visual acuity of the right eye, motility of the left eye, and systemic weakness.

A 77-year-old man who underwent a heart transplant 7 years ago presented with multiple bloody bowel movements. Endoscopic and histologic evaluation revealed chronic active ileitis, granulomatous inflammation, multinucleated giant cells, and a rare, equivocal acid-fast bacterium in the terminal ileum. Positive sputum cultures for Mycobacterium tuberculosis and acid-fast bacilli established a diagnosis of intestinal tuberculosis, and RIPE (rifabutin, isoniazid, pyrazinamide, ethambutol) therapy was initiated. Elevated IgG levels on quantitative immunoglobulin testing and a bone marrow biopsy specimen of ≥60% plasma cells confirmed the diagnosis of multiple myeloma that later transformed into its aggressive form, plasma cell leukemia. Induction chemotherapy was initiated; however, the patient experienced retroperitoneal bleeding and pancytopenias, limiting the continuation of chemotherapy, and as a result, the patient was transitioned to palliative care.

Endocannabinoids (eCBs) are lipid-signaling molecules involved in the regulation of numerous behaviors and physiological functions. Released by postsynaptic neurons, eCBs mediate retrograde modulation of synaptic transmission and plasticity by activating presynaptic cannabinoid receptors. While the cellular mechanisms by which eCBs control synaptic function have been well characterized, the mechanisms controlling their retrograde synaptic transport remain unknown. Here, we demonstrate that fatty-acid-binding protein 5 (FABP5), a canonical intracellular carrier of eCBs, is indispensable for retrograde eCB transport in the dorsal raphe nucleus (DRn). Thus, pharmacological inhibition or genetic deletion of FABP5 abolishes both phasic and tonic eCB-mediated control of excitatory synaptic transmission in the DRn. The blockade of retrograde eCB signaling induced by FABP5 inhibition is not mediated by impaired cannabinoid receptor function or reduced eCB synthesis. These findings indicate that FABP5 is essential for retrograde eCB signaling and may serve as a synaptic carrier of eCBs at central synapses.

Immunotherapies are becoming a promising strategy for malignant disease. Selectively directing host immune responses to target cancerous tissue is a milestone of human health care. The roles of the innate and adaptive immune systems in both cancer progression and elimination are now being realized. Defining the immune cell environment and identifying the contributions of each sub-population of these cells has lead to an understanding of the immunotherapeutic processes, and demonstrated the potential of the immune system to drive cancer shrinkage and sustained immunity against disease. Poorly treated diseases, such as high-grade glioma, suffer from lack of therapeutic efficacy and rapid progression. Immunotherapeutic success in other solid malignancies, such as melanoma, now provides the principals for which this treatment paradigm can be adapted for primary brain cancers. The central nervous system is complex, and relative contributions of immune sub-populations to high grade glioma progression are not fully characterized. Here, we summarize recent research in both animal and humans which add to the knowledge base of how innate and adaptive immune cells contribute to glioma progression, and outline work which has demonstrated their potential to elicit anti-tumorigenic responses. Additionally, we highlight Neuropilin 1, a cell surface receptor protein, describe its signaling functions in the context of immunity, and point to its potential to slow glioma progression.

Glioma-associated microglia and macrophages (GAM), which infiltrate high-grade gilomas, constitute a major cellular component of these lesions. GAM behavior is influenced by tumor-derived cytokines that suppress initial antitumorigenic properties, causing them to support tumor growth and to convert and suppress adaptive immune responses to the tumor. Mice that lack the transmembrane receptor neuropilin-1 (Nrp1), which modulates GAM immune polarization, exhibit a decrease in glioma volumes and neoangiogenesis and an increase in antitumorigenic GAM infiltrate. Here we show that replacing the peripheral macrophage populations of wild-type mice with Nrp1-depleted bone marrow-derived macrophages (BMDM) confers resistance to the development of glioma. This resistance occurred in a similar fashion seen in mice in which all macrophages lacked Nrp1 expression. Tumors had decreased volumes, decreased vascularity, increased CTL infiltrate, and Nrp1-depleted BMDM adopted a more antitumorigenic phenotype relative to wild-type GAMs within the tumors. Mice with Nrp1-deficient microglia and wild-type peripheral macrophages showed resistance to glioma development and had higher microglial infiltrate than mice with wild-type GAMs. Our findings show how manipulating Nrp1 in either peripheral macrophages or microglia reprograms their phenotype and their pathogenic roles in tumor neovascularization and immunosuppression. Significance: This study highlights the proangiogenic receptor neuropilin 1 in macrophages and microglial cells in gliomas as a pivotal modifier of tumor neovascularization and immunosuppression, strengthening emerging evidence of the functional coordination of these two fundamental traits of cancer. Cancer Res; 78(3); 685–94. ©2017 AACR.

Understanding the nature of interactions between nanomaterials, such as commercially ubiquitous hematite (α-Fe2O3) nanorhombohedra (N-Rhomb) and biological systems is of critical importance for gaining insight into the practical applicability of nanomaterials. Microglia represent the first line of defense in the central nervous system (CNS) during severe injury or disease such as Parkinson's and Alzheimer's disease as illustrative examples. Hence, to analyze the potential cytotoxic effect of N-Rhomb exposure in the presence of microglia, we have synthesized Rhodamine B (RhB)-labeled α-Fe2O3 N-Rhomb, with lengths of 47 ± 10 nm and widths of 35 ± 8 nm. Internalization of RhB-labeled α-Fe2O3 N-Rhomb by microglia in the mouse brain was observed, and a dose-dependent increase in the cellular iron content as probed by cellular fluorescence was detected in cultured microglia after nanoparticle exposure. The cells maintained clear functional viability, exhibiting little to no cytotoxic effects after 24 and 48 hours at acceptable, physiological concentrations. Importantly, the nanoparticle exposure did not induce microglial cells to produce either tumor necrosis factor alpha (TNFα) or interleukin 1-beta (IL1β), two pro-inflammatory cytokines, nor did exposure stimulate the production of nitrites and reactive oxygen species (ROS), which are common indicators for the onset of inflammation. Finally, we propose that under the conditions of our experiments, i.e. in the presence of RhB labeled-α-Fe2O3 N-Rhomb maintaining concentrations of up to 100 μg mL−1 after 48 hours of incubation, the in vitro and in vivo internalization of RhB-labeled α-Fe2O3 N-Rhomb are likely to be clathrin-dependent, which represents a conventional mechanistic uptake route for most cells. Given the crucial role that microglia play in many neurological disorders, understanding the potential cytotoxic effects of these nanostructures is of fundamental importance if they are to be used in a therapeutic setting.

We report the design, synthesis, and biological evaluation of some potent small-molecule neuropilin-1 (NRP1) antagonists. NRP1 is implicated in the immune response to tumors, particularly in Treg cell fragility, required for PD1 checkpoint blockade. The design of these compounds was based on a previously identified compound EG00229. The design of these molecules was informed and supported by X-ray crystal structures. Compound 1 (EG01377) was identified as having properties suitable for further investigation. Compound 1 was then tested in several in vitro assays and was shown to have antiangiogenic, antimigratory, and antitumor effects. Remarkably, 1 was shown to be selective for NRP1 over the closely related protein NRP2. In purified Nrp1+, FoxP3+, and CD25+ populations of Tregs from mice, 1 was able to block a glioma-conditioned medium-induced increase in TGFβ production. This comprehensive characterization of a small-molecule NRP1 antagonist provides the basis for future in vivo studies.

Gliomas are primary malignancies of the brain. Tumors are staged based on malignancy, nuclear atypia, and infiltration of the surrounding brain parenchyma. Tumors are often diagnosed once patients become symptomatic, at which time the lesion is sizable. Glioblastoma (grade IV glioma) is highly aggressive and difficult to treat. Most tumors are diagnosed de novo. The gold standard of therapy, implemented over a decade ago, consists of fractionated radiotherapy and temozolomide, but unfortunately, chemotherapeutic resistance arises. Recurrence is common after initial therapy. The tumor microenvironment plays a large role in cancer progression and its manipulation can repress progression. The advent and implementation of immunotherapy, via manipulation and activation of cytotoxic T cells, have had an outstanding impact on reducing morbidity and mortality associated with peripheral cancers under certain clinical circumstances. An arsenal of immunotherapeutics is currently under clinical investigation for safety and efficacy in the treatment of newly diagnosed and recurrent high grade gliomas. These immunotherapeutics encompass antibody-drug conjugates, autologous infusions of modified chimeric antigen receptor expressing T cells, peptide vaccines, autologous dendritic cell vaccines, immunostimulatory viruses, oncolytic viruses, checkpoint blockade inhibitors, and drugs which alter the behavior of innate immune cells. Effort is focusing on determining which patient populations will benefit the most from these treatments and why. Research addressing synergism between treatment options is gaining attention. While advances in the treatment of glioma stagnated in the past, we may see a considerable evolution in the management of the disease in the upcoming years.

Comorbid post-traumatic stress disorder with traumatic brain injury (TBI) produce more severe affective and cognitive deficits than PTSD or TBI alone. Both PTSD and TBI produce long-lasting neuroinflammation, which may be a key underlying mechanism of the deficits observed in co-morbid TBI/PTSD. We developed a model of co-morbid TBI/PTSD by combining the closed head (CHI) model of TBI with the chronic variable stress (CVS) model of PTSD and examined multiple behavioral and neuroinflammatory outcomes. Male C57/Bl6 mice received sham treatment, CHI, CVS, CHI then CVS (CHI → CVS) or CVS then CHI (CVS → CHI). The CVS → CHI group had deficits in Barnes maze or active place avoidance not seen in the other groups. The CVS → CHI, CVS and CHI → CVS groups displayed increased basal anxiety level, based on performance on elevated plus maze. The CVS → CHI had impaired performance on Barnes Maze, and Active Place Avoidance. These performance deficits were strongly correlated with increased hippocampal Iba-1 level an indication of activated MP/MG. These data suggest that greater cognitive deficits in the CVS → CHI group were due to increased inflammation. The increased deficits and neuroinflammation in the CVS → CHI group suggest that the order by which a subject experiences TBI and PTSD is a major determinant of the outcome of brain injury in co-morbid TBI/PTSD.

We evaluated the efficacy and safety of superselective embolization with assistance of colonoscopy for acute colonic hemorrhage.Of 92 cases of acute colonic hemorrhage requiring colonoscopic intervention, 11 (12 %) could not be successfully treated. Of these, 10 patients (9 men, mean age 65.5 years, range 39-75 years) underwent superselective embolization. Hemorrhage was caused by diverticular disease (n = 8), polypectomy (n = 1), and vascular malformation (n = 1). In all 10 cases, the radiopaque clips were placed at the bleeding point via colonoscopy. Microcatheters were used in all procedures, and embolization was performed at the level of the vasa recta leading to or near the clips with Gelfoam particles, microcoils, or both.Immediate hemostasis was achieved in all patients. In 6 of 10 patients (60 %), selective angiograms showed no active extravasation at the time of the procedure and the embolization was performed using clips as a landmark. In the remaining four patients, selective angiograms showed active extravasation from the vasa recta leading to the clips. The mean number of embolized vessels with no active extravasation and with active extravasation was 1.83 (range 1-3) and 1.25 (range 1-2), respectively. The mean duration of clinical follow-up was 11.6 months (range 1-29 months). One patient (10 %) bled from a different site than the treated site a month after embolization, but the bleeding ceased after endoscopic intervention. All the patients (100 %) were evaluated for objective evidence of ischemia by colonoscopy. Four of the 10 patients (40 %) were found endoscopically to have small areas of ischemia involving only the mucosa, but they remained asymptomatic. There was no bowel infarction or stricture.Colonoscopy-assisted superselective embolization may be a safe and useful procedure for acute colonic hemorrhage without active extravasation on angiogram.

We find that small particles (∼1 nm) of solid argon are densely precipitated in a Pd40Ni20P20 metallic glass matrix after argon ion-beam irradiation with an accelerating voltage of 4 keV. This is in sharp contrast to the case of noble-gas implantations into crystalline metals, for which high-energy beam (50–300 keV) has been essential to promote creations of precursor defects, such as voids or vacancy aggregates for initial confinements of noble-gas atoms. Therefore, the present low-energy implantation implies that the argon confinements have occurred at pre-existing low-density regions in the glass matrix, providing an important clue to phenomenological free-volume entities.

The aim of this study was to investigate the efficacy of prone-position computed tomography (CT) for detecting and classifying inguinal hernia relative to supine-position CT before laparoscopic inguinal hernia repair. Seventy-nine patients who underwent laparoscopic transabdominal preperitoneal repair of inguinal hernia were enrolled in this prospective study. Patients diagnosed with inguinal hernia by physical examination underwent abdominal CT in the supine and prone positions for preoperative assessment. The anatomy of the right and left inguinal regions was confirmed during the surgery and compared with the preoperative CT findings. The 79 cases included 87 operated lesions and 71 non-operated contralateral inguinal sites. Of the 84 clinical hernias, inguinal hernia was detected significantly more frequently on prone-position CT images (84, 100%) than on supine-position CT images (55, 65.5%). In addition, the inguinal hernia type was determined with significantly greater accuracy on prone-position CT images (96.4%) than on supine-position CT images (58.3%). Twenty-two occult hernias were detected by laparoscopy. The detection rate and accuracy for determining the type of occult hernia were significantly greater when using prone-position CT images [19 of 22 lesions (86.4%) and 77.3%, respectively] than when using supine-position CT images [8 of 22 lesions (36.4%) and 27.3%, respectively]. Prone-position CT is adequate for detecting and classifying inguinal hernia and for evaluating occult hernia.

Understanding the nature of interactions between nanomaterials, such as commercially ubiquitous hematite (α-Fe2O3) Nanorhombohedra (N-Rhomb) and biological systems is of critical importance for gaining insight into the practical applicability of nanomaterials. Microglia represent the first line of defense in the central nervous system (CNS) during severe injury or disease such as Parkinson’s and Alzheimer’s disease as illustrative examples. Hence, to analyze the potential cytotoxic effect of nanorhombohedra exposure in the presence of microglia, we have synthesized Rhodamine B (RhB) labeled-α-Fe2O3 N-Rhomb, with lengths of 47 ± 10 nm and widths of 35 ± 8 nm. Internalization of RhB labeled-α-Fe2O3 N-Rhomb by microglia in the mouse brain was observed, and a dose-dependent increase in the cellular iron content as probed by cellular fluorescence was detected in cultured microglia after nanoparticle exposure. The cells maintained clear functional viability, exhibiting little to no cytotoxic effects after 24 and 48 hours at acceptable, physiological concentrations. Importantly, the nanoparticle exposure did not induce microglial cells to produce either tumor necrosis factor alpha (TNFα) or interleukin 1-beta (IL1β), two pro-inflammatory cytokines, nor did exposure induce the production of nitrites and reactive oxygen species (ROS), which are common indicators for the onset of inflammation. Finally, we propose that under the conditions of our experiments, i.e. in the presence of RhB labeled-α-Fe2O3 N-Rhomb maintaining concentrations of up to 100 µg/mL after 48 hours of incubation, the in vitro and in vivo internalization of RhB labeled-α-Fe2O3 N-Rhomb are likely to be clathrin-dependent, which represents a conventional mechanistic uptake route for most cells. Given the crucial role that microglia play in many neurological disorders, understanding the potential cytotoxic effects of these nanostructures is of fundamental importance if they are to be used in a therapeutic setting.

In electromagnetics education, it is important for beginners, who start to learn electromagnetics, to give an illustration of magnetic field. In this paper we propose a new real-time visualization system. It can visualize a composite image of source materials and their generated magnetic field utilizing the Augmented Reality technique to the users. With this real-time visualization system, electromagnetics learners can observe the visualized magnetic field as a realistic magnetic distribution on real-time and the visualized field changes immediately they move the objects.

The K,Cl cotransporters (KCCs) of the SLC12 superfamily play critical roles in the regulation of cell volume, concentrations of intracellular Cl−, and epithelial transport in vertebrate tissues. To date, the role(s) of KCCs in the renal functions of mosquitoes and other insects is less clear. In the present study, we sought molecular and functional evidence for the presence of a KCC in renal (Malpighian) tubules of the mosquito Aedes aegypti . Using RT-PCR on Aedes Malpighian tubules, we identified five alternatively spliced partial cDNAs that encode putative SLC12-like KCCs. The majority transcript is AeKCC1-A1; its full-length cDNA was cloned. After expression of the AeKCC1-A protein in Xenopus oocytes, the Cl−-dependent uptake of86Rb+is 1) activated by 1 mM N-ethylmaleimide and cell swelling, 2) blocked by 100 μM dihydroindenyloxyalkanoic acid (DIOA), and 3) dependent upon N-glycosylation of AeKCC1-A. In Aedes Malpighian tubules, AeKCC1 immunoreactivity localizes to the apical brush border of principal cells, which are the predominant cell type in the epithelium. In vitro physiological assays of Malpighian tubules show that peritubular DIOA (10 μM): 1) significantly reduces both the control and diuretic rates of transepithelial fluid secretion and 2) has negligible effects on the membrane voltage and input resistance of principal cells. Taken together, the above observations indicate the presence of a KCC in the apical membrane of principal cells where it participates in a major electroneutral transport pathway for the transepithelial secretion of fluid in this highly electrogenic epithelium.

In the past, we have used the kinins of the cockroach Leucophaea (the leucokinins) to evaluate the mechanism of diuretic action of kinin peptides in Malpighian tubules of the yellow fever mosquito Aedes aegypti . Now using the kinins of Aedes (the aedeskinins), we have found that in isolated Aedes Malpighian tubules all three aedeskinins (1 μM) significantly 1) increased the rate of fluid secretion (V̇S), 2) hyperpolarized the basolateral membrane voltage (Vbl), and 3) decreased the input resistance (Rin) of principal cells, consistent with the known increase in the Cl−conductance of the paracellular pathway in Aedes Malpighian tubules. Aedeskinin-III, studied in further detail, significantly increased V̇Swith an EC50of 1.5 × 10−8M. In parallel, the Na+concentration in secreted fluid significantly decreased, and the K+concentration significantly increased. The concentration of Cl−remained unchanged. While the three aedeskinins triggered effects on Vbl, Rin, and V̇S, synthetic kinin analogs, which contain modifications of the COOH-terminal amide pentapeptide core sequence critical for biological activity, displayed variable effects. For example, kinin analog 1578 significantly stimulated V̇Sbut had no effect on Vbland Rin, whereas kinin analog 1708 had no effect on V̇Sbut significantly affected Vbland Rin. These observations suggest separate signaling pathways activated by kinins. One triggers the electrophysiological response, and the other triggers fluid secretion. It remains to be determined whether the two signaling pathways emanate from a single kinin receptor via agonist-directed signaling or from a differentially glycosylated receptor. Occasionally, Malpighian tubules did not exhibit a detectable response to natural and synthetic kinins. Hypothetically, the expression of the kinin receptor may depend on developmental, nutritional, and/or reproductive signals.

A glycylprocyl aminopeptidase from cell extracts of Bacteriodes gingivalis 381 was purified 1058-fold by hydrophobic adsorbent, HPLC anion exchange, and HPLC gel filtration column chromatography. The final enzyme preparation was homogeneous with a molecular weight of 75,000 daltons by SDS-PAGE, and the isoelectric point was 6.2. The optimum pH of the enzyme was 8.0, and the enzyme activity was inhibited by DFP Ni2+ and Hg2+.

Microglia are active players in inflammation, but also have important supporting roles in CNS maintenance and function, including modulation of neuronal activity. We previously observed an increase in the frequency of excitatory postsynaptic current in organotypic brain slices after depletion of microglia using clodronate. Here, we describe that local hippocampal depletion of microglia by clodronate alters performance in tests of spatial memory and sociability. Global depletion of microglia by high-dose oral administration of a Csf1R inhibitor transiently altered spatial memory but produced no change in sociability behavior. Microglia depletion and behavior effects were both reversible, consistent with a dynamic role for microglia in the regulation of such behaviors.

Gliomas are the most commonly diagnosed primary tumors of the central nervous system (CNS). Median times of survival are dismal regardless of the treatment approach, underlying the need to develop more effective therapies. Modulation of the immune system is a promising strategy as innate and adaptive immunity play important roles in cancer progression. Glioma associated microglia and macrophages (GAMs) can comprise over 30% of the cells in glioma biopsies. Gliomas secrete cytokines that suppress the anti-tumorigenic properties of GAMs, causing them to secrete factors that support the tumor's spread and growth. Neuropilin 1 (Nrp1) is a transmembrane receptor that in mice both amplifies pro-angiogenic signaling in the tumor microenvironment and affects behavior of innate immune cells. Using a Cre-lox system, we generated mice that lack expression of Nrp1 in GAMs. We demonstrate, using an in vivo orthotopic glioma model, that tumors in mice with Nrp1-deficient GAMs exhibit less vascularity, grow at a slower pace, and are populated by increased numbers of anti-tumorigenic GAMs. Moreover, glioma survival times in mice with Nrp1-deficient GAMs were significantly longer. Treating wild-type mice with a small molecule inhibitor of Nrp1's b1 domain, EG00229, which we show here is selective for Nrp1 over Nrp2, yielded an identical outcome. Nrp1-deficient or EG00229-treated wild-type microglia exhibited a shift towards anti-tumorigenicity as evident by altered inflammatory marker profiles in vivo and decreased SMAD2/3 activation when conditioned in the presence of glioma-derived factors. These results provide support for the proposal that pharmacological inhibition of Nrp1 constitutes a potential strategy for suppressing glioma progression.

HTLV-I is the pathogen that causes adult T-cell leukemia (ATL) and HTLV-I-associated myelopathy (HAM). The rate of disease development is low and the latency time is a few decades. However, the possible influence of immunosuppression on this disease development is unclear. The purpose of this study was to investigate the risk of development of ATL and HAM among the large number of HTLV-I-positive renal transplant recipients in western Japan. In principle immunosuppressive drugs have the possibilities to accelerate ATL development but are thought to suppress HAM development. Of 120 renal transplant recipients, 10 HTLV-I-positive recipients were reviewed, none of whom developed ATL or HAM. There are 11,896 dialysis patients in Japan and 300 dialysis patients in Okinawa who are registered with the JOTN for cadaveric renal transplant. The numbers of HTLV-I-positive patients in these groups were 97 (0.82%) and 26 (8.67%), respectively. These numbers are thought to be sufficient for an HTLV-I-positive recipient pool for HTLV-I-positive donors. Ten cases of ATL development and two of HAM development have been previously reported. Because of low number of ATL development, renal transplantation does not appear to be a contraindication for HTLV-I-positive chronic renal failure patients. In other words, kidneys from HTLV-I carriers, which include cadaveric donors, could be used for HTLV-I-positive recipients.

Recently, environmental protection has become one of the most critical concerns on a global scale. Currently, it is widely recognized that lifecycle assessment (LCA) is a very effective instrument used to evaluate the environmental impact of various products quantitatively across their whole lifecycle. A basic LCA survey of Shinkansen vehicles and cross ties was conducted as a case study for the railway system. Through this study, the following results were confirmed. For any type of vehicle, more than 95 per cent of lifecycle energy consumption (LCE) and lifecycle CO2 emission LCCO2 is attributable to vehicle running. Lightweight vehicles, reduction of running resistance and the use of regenerative brakes contribute to energy saving in vehicle running. Regarding the CO2 emission from four types of ties (wood, concrete, synthetic and steel), wood ties emit the least amount of CO2 and synthetic ties the most. When the effect throughout the lifetime is considered, however, wood ties are by no means insignificant in terms of the environmental load. As a result of this survey, useful knowledge for applying LCA to railways was obtained.

High purity erbium nitride (ErN) spheres with the size range of 150-180 µm and 180-212 µm were prepared by nitriding Er metal spheres with low oxygen content. The initial regenerator material of HoCu2 on the cold end of the second regenerator column in 4K-GM cryocooler with nominal cooling power of 0.1 W at 4.2 K was replaced by ErN with different sizes. Higher cooling power was obtained when ErN of smaller size with lower oxygen content was used. We investigated the effect of partial replacement of HoCu2 by ErN in the cold end side of second stage regenerator column on cooling power of 4K-GM cryocoolers. When ErN were substituted for 20 % of HoCu2, the cooling power at 4.2 K reached 0.318 W. This value was 1.36 times as high as that of the cooling power of the GM cryocooler with commercially available regenerator arrangement. Therefore, use of ErN regenerator materials leads to the energy-saving and downsizing of 4K-GM cryocoolers.

Gliomas are the most commonly diagnosed primary tumors of the central nervous system (CNS). Median times of survival are dismal regardless of the treatment approach, underlying the need to develop more effective therapies. Modulation of the immune system is a promising strategy as innate and adaptive immunity play important roles in cancer progression. Glioma associated microglia and macrophages (GAMs) can comprise over 30% of the cells in glioma biopsies. Gliomas secrete cytokines that suppress the anti-tumorigenic properties of GAMs, causing them to secrete factors that support the tumor’s spread and growth. Neuropilin 1 (Nrp1) is a transmembrane receptor that in mice both amplifies pro-angiogenic signaling in the tumor microenvironment and affects behavior of innate immune cells. Using a Cre-lox system, we generated mice that lack expression of Nrp1 in GAMs. We demonstrate, using an in vivo orthotopic glioma model, that tumors in mice with Nrp1-deficient GAMs exhibit less vascularity, grow at a slower pace, and are populated by increased numbers of anti-tumorigenic GAMs. Moreover, glioma survival times in mice with Nrp1-deficient GAMs were significantly longer. Treating wild-type mice with a small molecule inhibitor of Nrp1’s b1 domain, EG00229, which we show here is selective for Nrp1 over Nrp2, yielded an identical outcome. Moreover, transplanting bone marrow from mice with Nrp1-deficient macrophages to wild type recipient mice led to reductions in tumor growth, al-be-it not to the extent seen in knockout mice. Nrp1-deficient or EG00229-treated wild-type microglia exhibited a shift towards anti-tumorigenicity as evident by altered inflammatory marker profiles in vivo and decreased SMAD2/3 activation when conditioned in the presence of glioma-derived factors. These results provide support for the proposal that pharmacological inhibition of Nrp1 constitutes a potential strategy for suppressing glioma progression. Citation Format: Jeremy T. Miyauchi, Danling Chen, Matthew K. Choi, Kenneth Shroyer, David Selwood, Stella E. Tsirka. Ablation of neuropilin 1 from glioma-associated microglia and macrophages slows tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4919. doi:10.1158/1538-7445.AM2017-4919

Δ(9)-Tetrahydrocannabinol (THC) and cannabidiol (CBD) occur naturally in marijuana (Cannabis) and may be formulated, individually or in combination in pharmaceuticals such as Marinol or Sativex. Although it is known that these hydrophobic compounds can be transported in blood by albumin or lipoproteins, the intracellular carrier has not been identified. Recent reports suggest that CBD and THC elevate the levels of the endocannabinoid anandamide (AEA) when administered to humans, suggesting that phytocannabinoids target cellular proteins involved in endocannabinoid clearance. Fatty acid-binding proteins (FABPs) are intracellular proteins that mediate AEA transport to its catabolic enzyme fatty acid amide hydrolase (FAAH). By computational analysis and ligand displacement assays, we show that at least three human FABPs bind THC and CBD and demonstrate that THC and CBD inhibit the cellular uptake and catabolism of AEA by targeting FABPs. Furthermore, we show that in contrast to rodent FAAH, CBD does not inhibit the enzymatic actions of human FAAH, and thus FAAH inhibition cannot account for the observed increase in circulating AEA in humans following CBD consumption. Using computational molecular docking and site-directed mutagenesis we identify key residues within the active site of FAAH that confer the species-specific sensitivity to inhibition by CBD. Competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids. These data shed light on the mechanism of action of CBD in modulating the endocannabinoid tone in vivo and may explain, in part, its reported efficacy toward epilepsy and other neurological disorders.

Basigin (Bsg) is a transmembrane glycoprotein belonging to the immunoglobulin superfamily and widely expressed in the central nervous system. To elucidate functional role of Bsg in the central nervous system, the effects of its glutathione-S-transferase (GST) fusion protein on the number and neurite outgrowth of cultured rat mesencephalic dopaminergic neurons were measured. The fusion protein was not able to promote the survival and neurite outgrowth of tyrosine hydroxylase (TH)-positive neurons under serum-free condition. However, the treatment of 1-methyl-4-phenylpyridinium (MPP+)-exposed cultures with the fusion protein resulted in stimulation of the regrowth of damaged TH-positive fibers. Basic fibroblast growth factor (bFGF) also stimulated the regrowth of neurites in damaged neurons. These results indicate that Bsg may play an important role in the regrowth of damaged dopaminergic fibers.

Despite early surgical intervention, the results of treating hepatic artery thrombosis remain poor. The use of omental flaps is well documented for its angiogenic potential in promoting neovascularization in ischemic tissues. This experimental study evaluated the formation of new blood-vessels after omental implantation (OI) in rats after ligation of the hepatic artery. Wistar rats were used and divided into the following groups: I OI with HAL, II OI without HAL, III hepatic artery ligation (HAL). For angiography, measurements were made of liver tissue blood flow by the laser Doppler method and of hepatic artery flow by the colored microsphere method (CMS), and immunohistochemical study was done for vascular endothelial growth factor (VEGF). The rats were killed at 1, 3, 7 or 30 days after laparotomy. Relative arterial hepatic blood flow in the implanted lobe of group I, as determined by CMS, reached 50% of control values 7 days after surgery. Angiography and microscopic studies of the excised liver revealed distinct angiogenesis surrounding the omental implant in the liver for 7 days postoperatively. The formation of new blood-vessels after OI was not observed in livers without HAL. Omental implantation appears to be useful in preventing organ anoxia after hepatic artery thrombosis.

High-field magnetization measurements of CeCu 2 X 2 ( X = Si and Ge) and YbCu 2 Si 2 were carried out up to 50 T. The magnetization of CeCu 2 Ge 2 at 1.3 K increases linearly, with a small metamagnetic transition at 7.8 and 10.5 T for H//[1 1 0] and [1 0 0], respectively, and saturates at 27 T for H//[1 0 0] and [1 1 0], while the magnetization also saturates at 15.5 T for H//[0 0 1], without the metamagnetic transition. The high-field magnetization of YbCu 2 Si 2 at 1.3 K shows no metamagnetic transition.

Various side effects have been associated with the clinical use of contrast media. Immunological mechanisms have been proposed but there have been very few experimental studies with animal models. We have attempted to develop murine models to determine whether or not anaphylactic antibodies such as IgE and IgG1 against hapten (DNP) were enhanced with contrast medium (iopamidol) as an adjuvant or if the contrast medium itself produced antibodies of the IgE class. The results showed that anti-hapten IgE and IgG1 production was greatly enhanced with immunogen plus contrast medium. Anti-contrast medium antibodies of the IgE class could not be detected by PCA reactions. The enhancement of IgE and IgG1 production for hapten was associated with IL-4 release by the neutralization test used by monoclonal anti-IL-4 antibodies. This is the first observation to show that contrast media may have a strong adjuvant effect for the production of IgE and IgG1. This murine model demonstrates a possible immunological function of contrast media in vivo.

Synaptic plasticity is critical for elaboration and adaptation in the developing and developed brain. It is well established that astrocytes play an important role in the maintenance of what has been dubbed “the tripartite synapse”. Increasing evidence shows that a fourth cell type, microglia, is critical to this maintenance as well. Microglia are the resident macrophages of the central nervous system (CNS). Because of their well-characterized inflammatory functions, research has primarily focused on their innate immune properties. The role of microglia in the maintenance of synapses in development and in homeostasis is not as well defined. A number of significant findings have shed light on the critical role of microglia at the synapse. It is becoming increasingly clear that microglia play a seminal role in proper synaptic development and elimination.

Gliomas are the most commonly diagnosed primary tumors of the central nervous system (CNS). Median times of survival are dismal regardless of the treatment approach, underlying the need to develop more effective therapies. Modulation of the immune system is a promising strategy as innate and adaptive immunity play important roles in cancer progression. Glioma associated microglia and macrophages (GAMs) can comprise over 30% of the cells in glioma biopsies. Gliomas secrete cytokines that suppress the anti-tumorigenic properties of GAMs, causing them to secrete factors that support the tumor's spread and growth. Neuropilin 1 (Nrp1) is a transmembrane receptor that in mice both amplifies pro-angiogenic signaling in the tumor microenvironment and affects behavior of innate immune cells. Using a Cre-lox system, we generated mice that lack expression of Nrp1 in GAMs. We demonstrate, using an in vivo orthotopic glioma model, that tumors in mice with Nrp1-deficient GAMs exhibit less vascularity, grow at a slower pace, and are populated by increased numbers of anti-tumorigenic GAMs. Moreover, glioma survival times in mice with Nrp1-deficient GAMs were significantly longer. Treating wild-type mice with a small molecule inhibitor of Nrp1's b1 domain, EG00229, which we show here is selective for Nrp1 over Nrp2, yielded an identical outcome. Moreover, transplanting bone marrow from mice with Nrp1-deficient macrophages to wild type recipient mice led to reductions in tumor growth, al-be-it not to the extent seen in knockout mice. Nrp1-deficient or EG00229-treated wild-type microglia exhibited a shift towards anti-tumorigenicity as evident by altered inflammatory marker profiles in vivo and decreased SMAD2/3 activation when conditioned in the presence of glioma-derived factors. These results provide support for the proposal that pharmacological inhibition of Nrp1 constitutes a potential strategy for suppressing glioma progression. Citation Format: Jeremy T. Miyauchi, Danling Chen, Matthew Choi, Jillian Nissen, Kenneth Shroyer, David Selwood, Stella E. Tsirka. Ablation of neuropilin 1 from glioma associated macrophages and microglia slows tumor progression [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A129.

A serial urodynamic study was performed in 491 patients with uterine cancer following radical hysterectomy (RH) involving postoperative pelvic radiation (RH+RT) and extended hysterectomy (EH) for 10 years after these respective treatments. The following evidence is presented: (1) increased volume of residual urine and sensory impairment occurred 1–2 months after radical hysterectomy with or without radiation, but was rarely seen in the EH group: (2) increased residual urine volume in the RH group gradually subsided 1–3 years after the treatment, while the RH+RT treatment resulted in a slight reduction: (3) late maximum cytometric capacity in the EH and RH groups remained stable throughout the study, but the RH+RT group showed a lower capacity (P

Although endothelin-1 (ET-1) has been shown to have potent hypertrophic effects in cultured cardiac myocytes, there is no evidence that the production of ET-1 is altered in the hypertrophied heart in vivo. We investigated mRNA and peptide levels of ET-1 in the rat heart hypertrophied due to pressure or volume overload. One week after surgery of abdominal aortic banding (AB) or aortic valve regurgitation (AR; the aortic valve was destroyed by a polyethylene catheter), the rats were sacrificed. Control sham-operated rats were also studied (AB-sham and AR-sham). The left ventricular (LV) weight to body weight ratio was significantly higher in AB rats than in AB-sham rats. It was also significantly higher in AR rats than in AR-sham rats. Therefore, AB rats and AR rats developed LV hypertrophy due to pressure and volume overload, respectively. The expression of ET-1 mRNA in the LV was markedly higher in AB rats than in AB-sham rats. The peptide level of ET-1 was also significantly higher in the LV of AB rats than in that of AB-sham rats. However, the expression of ET-1 mRNA in the LV of AR rats was similar to that of AR-sham rats. The present findings suggest that the production of ET-1 in the heart differs between pressure and volume overload-induced hypertrophy in rats.

To study the role of endothelin receptor subtypes in rabbit retinal arteries, endothelin-1 (ET-1)-induced vasoconstriction was analyzed using the ETA receptor antagonist BQ-123 and the ETB receptor agonist BQ-3020. A cumulative injection of ET-1 (1 approximately 100 pmole) into the posterior vitreous body in anesthetized rabbits caused dose-dependent vasoconstriction in the retinal arteries, and ultimately caused complete obstruction. Fifteen minutes after BQ-123 (1 mumole) was injected into the posterior vitreous body, the dose-response curve of ET-1 was significantly shifted to the right. Intravitreal injection of BQ-3020 caused a significant retinal vasoconstriction only at the highest dose (1000 pmole). Therefore, in rabbit retinal arteries, ET-1-induced vasoconstriction appears to be mediated mainly through ETA receptors.