An Immune-Modulating Diet in Combination with Chemotherapy Prevents Cancer Cachexia by Attenuating Systemic Inflammation in Colon 26 Tumor-Bearing Mice.

PubMed

Nakamura, Kentaro; Sasayama, Akina; Takahashi, Takeshi; Yamaji, Taketo

2015-01-01

Cancer cachexia is characterized by muscle wasting caused partly by systemic inflammation. We previously demonstrated an immune-modulating diet (IMD), an enteral diet enriched with immunonutrition and whey-hydrolyzed peptides, to have antiinflammatory effects in some experimental models. Here, we investigated whether the IMD in combination with chemotherapy could prevent cancer cachexia in colon 26 tumor-bearing mice. Forty tumor-bearing mice were randomized into 5 groups: tumor-bearing control (TB), low dose 5-fluorouracil (5-FU) and standard diet (LF/ST), low dose 5-FU and IMD (LF/IMD), high dose 5-FU and standard diet (HF/ST) and high dose 5-FU and IMD (HF/IMD). The ST and IMD mice received a standard diet or the IMD ad libitum for 21 days. Muscle mass in the IMD mice was significantly higher than that in the ST mice. The LF/IMD in addition to the HF/ST and HF/IMD mice preserved their body and carcass weights. Plasma prostaglandin E2 levels were significantly lower in the IMD mice than in the ST mice. A combined effect was also observed in plasma interleukin-6, glucose, and vascular endothelial growth factor levels. Tumor weight was not affected by different diets. In conclusion, the IMD in combination with chemotherapy prevented cancer cachexia without suppressing chemotherapeutic efficacy.

Superconducting MgB2 wires with vanadium diffusion barrier

NASA Astrophysics Data System (ADS)

Hušek, I.; Kováč, P.; Melišek, T.; Kulich, M.; Rosová, A.; Kopera, L.; Szundiová, B.

2017-10-01

Single-core MgB2 wires with a vanadium barrier and Cu stabilization have been made by the in situ powder-in-tube (PIT) and internal magnesium diffusion (IMD) into boron processes. Heat treatment of PIT wires was done at the temperature range of 650 °C-850 °C/30 min. Critical currents of differently treated MgB2/V/Cu wires have been measured and related with the structure of MgB2. It was found that critical current density of MgB2/V wire annealed above 700 °C decreases rapidly. The obtained results clearly show that vanadium is a well formable metal and can be applied as an effective diffusion barrier for MgB2 wires heat-treated at temperatures ≤700 °C. This temperature limit is well applicable for MgB2 wires with high current densities made by PIT and also by the IMD process.

Effects of intermedin on dorsal root ganglia in the transmission of neuropathic pain in chronic constriction injury rats.

PubMed

Xiong, Wei; Qiu, Shu-yi; Xu, Ling-yun; Zhang, Chun-ping; Yi, Yun; Wu, Qin; Huang, Li-ping; Liu, Shuang-mei; Wu, Bing; Peng, Li-chao; Song, Miao-miao; Gao, Yun; Liang, Shang-dong

2015-07-01

Neuropathic pain is a common and severely disabling state that affects millions of people worldwide. The P2X3 receptor plays a crucial role in facilitating pain transmission. Intermedin (IMD), which is also known as adrenomedullin 2 (AMD2) is a newly discovered hormone that is a member of the calcitonin/calcitonin gene-related peptide family. The present research investigates the effects of IMD on pain transmission in neuropathic pain states as mediated by P2X3 receptors in dorsal root ganglia (DRG). Chronic constriction injury (CCI) rats were used as the neuropathic pain model. Adult male Sprague-Dawley rats were randomly assigned to five groups as follows: blank control group (Control), sham operation group (Sham), CCI rats treated with saline group (CCI+NS), CCI rats treated with IMD1-53 group (CCI+IMD1-53 ), and CCI rats treated with IMD inhibitor IMD14-47 group (CCI+IMD14-47 ). The mechanical withdrawal threshold (MWT) was tested by the von Frey method, and the thermal withdrawal latency (TWL) was tested via automatic thermal stimulus instruments. Changes in the expression of P2X3 receptors and IMD in CCI rat L4/L5 DRG were detected using immunohistochemistry, reverse transcription-polymerase chain reaction, and Western blotting. After treatment with intrathecal injection (i.t.), mechanical and thermal hyperalgesia in the CCI+IMD1-53 group was maintained, but MWT and TWL in the CCI+IMD14-47 groups increased. The expression levels of P2X3 receptors and IMD in L4/L5 DRG in the CCI+NS and CCI+IMD1-53 groups were significantly increased compared with those in the Control group or the Sham group. After application of IMD14-47 in CCI rats, there was a decrease in the expression levels of P2X3 receptors and IMD in L4/L5 DRG. The phosphorylation of p38 and ERK1/2 in L4/L5 DRG in the CCI+NS group and the CCI+IMD1-53 group was stronger than that in the Control group or the Sham group; however, the phosphorylation of p38 and ERK1/2 in the CCI+IMD14-47 group was much lower than that in the CCI+NS group or the CCI+IMD1-53 group. Our findings indicate that IMD might increase the sensitization effects of IMD on P2X3 receptors to alleviate chronic neuropathic pain injury. The IMD agonist IMD1-53 might enhance nociceptive responses mediated by P2X3 receptors in neuropathic pain, and the IMD inhibitor IMD14-47 could inhibit the sensitization of the P2X3 receptor in chronic neuropathic pain injury. © 2015 Wiley Publishing Asia Pty Ltd.

[The expression of IDH1 (R132H) is positively correlated with cell proliferation and angiogenesis in glioma samples].

PubMed

Shi, Jiankuan; Zhao, Yuanlin; Yuan, Yuan; Wang, Chao; Xie, Zhonglin; Gao, Xing; Xiao, Liming; Ye, Jing

2016-03-01

To explore the correlations of the expression of mutant isocitrate dehydrogenase (IDH1) (R132H) protein with angiogenesis and cell proliferation in glioma. We performed polymerase chain reaction-based IDH gene mutation screening in 385 glioma samples, and the subcellular localization and expression levels of IDH1 (R132H) was examined by immunohistochemistry (IHC). Ki-67 labeling index was introduced to determine the proliferation of glioma cells, and the microvessel density was measured through CD34 staining. Statistical analyses were performed to show the correlations of IDH1 mutation with cell proliferation and microvessel density. The mutant rates of IDH1 were about 50%-60% in grade II-III gliomas and secondary glioblastomas, which were significantly higher than those in pilocytic astrocytoma (grade I) and primary glioblastoma (grade IV). Moreover, the level of IDH1 (R132H) protein was positively correlated with Ki-67 labeling index and microvessel density. IDH mutation was common in grade II-III glioma and secondary glioblastoma, and the mutant IDH1 (R132H) might play a critical role in the cell proliferation and angiogenesis of glioma.

Intermedin Stabilized Endothelial Barrier Function and Attenuated Ventilator-induced Lung Injury in Mice

PubMed Central

Müller-Redetzky, Holger Christian; Kummer, Wolfgang; Pfeil, Uwe; Hellwig, Katharina; Will, Daniel; Paddenberg, Renate; Tabeling, Christoph; Hippenstiel, Stefan; Suttorp, Norbert; Witzenrath, Martin

2012-01-01

Background Even protective ventilation may aggravate or induce lung failure, particularly in preinjured lungs. Thus, new adjuvant pharmacologic strategies are needed to minimize ventilator-induced lung injury (VILI). Intermedin/Adrenomedullin-2 (IMD) stabilized pulmonary endothelial barrier function in vitro. We hypothesized that IMD may attenuate VILI-associated lung permeability in vivo. Methodology/Principal Findings Human pulmonary microvascular endothelial cell (HPMVEC) monolayers were incubated with IMD, and transcellular electrical resistance was measured to quantify endothelial barrier function. Expression and localization of endogenous pulmonary IMD, and its receptor complexes composed of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs) 1–3 were analyzed by qRT-PCR and immunofluorescence in non ventilated mouse lungs and in lungs ventilated for 6 h. In untreated and IMD treated mice, lung permeability, pulmonary leukocyte recruitment and cytokine levels were assessed after mechanical ventilation. Further, the impact of IMD on pulmonary vasoconstriction was investigated in precision cut lung slices (PCLS) and in isolated perfused and ventilated mouse lungs. IMD stabilized endothelial barrier function in HPMVECs. Mechanical ventilation reduced the expression of RAMP3, but not of IMD, CRLR, and RAMP1 and 2. Mechanical ventilation induced lung hyperpermeability, which was ameliorated by IMD treatment. Oxygenation was not improved by IMD, which may be attributed to impaired hypoxic vasoconstriction due to IMD treatment. IMD had minor impact on pulmonary leukocyte recruitment and did not reduce cytokine levels in VILI. Conclusions/Significance IMD may possibly provide a new approach to attenuate VILI. PMID:22563471

Variability in sublingual microvessel density and flow measurements in healthy volunteers.

PubMed

Hubble, Sheena M A; Kyte, Hayley L; Gooding, Kim; Shore, Angela C

2009-02-01

As sublingual microvascular indices are increasingly heralded as new resuscitation end-points, better population data are required to power clinical studies. This paper describes improved methods to quantify sublingual microvessel flow and density in images obtained by sidestream dark field (SDF) technology in healthy volunteers, including vessels under 10 microm in diameter. Measurements of sublingual capillary density and flow were obtained by recording three 15-second images in 20 healthy volunteers over three days. Two independent observers quantified capillary density by using two methods: total vessel length (mm/mm2) and counting (number/mm). Both intraoral and temporal variabilities within subject and observer reproducibilities were determined by using coefficients of variability and reproducibility indices. For small (1-10 microm), medium (11-20 microm), and large (21-50 microm) diameter, mean vessel density with standard deviations (SDs) in volunteers was 21.3(+/- 4.9), 5.2 (+/- 1.2), and 2.7 (+/- 0.9) mm/mm2, respectively. Also, 94.0 +/- 1.4% of small vessels, 94.5 +/- 1.4% of medium vessels, and 94.5+/- 4.0% of large vessels had continuous perfusion. Within subjects, the means of all measurements over three days varied less than 13, 22, and 35% in small, medium, and large vessels, respectively. Interobserver reproducibility was good, especially for capillary (1-10 microm) density and flow measurements. Our methods of microvessel flow and density quantification have low observer variability and confirm the stability of microcirculatory measurements over time. These results facilitate the development of SDF-acquired sublingual microvascular indices as feasible microperfusion markers in shock resuscitation.

Defining the Phosphodiesterase Superfamily Members in Rat Brain Microvessels

PubMed Central

2011-01-01

Eleven phosphodiesterase (PDE) families are known, each having several different isoforms and splice variants. Recent evidence indicates that expression of individual PDE family members is tissue-specific. Little is known concerning detailed PDE component expression in brain microvessels where the blood-brain-barrier and the local cerebral blood flow are thought to be regulated by PDEs. The present study attempted to identify PDE family members that are expressed in brain microvessels. Adult male F344 rats were sacrificed and blocks of the cerebral cortex and infratentorial areas were dissected. Microvessels were isolated using a filtration method, and total RNA was extracted. RNA quality and quantity were determined using an Agilent bioanalyzer. The isolated cortical and infratentorial microvessel total RNA amounts were 2720 ± 750 ng (n = 2) and 250 ± 40 ng (n = 2), respectively. Microarrays with 22 000 transcripts demonstrated that there were 16 PDE transcripts in the PDE superfamily, exhibiting quantifiable density in the microvessels. An additional immunofluorescent study verified that PDE4D (cAMP-specific) and PDE5A (cGMP-specific) were colocalized with RECA-1 (an endothelial marker) in the cerebral cortex using both F344 rats and Sprague–Dawley rats (n = 3–6/strain). In addition, PDE4D and PDE5A were found to be colocalized with alpha-smooth muscle actin which delineates cerebral arteries and arterioles as well as pericytes. In conclusion, a filtration method followed by microarray analyses allows PDE components to be identified in brain microvessels, and confirmed that PDE4D and PDE5A are the primary forms expressed in rat brain microvessels. PMID:22860158

Prognostic significance of microvessel density and mast cell density for the survival of Thai patients with primary colorectal cancer.

PubMed

Yodavudh, Sirisanpang; Tangjitgamol, Siriwan; Puangsa-art, Supalarp

2008-05-01

Angiogenesis has been found to be a reliable prognostic indicator for several types of malignancies. In colorectal cancer, however there has been controversy as to whether there is a correlation between this feature and the tumors' behavior. Determine the correlation between microvessel density (MVD) and mast cell density (MCD) in order to evaluate these factors in terms of their prognostic relevance for primary colorectal carcinoma in Thai patients. One hundred and thirty colorectal carcinoma patients diagnosed between January 2002 and December 2004 were identified. Eleven patients were excluded from the present study due to recurrence of colorectal carcinoma in eight cases whereas pathologic blocks were not found in three cases. One hundred and nineteen patients met all inclusion criteria and were included in the present study. Representative paraffin sections obtained by the tissue micro-array technique (9 x 5 arrays per slide) from areas of highest vascular density (hot spots) were prepared. Sections were immuno-stained by monoclonal anti CD 31 for microvessel and antibody mast cell tryptase for mast cell detections, respectively. Three readings at different periods of time under a microscopic examination of high power magnification were examined by a pathologist who was blinded to clinical data. The highest microvessel and mast cell counts were recorded as MVD and MCD. Patients were then divided into groups of high and low MVD and high and low MCD by median values (20.5 and 14.5, respectively). Overall survival of the patients in each group was estimated by the Kaplan-Meier Method while a multivariate Cox regression backward stepwise analysis was employed to find out independent prognostic factors. Significant positive correlation was found to exist between MVD and MCD in the hot spots (R = 0.697, p < 0.0001). Regarding their prognostic role, patients with tumors of low MVD (hypovascular) and low MCD (low mast cell counts) had significantly longer survival rates than those with hypervascular and high mast cell counts (p < 0.0001). The Multivariate Cox hazard showed that MVD and distance metastasis of cancer were independent poor prognostic factors to survival (p = 0.036 and p = 0.024, respectively). The patients with high MVD (hypervascular) tumors and with presence of distant metastasis had 1.9 and 2.5 times higher death rates than the corresponding hypovascular and non-metastatic groups, respectively during the period from January 2002 to September 2007. Assessment of microvessel density in the invasive front of primary colorectal carcinoma could serve as useful prognosis tool of primary colorectal carcinoma in Thai patients.

Security mechanism based on Hospital Authentication Server for secure application of implantable medical devices.

PubMed

Park, Chang-Seop

2014-01-01

After two recent security attacks against implantable medical devices (IMDs) have been reported, the privacy and security risks of IMDs have been widely recognized in the medical device market and research community, since the malfunctioning of IMDs might endanger the patient's life. During the last few years, a lot of researches have been carried out to address the security-related issues of IMDs, including privacy, safety, and accessibility issues. A physician accesses IMD through an external device called a programmer, for diagnosis and treatment. Hence, cryptographic key management between IMD and programmer is important to enforce a strict access control. In this paper, a new security architecture for the security of IMDs is proposed, based on a 3-Tier security model, where the programmer interacts with a Hospital Authentication Server, to get permissions to access IMDs. The proposed security architecture greatly simplifies the key management between IMDs and programmers. Also proposed is a security mechanism to guarantee the authenticity of the patient data collected from IMD and the nonrepudiation of the physician's treatment based on it. The proposed architecture and mechanism are analyzed and compared with several previous works, in terms of security and performance.

Security Mechanism Based on Hospital Authentication Server for Secure Application of Implantable Medical Devices

PubMed Central

2014-01-01

After two recent security attacks against implantable medical devices (IMDs) have been reported, the privacy and security risks of IMDs have been widely recognized in the medical device market and research community, since the malfunctioning of IMDs might endanger the patient's life. During the last few years, a lot of researches have been carried out to address the security-related issues of IMDs, including privacy, safety, and accessibility issues. A physician accesses IMD through an external device called a programmer, for diagnosis and treatment. Hence, cryptographic key management between IMD and programmer is important to enforce a strict access control. In this paper, a new security architecture for the security of IMDs is proposed, based on a 3-Tier security model, where the programmer interacts with a Hospital Authentication Server, to get permissions to access IMDs. The proposed security architecture greatly simplifies the key management between IMDs and programmers. Also proposed is a security mechanism to guarantee the authenticity of the patient data collected from IMD and the nonrepudiation of the physician's treatment based on it. The proposed architecture and mechanism are analyzed and compared with several previous works, in terms of security and performance. PMID:25276797

Visible light optical spectroscopy is sensitive to neovascularization in the dysplastic cervix

NASA Astrophysics Data System (ADS)

Chang, Vivide Tuan-Chyan; Bean, Sarah M.; Cartwright, Peter S.; Ramanujam, Nirmala

2010-09-01

Neovascularization in cervical intraepithelial neoplasia (CIN) is studied because it is the precursor to the third most common female cancer worldwide. Diffuse reflectance from 450-600 nm was collected from 46 patients (76 sites) undergoing colposcopy at Duke University Medical Center. Total hemoglobin, derived using an inverse Monte Carlo model, significantly increased in CIN 2+ (N=12) versus CIN 1 (N=16) and normal tissues (N=48) combined with P<0.004. Immunohistochemistry using monoclonal anti-CD34 was used to quantify microvessel density to validate the increased hemoglobin content. Biopsies from 51 sites were stained, and up to three hot spots per slide were selected for microvessel quantification by two observers. Similar to the optical study results, microvessel density was significantly increased in CIN 2+ (N=16) versus CIN 1 (N=21) and normal tissue (N=14) combined with P<0.007. Total vessel density, however, was not significantly associated with dysplastic grade. Hence, our quantitative optical spectroscopy system is primarily sensitive to dysplastic neovascularization immediately beneath the basement membrane, with minimal confounding from vascularity inherent in the normal stromal environment. This tool could have potential for in vivo applications in screening for cervical cancer, prognostics, and monitoring of antiangiogenic effects in chemoprevention therapies.

Expression of adrenomedullin 2/intermedin in human adrenal tumors and attached non-neoplastic adrenal tissues.

PubMed

Morimoto, Ryo; Satoh, Fumitoshi; Murakami, Osamu; Hirose, Takuo; Totsune, Kazuhito; Imai, Yutaka; Arai, Yoichi; Suzuki, Takashi; Sasano, Hironobu; Ito, Sadayoshi; Takahashi, Kazuhiro

2008-07-01

Adrenomedullin 2/intermedin (AM2/IMD) is a new member of calcitonin/calcitonin gene-related peptide family. AM is expressed in various tumors including adrenocortical tumors and modulates tumor growth. The AM2/IMD expression has not been studied, however, in adrenal tumors. The expression of AM2/IMD and AM was therefore studied in human adrenal tumors and attached non-neoplastic adrenal tissues by immunocytochemistry (ICC). Immunoreactive (IR)-AM2/IMD was measured by RIA. Furthermore, the expression of AM2/IMD and its receptor components, calcitonin receptor-like receptor (CRLR), and receptor activity-modifying proteins (RAMPs) 1, 2, and 3 mRNA in these tissues was studied by reverse transcription PCR (RT-PCR). ICC showed that AM2/IMD and AM immunoreactivities were localized in adrenocortical tumors and pheochromocytomas. AM2/IMD and AM immunoreactivities were detected in medulla of attached non-neoplastic tissues, while the degree of immunoreactivity for AM2/IMD and AM in cortices of attached adrenals was relatively weak or undetectable. RIA detected IR-AM2/IMD in adrenal tumors (0.414+/-0.12 to 0.786+/-0.27 pmol/g wet weight, mean+/-S.E.M.) and attached adrenal tissues (0.397+/-0.052 pmol/g wet weight). Reverse-phase high-performance liquid chromatography showed one broad peak eluted in the similar position to synthetic AM2/IMD with several minor peaks. RT-PCR showed expression of AM2/IMD, CRLR, and RAMP1, RAMP2, and RAMP3 mRNA in tissues of adrenal tumors and attached adrenal glands. In conclusion, AM2/IMD is expressed in human adrenal tumors and attached non-neoplastic adrenal tissues and may play (patho-)physiological roles in normal and neoplastic adrenals as an autocrine/paracrine regulator.

Trustworthy data collection from implantable medical devices via high-speed security implementation based on IEEE 1363.

PubMed

Hu, Fei; Hao, Qi; Lukowiak, Marcin; Sun, Qingquan; Wilhelm, Kyle; Radziszowski, Stanisław; Wu, Yao

2010-11-01

Implantable medical devices (IMDs) have played an important role in many medical fields. Any failure in IMDs operations could cause serious consequences and it is important to protect the IMDs access from unauthenticated access. This study investigates secure IMD data collection within a telehealthcare [mobile health (m-health)] network. We use medical sensors carried by patients to securely access IMD data and perform secure sensor-to-sensor communications between patients to relay the IMD data to a remote doctor's server. To meet the requirements on low computational complexity, we choose N-th degree truncated polynomial ring (NTRU)-based encryption/decryption to secure IMD-sensor and sensor-sensor communications. An extended matryoshkas model is developed to estimate direct/indirect trust relationship among sensors. An NTRU hardware implementation in very large integrated circuit hardware description language is studied based on industry Standard IEEE 1363 to increase the speed of key generation. The performance analysis results demonstrate the security robustness of the proposed IMD data access trust model.

Retinal Microvascular Network and Microcirculation Assessments in High Myopia.

PubMed

Li, Min; Yang, Ye; Jiang, Hong; Gregori, Giovanni; Roisman, Luiz; Zheng, Fang; Ke, Bilian; Qu, Dongyi; Wang, Jianhua

2017-02-01

To investigate the changes of the retinal microvascular network and microcirculation in high myopia. A cross-sectional, matched, comparative clinical study. Twenty eyes of 20 subjects with nonpathological high myopia (28 ± 5 years of age) with a refractive error of -6.31 ± 1.23 D (mean ± SD) and 20 eyes of 20 age- and sex-matched control subjects (30 ± 6 years of age) with a refractive error of -1.40 ± 1.00 D were recruited. Optical coherence tomography angiography (OCTA) was used to image the retinal microvascular network, which was later quantified by fractal analysis (box counting [D box ], representing vessel density) in both superficial and deep vascular plexuses. The Retinal Function Imager was used to image the retinal microvessel blood flow velocity (BFV). The BFV and microvascular density in the myopia group were corrected for ocular magnification using Bennett's formula. The density of both superficial and deep microvascular plexuses was significantly decreased in the myopia group in comparison to the controls (P < .05). The decrease of the microvessel density of the annular zone (0.6-2.5 mm), measured as D box , was 2.1% and 2.9% in the superficial and deep vascular plexuses, respectively. Microvessel density reached a plateau from 0.5 mm to 1.25 mm from the fovea in both groups, but that in the myopic group was about 3% lower than the control group. No significant differences were detected between the groups in retinal microvascular BFV in either arterioles or venules (P > .05). Microvascular densities in both superficial (r = -0.45, P = .047) and deep (r = -0.54, P = .01) vascular plexuses were negatively correlated with the axial lengths in the myopic eye. No correlations were observed between BFV and vessel density (P > .05). Retinal microvascular decrease was observed in the high myopia subjects, whereas the retinal microvessel BFV remained unchanged. The retinal microvascular network alteration may be attributed to ocular elongation that occurs with the progression of myopia. The novel quantitative analyses of the retinal microvasculature may help to characterize the underlying pathophysiology of myopia and enable early detection and prevention of myopic retinopathy. Copyright © 2016 Elsevier Inc. All rights reserved.

National Centers for Environmental Prediction

Science.gov Websites

: Monsoon progress image (Link) IITM : 2017 Monsoon (Link) SW Monsoon, 2016 IMD : Daily rainfall report (30th September, 2016) (Link) IMD : End of season Monsoon Report (2016) (Link) SW Monsoon, 2015 IMD : Daily rainfall report (30th September, 2015) (Link) IMD : End of season Monsoon Report (2015) (Link

Understanding heterogeneity in metropolitan India: The added value of remote sensing data for analyzing sub-standard residential areas

NASA Astrophysics Data System (ADS)

Baud, Isa; Kuffer, Monika; Pfeffer, Karin; Sliuzas, Richard; Karuppannan, Sadasivam

2010-10-01

Analyzing the heterogeneity in metropolitan areas of India utilizing remote sensing data can help to identify more precise patterns of sub-standard residential areas. Earlier work analyzing inequalities in Indian cities employed a constructed index of multiple deprivations (IMDs) utilizing data from the Census of India 2001 ( http://censusindia.gov.in). While that index, described in an earlier paper, provided a first approach to identify heterogeneity at the citywide scale, it neither provided information on spatial variations within the geographical boundaries of the Census database, nor about physical characteristics, such as green spaces and the variation in housing density and quality. In this article, we analyze whether different types of sub-standard residential areas can be identified through remote sensing data, combined, where relevant, with ground-truthing and local knowledge. The specific questions address: (1) the extent to which types of residential sub-standard areas can be drawn from remote sensing data, based on patterns of green space, structure of layout, density of built-up areas, size of buildings and other site characteristics; (2) the spatial diversity of these residential types for selected electoral wards; and (3) the correlation between different types of sub-standard residential areas and the results of the index of multiple deprivations utilized at electoral ward level found previously. The results of a limited number of test wards in Delhi showed that it was possible to extract different residential types matching existing settlement categories using the physical indicators structure of layout, built-up density, building size and other site characteristics. However, the indicator 'amount of green spaces' was not useful to identify informal areas. The analysis of heterogeneity showed that wards with higher IMD scores displayed more or less the full range of residential types, implying that visual image interpretation is able to zoom in on clusters of deprivation of varying size. Finally, the visual interpretation of the diversity of residential types matched the results of the IMD analysis quite well, although the limited number of test wards would need to be expanded to strengthen this statement. Visual image analysis strengthens the robustness of the IMD, and in addition, gives a better idea of the degree of heterogeneity in deprivations within a ward.

Endoglin (CD105) expression on microvessel endothelial cells in juvenile nasopharyngeal angiofibroma: tissue microarray analysis and association with prognostic significance.

PubMed

Wang, Jing-Jing; Sun, Xi-Cai; Hu, Li; Liu, Zhuo-Fu; Yu, Hua-Peng; Li, Han; Wang, Shu-Yi; Wang, De-Hui

2013-12-01

The purpose of this study was to examine endoglin (CD105) expression on microvessel endothelial cells (ECs) in juvenile nasopharyngeal angiofibroma (JNA) and its relationship with recurrence. Immunohistochemistry was performed to detect CD105 expression in a tissue microarray from 70 patients with JNA. Correlation between CD105 expression on microvessel ECs and clinicopathological features, as well as tumor recurrence, were analyzed. Immunohistochemistry revealed CD105 expression on ECs but not in stroma of patients with JNA. Chi-square analysis indicated CD105-based microvessel density (MVD) was correlated with JNA recurrence (p = .013). Univariate and multivariate analyses determined that MVD was a significant predictor of time to recurrence (p = .009). The CD105-based MVD was better for predicting disease recurrence (AUROC: 0.673; p = .036) than other clinicopathological features. MVD is a useful predictor for poor prognosis of patients with JNA after curative resection. Angiogenesis, which may play an important role in the occurrence and development of JNA, is therefore a potential therapeutic target for JNA. Copyright © 2013 Wiley Periodicals, Inc., A Wiley Company.

Characterization of a microfluidic microbial fuel cell as a power generator based on a nickel electrode.

PubMed

Mardanpour, Mohammad Mahdi; Yaghmaei, Soheila

2016-05-15

This study reports the fabrication of a microfluidic microbial fuel cell (MFC) using nickel as a novel alternative for conventional electrodes and a non-phatogenic strain of Escherichia coli as the biocatalyst. The feasibility of a microfluidic MFC as an efficient power generator for production of bioelectricity from glucose and urea as organic substrates in human blood and urine for implantable medical devices (IMDs) was investigated. A maximum open circuit potential of 459 mV was achieved for the batch-fed microfluidic MFC. During continuous mode operation, a maximum power density of 104 Wm(-3) was obtained with nutrient broth. For the glucose-fed microfluidic MFC, the maximum power density of 5.2 μW cm(-2) obtained in this study is significantly greater than the power densities reported previously for microsized MFCs and glucose fuel cells. The maximum power density of 14 Wm(-3) obtained using urea indicates the successful performance of a microfluidic MFC using human excreta. It features high power density, self-regeneration, waste management and a low production cost (<$1), which suggest it as a promising alternative to conventional power supplies for IMDs. The performance of the microfluidic MFC as a power supply was characterized based on polarization behavior and cell potential in different substrates, operational modes, and concentrations. Copyright © 2015 Elsevier B.V. All rights reserved.

AM1-receptor-dependent protection by intermedin of human vascular and cardiac non-vascular cells from ischaemia–reperfusion injury

PubMed Central

Bell, David; Campbell, Malcolm; Ferguson, Matthew; Sayers, Leah; Donaghy, Liz; O'Regan, Anna; Jewhurst, Victoria; Harbinson, Mark

2012-01-01

Intermedin (IMD) protects rodent heart and vasculature from oxidative stress and ischaemia. Less is known about distribution of IMD and its receptors and the potential for similar protection in man. Expression of IMD and receptor components were studied in human aortic endothelium cells (HAECs), smooth muscle cells (HASMCs), cardiac microvascular endothelium cells (HMVECs) and fibroblasts (v-HCFs). Receptor subtype involvement in protection by IMD against injury by hydrogen peroxide (H2O2, 1 mmol l−1) and simulated ischaemia and reperfusion were investigated using receptor component-specific siRNAs. IMD and CRLR, RAMP1, RAMP2 and RAMP3 were expressed in all cell types. When cells were treated with 1 nmol l−1 IMD during exposure to 1 mmol l−1 H2O2 for 4 h, viability was greater vs. H2O2 alone (P < 0.05 for all cell types). Viabilities under 6 h simulated ischaemia differed (P < 0.05) in the absence and presence of 1 nmol l−1 IMD: HAECs 63% and 85%; HMVECs 51% and 68%; v-HCFs 42% and 96%. IMD 1 nmol l−1 present throughout ischaemia (3 h) and reperfusion (1 h) attenuated injury (P < 0.05): viabilities were 95%, 74% and 82% for HAECs, HMVECs and v-HCFs, respectively, relative to those in the absence of IMD (62%, 35%, 32%, respectively). When IMD 1 nmol l−1 was present during reperfusion only, protection was still evident (P < 0.05, 79%, 55%, 48%, respectively). Cytoskeletal disruption and protein carbonyl formation followed similar patterns. Pre-treatment (4 days) of HAECs with CRLR or RAMP2, but not RAMP1 or RAMP3, siRNAs abolished protection by IMD (1 nmol l−1) against ischaemia–reperfusion injury. IMD protects human vascular and cardiac non-vascular cells from oxidative stress and ischaemia–reperfusion, predominantly via AM1 receptors. PMID:22183724

The Novel IκB Kinase β Inhibitor, IMD-0560, Has Potent Therapeutic Efficacy in Ovarian Cancer Xenograft Model Mice.

PubMed

Sawada, Ikuko; Hashimoto, Kae; Sawada, Kenjiro; Kinose, Yasuto; Nakamura, Koji; Toda, Aska; Nakatsuka, Erika; Yoshimura, Akihiko; Mabuchi, Seiji; Fujikawa, Tomoyuki; Itai, Akiko; Kimura, Tadashi

2016-05-01

Aberrant activation of nuclear factor-kappa β (NF-κB) signaling has been correlated with poor outcome among patients with ovarian cancer. Although the therapeutic potential of NF-κB pathway disruption in cancers has been extensively studied, most classical NF-κB inhibitors are poorly selective, exhibit off-target effects, and have failed to be applied in clinical use. IMD-0560, N-[2,5-bis (trifluoromethyl) phenyl]-5-bromo-2-hydroxybenzamide, is a novel low-molecular-weight compound that selectively inhibits the IκB kinase complex and works as an inhibitor of NF-κB signaling. The aim of this study was to assess the therapeutic potential of IMD-0560 against ovarian cancer in vitro and in vivo. NF-κB activity (phosphorylation) was determined in 9 ovarian cancer cell lines and the inhibitory effect of IMD-0560 on NF-κB activation was analyzed by Western blotting. Cell viability, cell cycle, vascular endothelial growth factor (VEGF) expression, and angiogenesis were assessed in vitro to evaluate the effect of IMD-0560 on ovarian cancer cells. In vivo efficacy of IMD-0560 was also investigated using an ovarian cancer xenograft mouse model. The NF-κB signaling pathway was constitutively activated in 8 of 9 ovarian cancer cell lines. IMD-0560 inhibited NF-κB activation and suppressed ovarian cancer cell proliferation by inducing G1 phase arrest. IMD-0560 decreased VEGF secretion from cancer cells and inhibited the tube formation of human umbilical vein endothelial cells. IMD-0560 significantly inhibited peritoneal metastasis and prolonged the survival in an ovarian cancer xenograft mice model. Immunohistochemical staining of excised tumors revealed that IMD-0560 suppressed VEGF expression, tumor angiogenesis, and cancer cell proliferation. IMD-0560 showed promising therapeutic efficacy against ovarian cancer xenograft mice by inducing cell cycle arrest and suppressing VEGF production from cancer cells. IMD-0560 may be a potential future option in regimens for the treatment of ovarian cancer.

Security Belt for Wireless Implantable Medical Devices.

PubMed

Kulaç, Selman

2017-09-19

In this study, a new protective design compatible with existing non-secure systems was proposed, since it is focused on the secure communication of wireless IMD systems in all transmissions. This new protector is an external wearable device and appears to be a belt fitted around for the patients IMD implanted. However, in order to provide effective full duplex transmissions and physical layer security, some sophisticated transceiver antennas have been placed on the belt. In this approach, beam-focused multi-antennas in optimal positions on the belt are randomly switched when transmissions to the IMD are performed and multi-jammer switching with MRC combining or majority-rule based receiving techniques are applied when transmissions from the IMD are carried out. This approach can also reduce the power consumption of the IMDs and contribute to the prolongation of the IMD's battery life.

Hypercholesterolemia Up-Regulates the Expression of Intermedin and Its Receptor Components in the Aorta of Rats via Inducing the Oxidative Stress.

PubMed

Meng, Qingtao; Shi, Di; Feng, Jiayue; Su, Yanling; Long, Yang; He, Sen; Wang, Si; Wang, Yong; Zhang, Xiangxun; Chen, Xiaoping

2016-01-01

Hypercholesterolemia can cause damage to the artery. Intermedin (IMD) is a novel member of the calcitonin gene-related peptide family. This study aims to investigate the aortic expression of IMD and its receptors in hypercholesterolemia without atherosclerosis. Male Wistar rats were fed with high cholesterol diet, with or without simvastatin and vitamin C. Both the malondialdehyde (MDA) and superoxide dismutase (SOD) in plasma and aorta were determined as the oxidative stress biomarkers. The plasma IMD was assessed by radioimmunoassay. Within the aorta, the mRNA expression of IMD along with its receptor components was determined, and the corresponding protein level of the CRLR/RAMPs was also assessed. The hypercholesterolemia rats without atherosclerotic lesion manifested a higher level of MDA and SOD and the plasma IMD elevated. Increased expression of IMD and all its receptor components (CRLR, RAMP1, RAMP2, and RAMP3) were displayed within the aorta. The simvastatin indirectly attenuated oxidative stress by improving lipid profiles, while the vitamin C directly reduced oxidative stress without interfering with the serum lipids. Both simvastatin and vitamin C ameliorated the aortic injury, decreased the plasma IMD level, and recovered the expression of IMD and its receptors within the aorta. The up-regulated expression of IMD is observed within the aorta of the hypercholesterolemia rats. In addition, the oxidative stress participates in the up-regulation. © 2016 by the Association of Clinical Scientists, Inc.

Impact of imidacloprid residues on the development of Eisenia fetida during vermicomposting of greenhouse plant waste.

PubMed

Fernández-Gómez, Manuel J; Romero, Esperanza; Nogales, Rogelio

2011-09-15

Pesticide application in agriculture causes residues in post-harvest plant waste at different concentrations. Knowledge concerning how pesticide concentrations in such waste affect earthworms is essential for recycling greenhouse plant debris through vermicomposting. Here, we have evaluated the effects of imidacloprid (IMD) residues on earthworms (Eisenia fetida) during the vermicomposting of plant waste from greenhouse crops in Spain. Before, the effect of different IMD concentrations on earthworms was tested using cattle manure as an optimum waste for worm development. The results after using cattle manure indicate that IMD dose ≥ 5 mg kg(-1) hinders worm growth and even causes death, whereas IMD dose ≤ 2 mg IMD kg(-1) allows worm growth similar to control but impedes reproduction. The results from the vermicomposting of plant waste reveal that IMD inhibits adequate worm growth and increases mortality. Although 89% worms became sexually mature in substrate containing 2 mg IMD kg(-1), they did not produce cocoons. IMD also affected microorganisms harboured in the substrates for vermicomposting, as indicated by the reduction in their dehydrogenase activity. This enzyme activity was restored after vermicomposting. This study provides a sound basis for the vermicomposting of pesticide-contaminated plant waste. Copyright © 2011 Elsevier B.V. All rights reserved.

Microbiota activates IMD pathway and limits Sindbis infection in Aedes aegypti.

PubMed

Barletta, Ana Beatriz Ferreira; Nascimento-Silva, Maria Clara L; Talyuli, Octávio A C; Oliveira, José Henrique M; Pereira, Luiza Oliveira Ramos; Oliveira, Pedro L; Sorgine, Marcos Henrique F

2017-02-23

Aedes aegypti is the main vector of important arboviruses such as dengue, Zika and chikungunya. During infections mosquitoes can activate the immune pathways Toll, IMD and JAK/STAT to limit pathogen replication. Here, we evaluate the immune response profile of Ae. aegypti against Sindbis virus (SINV). We analyzed gene expression of components of Toll, IMD and JAK/STAT pathways and showed that a blood meal and virus infection upregulated aaREL2 in a microbiota-dependent fashion, since this induction was prevented by antibiotic. The presence of the microbiota activates IMD and impaired the replication of SINV in the midgut. Constitutive activation of the IMD pathway, by Caspar depletion, leads to a decrease in microbiota levels and an increase in SINV loads. Together, these results suggest that a blood meal is able to activate innate immune pathways, through a nutrient induced growth of microbiota, leading to upregulation of aaREL2 and IMD activation. Microbiota levels seemed to have a reciprocal interaction, where the proliferation of the microbiota activates IMD pathway that in turn controls bacterial levels, allowing SINV replication in Ae. aegypti mosquitoes. The activation of the IMD pathway seems to have an indirect effect in SINV levels that is induced by the microbiota.

Effects of a herbal medicine, Hippophae rhamnoides, on cardiovascular functions and coronary microvessels in the spontaneously hypertensive stroke-prone rat.

PubMed

Koyama, Tomiyasu; Taka, Akira; Togashi, Hiroko

2009-01-01

The dry fruits of Hippophae rhamnoides (so-called "Saji" or "Sea buckthorn") are used in China as a herbal medicine. The present work studied the effects on microvessels in the left ventricular wall, hematological parameters, cardiovascular performance and plasma constituents in spontaneously hypertensive stroke-prone rats (SHRSP/EZO) treated with Hippophae for 60 days. Analyses showed that the powder made of dry Hippophae fruits contains the vitamins C, B1, B2 and E, provitamin A, rutin, serotonin, cytosterol, selenium and zinc, among other constituents. The experimental rats were fed ad libitum with blocks of rat chow supplemented with Hippophae powder at a concentration of 0.7 g/kg in rat powder chow, while control rats were unsupplemented chow. The mean arterial blood pressure, heart rate, total plasma cholesterol, triglycerides, and glycated hemoglobin were significantly decreased by the Hippophae treatment. The arteriolar capillary portions of microvessels expressing alkaline phosphatase decreased, but there was a trend for an increase in the total capillary density. It was concluded that Hippophae fruits improved the metabolic processes accompanied by reduction of hypertensive stress on the ventricular microvessels.

An intercomparison of observational precipitation data sets over Northwest India during winter

NASA Astrophysics Data System (ADS)

Nageswararao, M. M.; Mohanty, U. C.; Ramakrishna, S. S. V. S.; Dimri, A. P.

2018-04-01

Winter (DJF) precipitation over Northwest India (NWI) is very important for the cultivation of Rabi crops. Thus, an accurate estimation of high-resolution observations, evaluation of high-resolution numerical models, and understanding the local variability trends are essential. The objective of this study is to verify the quality of a new high spatial resolution (0.25° × 0.25°) gridded daily precipitation data set of India Meteorological Department (IMD1) over NWI during winter. An intercomparison with four existing precipitation data sets at 0.5° × 0.5° of IMD (IMD2), 1° × 1° of IMD (IMD3), 0.25° × 0.25° of APHRODITE (APRD1), and 0.5° × 0.5° of APHRODITE (APRD1) resolution during a common period of 1971-2003 is done. The evaluation of data quality of these five data sets against available 26 station observations is carried out, and the results clearly indicate that all the five data sets reasonably agreed with the station observation. However, the errors are relatively more in all the five data sets over Jammu and Kashmir-related four stations (Srinagar, Drass, Banihal top, and Dawar), while these errors are less in the other stations. It may be due to the lack of station observations over the region. The quality of IMD1 data set over NWI for winter precipitation is reasonably well than the other data sets. The intercomparison analysis suggests that the climatological mean, interannual variability, and coefficient of variation from IMD1 are similar with other data sets. Further, the analysis extended to the India meteorological subdivisions over the region. This analysis indicates overestimation in IMD3 and underestimation in APRD1 and APRD2 over Jammu and Kashmir, Himachal Pradesh, and NWI as a whole, whereas IMD2 is closer to IMD1. Moreover, all the five data sets are highly correlated (>0.5) among them at 99.9% confidence level for all subdivisions. It is remarkably noticed that multicategorical (light precipitation, moderate precipitation, heavy precipitation, and very heavy precipitation) skill score of accuracy (>0.8) for the four data sets against IMD1 is good for all the subdivisions as well as NWI and is more in IMD2. IMD1 performs well in capturing the relationships of winter precipitation with climate indices such as Nino 3.4 region sea surface temperature, Southern Oscillation Index, Arctic Oscillation, and North Atlantic Oscillation. The results conclude that IMD1 is useful to understand the variability trends at the local climate scale and its global teleconnections.

Public health management of invasive meningococcal disease in Baden-Wuerttemberg, Germany, 2012: adherence to guidance and estimation of resources required as determined in a survey of local health authorities.

PubMed

Murajda, Lukas; Aichinger, Elisabeth; Pfaff, Guenter; Hellenbrand, Wiebke

2015-04-12

Invasive meningococcal disease (IMD) incidence in Germany is low, but management of contacts to prevent subsequent cases still requires resources. Local public health authorities (LHA) advise antibiotic post-exposure prophylaxis (PEP) and vaccination to close contacts as defined in national guidance. We aimed to audit implementation of recommendations for IMD public health management in the state of Baden-Wuerttemberg, Germany, and to estimate associated costs. We surveyed all 38 LHAs in Baden-Wuerttemberg to evaluate knowledge of national guidance and implementation of IMD contact management using standardized questionnaires. For IMD cases notified in 2012, we requested numbers of household and other contacts ascertained, including advice given regarding PEP and post-exposure vaccination, plus staff time required for their management. We estimated costs for advised antibiotics, LHA staff time and visits to emergency departments according to published sources. The cost of preventing a subsequent case was estimated based on the number of household contacts that received PEP per IMD case and on the previous finding that ~284 household contacts must receive PEP to prevent one subsequent IMD case. Although LHAs were familiar with national recommendations, they did not advise PEP to 4% of household contacts, while 72% and 100% of school and health provider contacts, respectively, were advised PEP. Only 25% of household contacts of a case with a vaccine-preventable serogroup were advised post-exposure vaccination. A mean of 11.0 contacts/IMD case (range 0-51), of which 3.6 were household contacts, were recommended PEP. Per IMD case, mean costs for LHA staff were estimated at €440.86, for antibiotics at €219.14 and for emergency department visits to obtain PEP at €161.70 - a total of €821.17/IMD case. Preventing a subsequent IMD case would cost ~ €65,000. Our results provide insight into costs of IMD public health management in Germany. We identified marked underuse of post-exposure vaccination in household contacts and overuse of PEP in school and health care contacts. In view of an estimated 3-6 quality-adjusted life years lost per case of IMD, our estimated cost of €65,000 for preventing a subsequent case seems justifiable.

Mammography in females with an implanted medical device: impact on image quality, pain and anxiety.

PubMed

Paap, Ellen; Witjes, Marloes; van Landsveld-Verhoeven, Cary; Pijnappel, Ruud M; Maas, Angela H E M; Broeders, Mireille J M

2016-10-01

To assess the image quality of mammograms in females with an implanted medical device (IMD), to evaluate pain and anxiety during mammography in these females and to investigate the experience of radiographers. Image quality was evaluated by two radiographers and one radiologist in the images of females with an IMD participating in the Dutch screening programme (clients). Pain and anxiety were scored using a Numeric Rating Scale in both clients visiting a screening organization and patients from the Isala Hospital, Zwolle. Experience of screening radiographers was collected with a questionnaire. Images of the breast with IMD showed reduced contrast in craniocaudal (CC) and mediolateral-oblique (MLO) views [by both the radiographers and radiologist (range: 11-29%)], less projected breast tissue [only radiographers; CC lateral side: 25.5%, 95% confidence interval (CI): 18.7-32.2] and reduced projection of the pectoral muscle (only radiographers; MLO width pectoral muscle: 31.5%, 95% CI: 24.4-38.7). Clients experienced more pain and anxiety during mammography in the breast with IMD compared to the breast without IMD in the breast (pain difference CC: 0.48 ± 0.16, p = 0.003; pain difference MLO: 0.46 ± 0.16, p = 0.004; anxiety difference 1.30 ± 0.22; p < 0.001). Patients experienced more pain (1.05 ± 0.12; p < 0.001) and anxiety (1.22 ± 0.15; p < 0.001) after placement of IMD. Radiographers are more cautious, more anxious and use less compression during mammography of breasts with IMD. Image quality in a breast with an IMD could be improved by projecting more breast tissue on the mammogram, thereby including (part of) the IMD between the paddles, if required. In addition, radiographers should pay sufficient attention to reducing discomfort both before and during the screening examination. Little is known about the quality of mammography in females with an IMD or how these females and radiographers experience the screening examination. The results of our study showed that having an IMD could result in a suboptimal mammogram and increased discomfort.

A positive correlation between immunohistochemical expression of CD31 and mast cell tryptase in odontogenic tumors.

PubMed

Kouhsoltani, Maryam; Halimi, Monireh; Dibazar, Sana

2015-06-01

In this study, we compared mast cell tryptase and CD31 expression between odontogenic tumors with the aim of predicting the clinical behavior of these lesions at the time of initial biopsy. We also evaluated the correlation between mast cell tryptase and CD31 expression to clarify the role of mast cells (MCs) in the growth of odontogenic tumors. Immunohistochemical staining with anti-MC tryptase and anti-CD31 antibodies was performed on 48 cases of odontogenic tumors including solid ameloblastoma (SAM), unicystic ameloblastoma (UAM), odontogenic myxoma (OM), cystic calcifying odontogenic tumor (CCOT) and adenomatoid odontogenic tumor (AOT). Ten high power fields were analyzed for each sample. Total MC count was significantly increased in SAM compared to other odontogenic tumors (p<0.05). Microvessel density was statistically higher in SAM and AOT compared to remaining odontogenic tumors (p<0.05). A significant correlation was observed between MCs and microvessels in odontogenic tumors (p=0.018, r=0.34). Our findings suggest a role for MCs in aggressive clinical behavior of odontogenic tumors. The significant correlation found between MC count and microvessel density in odontogenic tumors is in agreement with the theory of participation of MCs in tumor progression. Targeting MC activity may represent an important nonsurgical therapeutic approach, especially for aggressive odontogenic tumors.

Inhibition of endoplasmic reticulum stress by intermedin1-53 attenuates angiotensin II-induced abdominal aortic aneurysm in ApoE KO Mice.

PubMed

Ni, Xian-Qiang; Lu, Wei-Wei; Zhang, Jin-Sheng; Zhu, Qing; Ren, Jin-Ling; Yu, Yan-Rong; Liu, Xiu-Ying; Wang, Xiu-Jie; Han, Mei; Jing, Qing; Du, Jie; Tang, Chao-Shu; Qi, Yong-Fen

2018-06-26

Endoplasmic reticulum stress (ERS) is involved in the development of abdominal aortic aneurysm (AAA). Since bioactive peptide intermedin (IMD)1-53 protects against AAA formation, here we investigated whether IMD1-53 attenuates AAA by inhibiting ERS. AAA model was induced by angiotensin II (AngII) in ApoE KO mouse background. AngII-treated mouse aortas showed increased ERS gene transcription of caspase12, eukaryotic translation initiation factor 2a (eIf2a) and activating transcription factor 4(ATF4).The protein level of ERS marker glucose regulated protein 94(GRP94), ATF4 and C/EBP homologous protein 10(CHOP) was also up-regulated by AngII. Increased ERS levels were accompanied by severe VSMC apoptosis in human AAA aorta. In vivo administration of IMD1-53 greatly reduced AngII-induced AAA and abrogated the activation of ERS. To determine whether IMD inhibited AAA by ameliorating ERS, we used 2 non-selective ERS inhibitors phenyl butyrate (4-PBA) and taurine (TAU). Similar to IMD, PBA, and TAU significantly reduced the incidence of AAA and AAA-related pathological disorders. In vitro, AngII infusion up-regulated CHOP, caspase12 expression and led to VSMC apoptosis. IMD siRNA aggravated the CHOP, caspase12-mediated VSMC apoptosis, which was abolished by ATF4 silencing. IMD infusion promoted the phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) in aortas in ApoE KO mice, and the AMPK inhibitor compound C abolished the protective effect of IMD on VSMC ERS and apoptosis induced by AngII. In conclusion, IMD may protect against AAA formation by inhibiting ERS via activating AMPK phosphorylation.

Multi-octave analog photonic link with improved second- and third-order SFDRs

NASA Astrophysics Data System (ADS)

Tan, Qinggui; Gao, Yongsheng; Fan, Yangyu; He, You

2018-03-01

The second- and third-order spurious free dynamic ranges (SFDRs) are two key performance indicators for a multi-octave analogy photonic link (APL). The linearization methods for either second- or third-order intermodulation distortion (IMD2 or IMD3) have been intensively studied, but the simultaneous suppression for the both were merely reported. In this paper, we propose an APL with improved second- and third-order SFDRs for multi-octave applications based on two parallel DPMZM-based sub-APLs. The IMD3 in each sub-APL is suppressed by properly biasing the DPMZM, and the IMD2 is suppressed by balanced detecting the two sub-APLs. The experiment demonstrates significant suppression ratios for both the IMD2 and IMD3 after linearization in the proposed link, and the measured second- and third-order SFDRs with the operating frequency from 6 to 40 GHz are above 91 dB ṡHz 1 / 2 and 116 dB ṡHz 2 / 3, respectively.

Cloning and analysis of peptidoglycan recognition protein-LC and immune deficiency from the diamondback moth, Plutella xylostella.

PubMed

Zhan, Ming-Yue; Yang, Pei-Jin; Rao, Xiang-Jun

2018-02-01

Peptidoglycan (PGN) exists in both Gram-negative and Gram-positive bacteria as a component of the cell wall. PGN is an important target to be recognized by the innate immune system of animals. PGN recognition proteins (PGRP) are responsible for recognizing PGNs. In Drosophila melanogaster, PGRP-LC and IMD (immune deficiency) are critical for activating the Imd pathway. Here, we report the cloning and analysis of PGRP-LC and IMD (PxPGRP-LC and PxIMD) from diamondback moth, Plutella xylostella (L.), the insect pest of cruciferous vegetables. PxPGRP-LC gene consists of six exons encoding a polypeptide of 308 amino acid residues with a transmembrane region and a PGRP domain. PxIMD cDNA encodes a polypeptide of 251 amino acid residues with a death domain. Sequence comparisons indicate that they are characteristic of Drosophila PGRP-LC and IMD homologs. PxPGRP-LC and PxIMD were expressed in various tissues and developmental stages. Their mRNA levels were affected by bacterial challenges. The PGRP domain of PxPGRP-LC lacks key residues for the amidase activity, but it can recognize two types of PGNs. Overexpression of full-length and deletion mutants in Drosophila S2 cells induced expression of some antimicrobial peptide genes. These results indicate that PxPGRP-LC and PxIMD may be involved in the immune signaling of P. xylostella. This study provides a foundation for further studies of the immune system of P. xylostella. © 2017 Wiley Periodicals, Inc.

[Study on the relationship between intratumor microvessel density and neck metastasis of laryngeal and hypopharyngeal squamous cell carcinomas].

PubMed

Yu, Z; Wang, T; Luan, X

1997-06-01

Sixty-one laryngeal and hypopharyngeal squamous cell, carcinoma (LC, HPC) tissue slides were immunochemically stained using LSAB method to study epithelium cells. The results demonstrated that (1) intratumor microvessel density (ITMD) in LC and HPC group was higher than that of the benign group (P < 0.05). ITMD was higher in the subgroup of LC and HPC with positive lymph node positive than that with negative lymph nodes. This result suggest that ITMD is relevant not only to the nature of the tumor, but also to lymph node metastasis. The level of ITMD is an important predictive sign of metastasis. (2) The relationship between ITMD and the clinical staging had no statistic significance (P > 0.05). (3) The analysis on the relationship between ITMD and pathologic differentiation indicated that the level of ITMD raised gradually with the lowering of the pathologic differentiation.

A sublethal dose of a neonicotinoid insecticide disrupts visual processing and collision avoidance behaviour in Locusta migratoria.

PubMed

Parkinson, Rachel H; Little, Jacelyn M; Gray, John R

2017-04-20

Neonicotinoids are known to affect insect navigation and vision, however the mechanisms of these effects are not fully understood. A visual motion sensitive neuron in the locust, the Descending Contralateral Movement Detector (DCMD), integrates visual information and is involved in eliciting escape behaviours. The DCMD receives coded input from the compound eyes and monosynaptically excites motorneurons involved in flight and jumping. We show that imidacloprid (IMD) impairs neural responses to visual stimuli at sublethal concentrations, and these effects are sustained two and twenty-four hours after treatment. Most significantly, IMD disrupted bursting, a coding property important for motion detection. Specifically, IMD reduced the DCMD peak firing rate within bursts at ecologically relevant doses of 10 ng/g (ng IMD per g locust body weight). Effects on DCMD firing translate to deficits in collision avoidance behaviours: exposure to 10 ng/g IMD attenuates escape manoeuvers while 100 ng/g IMD prevents the ability to fly and walk. We show that, at ecologically-relevant doses, IMD causes significant and lasting impairment of an important pathway involved with visual sensory coding and escape behaviours. These results show, for the first time, that a neonicotinoid pesticide directly impairs an important, taxonomically conserved, motion-sensitive visual network.

Implanted medical devices in the radiation environment of commercial spaceflight.

PubMed

Reyes, David P; McClure, Steven S; Chancellor, Jeffery C; Blue, Rebecca S; Castleberry, Tarah L; Vanderploeg, James M

2014-11-01

Some commercial spaceflight participants (SFPs) may have medical conditions that require implanted medical devices (IMDs), such as cardiac pacemakers, defibrillators, insulin pumps, or similar electronic devices. The effect of space radiation on the function of IMDs is unknown. This review will identify known effects of terrestrial and aviation electromagnetic interference (EMI) and radiation on IMDs in order to provide insight into the potential effects of radiation exposures in the space environment. A systematic literature review was conducted on available literature on human studies involving the effects of EMI as well as diagnostic and therapeutic radiation on IMDs. The literature review identified potential transient effects from EMI and diagnostic radiation levels as low as 10 mGy on IMDs. High-energy, therapeutic, ionizing radiation can cause more permanent device malfunctions at doses as low as 40 mGy. Radiation doses from suborbital flight altitudes and durations are anticipated to be less than those experienced during an average round-trip, cross-country airline flight and are unlikely to result in significant detriment, though longer, orbital flights may expose SFPs to doses potentially harmful to IMD function. Individuals with IMDs should experience few, if any, radiation-related device malfunctions during suborbital flight, but could have problems with radiation exposures associated with longer, orbital flights.

Overexpression of c-kit(CD117), relevant with microvessel density, is an independent survival prognostic factor for patients with HBV-related hepatocellular carcinoma.

PubMed

Yan, Weiwei; Zhu, Zhenyu; Pan, Fei; Huang, Ang; Dai, Guang-Hai

2018-01-01

To explore new biomarkers for indicating the recurrence and prognosis in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients after tumor resection, we investigated the expression and prognostic value of c-kit(CD117) in HBV-related HCC. Immunohistochemistry was used to estimate the expression of c-kit(CD117) and CD34 in the liver cancer tissues. The correlations between the expression of these biomarkers and the clinicopathologic characteristics were analyzed. The positive rate of c-kit(CD117) expression in 206 HCC cases was 48.1%, and c-kit expression was significantly related with CD34-positive microvessel density. CD34-microvessel density numbers were much higher in c-kit(+) HCC tissues than in c-kit(-) HCC tissues (44.13±17.01 vs 26.87±13.16, P =0.003). The expression of c-kit was significantly higher in patients with Edmondson grade III-IV ( P <0.001) and TNM stage III ( P <0.001). Moreover, Kaplan-Meier survival analysis showed that c-kit ( P <0.001) expression was correlated with reduced disease-free survival (DFS). Multivariate analysis identified c-kit as an independent poor prognostic factor of DFS in HCC patients ( P <0.001). Increased c-kit expression could be considered as an independent unfavorable prognostic factor for predicting DFS in HBV-related HCC patients after surgery. These results could be used to identify patients at a higher risk of early tumor recurrence and poor prognosis.

Cost-effectiveness of alternate strategies for childhood immunization against meningococcal disease with monovalent and quadrivalent conjugate vaccines in Canada.

PubMed

Delea, Thomas E; Weycker, Derek; Atwood, Mark; Neame, Dion; Alvarez, Fabián P; Forget, Evelyn; Langley, Joanne M; Chit, Ayman

2017-01-01

Public health programs to prevent invasive meningococcal disease (IMD) with monovalent serogroup C meningococcal conjugate vaccine (MCV-C) and quadrivalent meningococcal conjugate vaccines (MCV-4) in infancy and adolescence vary across Canadian provinces. This study evaluated the cost-effectiveness of various vaccination strategies against IMD using current and anticipated future pricing and recent epidemiology. A cohort model was developed to estimate the clinical burden and costs (CAN$2014) of IMD in the Canadian population over a 100-year time horizon for three strategies: (1) MCV-C in infants and adolescents (MCV-C/C); (2) MCV-C in infants and MCV-4 in adolescents (MCV-C/4); and (3) MCV-4 in infants (2 doses) and adolescents (MCV-4/4). The source for IMD incidence was Canadian surveillance data. The effectiveness of MCV-C was based on published literature. The effectiveness of MCV-4 against all vaccination regimens was assumed to be the same as for MCV-C regimens against serogroup C. Herd effects were estimated by calibration to estimates reported in prior analyses. Costs were from published sources. Vaccines prices were projected to decline over time reflecting historical procurement trends. Over the modeling horizon there are a projected 11,438 IMD cases and 1,195 IMD deaths with MCV-C/C; expected total costs are $597.5 million. MCV-C/4 is projected to reduce cases of IMD by 1,826 (16%) and IMD deaths by 161 (13%). Vaccination costs are increased by $32 million but direct and indirect IMD costs are projected to be reduced by $46 million. MCV-C/4 is therefore dominant vs. MCV-C/C in the base case. Cost-effectiveness of MCV-4/4 was $111,286 per QALY gained versus MCV-C/4 (2575/206 IMD cases/deaths prevented; incremental costs $68 million). If historical trends in Canadian vaccines prices continue, use of MCV-4 instead of MCV-C in adolescents may be cost-effective. From an economic perspective, switching to MCV-4 as the adolescent booster should be considered.

The IMD innate immunity pathway of Drosophila influences somatic sex determination via regulation of the Doa locus.

PubMed

Zhao, Yunpo; Cocco, Claudia; Domenichini, Severine; Samson, Marie-Laure; Rabinow, Leonard

2015-11-15

The IMD pathway induces the innate immune response to infection by gram-negative bacteria. We demonstrate strong female-to-male sex transformations in double mutants of the IMD pathway in combination with Doa alleles. Doa encodes a protein kinase playing a central role in somatic sex determination through its regulation of alternative splicing of dsx transcripts. Transcripts encoding two specific Doa isoforms are reduced in Rel null mutant females, supporting our genetic observations. A role for the IMD pathway in somatic sex determination is further supported by the induction of female-to-male sex transformations by Dredd mutations in sensitized genetic backgrounds. In contrast, mutations in either dorsal or Dif, the two other NF-κB paralogues of Drosophila, display no effects on sex determination, demonstrating the specificity of IMD signaling. Our results reveal a novel role for the innate immune IMD signaling pathway in the regulation of somatic sex determination in addition to its role in response to microbial infection, demonstrating its effects on alternative splicing through induction of a crucial protein kinase. Copyright © 2015 Elsevier Inc. All rights reserved.

Nonlinear distortion analysis for single heterojunction GaAs HEMT with frequency and temperature

NASA Astrophysics Data System (ADS)

Alim, Mohammad A.; Ali, Mayahsa M.; Rezazadeh, Ali A.

2018-07-01

Nonlinearity analysis using two-tone intermodulation distortion (IMD) technique for 0.5 μm gate-length AlGaAs/GaAs based high electron mobility transistor have been investigated based on biasing conditions, input power, frequency and temperature. The outcomes indicate a significant modification on the output IMD power and as well as the minimum distortion level. The input IMD power effects the output current and subsequently the threshold voltage reduces, resulting to an increment in the output IMD power. Both frequency and temperature reduces the magnitude of the output IMDs. In addition, the threshold voltage response with temperature alters the notch point of the nonlinear output IMD’s accordingly. The aforementioned investigation will help the circuit designers to evaluate the best biasing option in terms of minimum distortion, maximum gain for future design optimizations.

Socioeconomic status, cognition, and hippocampal sclerosis.

PubMed

Baxendale, Sallie; Heaney, Dominic

2011-01-01

Poorer surgical outcomes in patients with low socioeconomic status have previously been reported, but the mechanisms underlying this pattern are unknown. Lower socioeconomic status may be a proxy marker for the limited economic opportunities associated with compromised cognitive function. The aim of this study was to examine the preoperative neuropsychological characteristics of patients with unilateral hippocampal sclerosis (HS) and their relationship to socioeconomic status. Two hundred ninety-two patients with medically intractable temporal lobe epilepsy and unilateral HS completed tests of memory and intellectual function prior to surgery. One hundred thirty-one had right HS (RHS), and 161 had left HS (LHS). The socioeconomic status of each participant was determined via the Index of Multiple Deprivation (IMD) associated with their postcode. The IMD was not associated with age at the time of assessment, age at onset of epilepsy, or duration of active epilepsy. The RHS and LHS groups did not differ on the IMD. The IMD was negatively correlated with all neuropsychological test scores in the LHS group. In the RHS group, the IMD was not significantly correlated with any of the neuropsychological measures. There were no significant correlations in the RHS group. Regression analyses suggested that IMD score explained 3% of variance in the measures of intellect, but 8% of the variance in verbal learning in the LHS group. The IMD explained 1% or less of the variance in neuropsychological scores in the RHS group. Controlling for overall level of intellectual function, the IMD score explained a small but significant proportion of the variance in verbal learning in the LHS group and visual learning for the RHS group. Our findings suggest that patients living in an area with a high IMD enter surgery with greater focal deficits associated with their epilepsy and more widespread cognitive deficits if they have LHS. Further work is needed to establish the direction of the relationship between low socioeconomic status and the neurocognitive sequelae of epilepsy. Copyright © 2010 Elsevier Inc. All rights reserved.

Characterization of nerve and microvessel damage and recovery in type 1 diabetic mice after permanent femoral artery ligation.

PubMed

Lozeron, Pierre; Mantsounga, Chris S; Broqueres-You, Dong; Dohan, Anthony; Polivka, Marc; Deroide, Nicolas; Silvestre, Jean-Sébastien; Kubis, Nathalie; Lévy, Bernard I

2015-09-01

Neuropathy is the most common complication of the peripheral nervous system during the progression of diabetes. The pathophysiology is unclear but may involve microangiopathy, reduced endoneurial blood flow, and tissue ischemia. We used a mouse model of type 1 diabetes to study parallel alterations of nerves and microvessels following tissue ischemia. We designed an easily reproducible model of ischemic neuropathy induced by irreversible ligation of the femoral artery. We studied the evolution of behavioral function, epineurial and endoneurial vessel impairment, and large nerve myelinated fiber as well as small cutaneous unmyelinated fiber impairment for 1 month following the onset of ischemia. We observed a more severe hindlimb dysfunction and delayed recovery in diabetic animals. This was associated with reduced density of large arteries in the hindlimb and reduced sciatic nerve epineurial blood flow. A reduction in sciatic nerve endoneurial capillary density was also observed, associated with a reduction in small unmyelinated epidermal fiber number and large myelinated sciatic nerve fiber dysfunction. Moreover, vascular recovery was delayed, and nerve dysfunction was still present in diabetic animals at day 28. This easily reproducible model provides clear insight into the evolution over time of the impact of ischemia on nerve and microvessel homeostasis in the setting of diabetes. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Risk factors for invasive meningococcal disease in southern Queensland, 2000-2001.

PubMed

McCall, B J; Neill, A S; Young, M M

2004-08-01

The aim of this paper is to describe the risk factors for invasive meningococcal disease (IMD) in southern Queensland. A case control study during the calendar years 2000-2001 was undertaken. Eighty-four laboratory-confirmed cases of IMD were notified. Four patients died and were excluded from the present study. Sixty-two (78%) eligible cases and 79 controls selected from the same age group and medical practice as cases, were interviewed. Univariate analysis found that IMD was associated with sharing bedrooms with two or more people (odds ratio (OR) 4.3; 95% confidence interval (CI) 1.2-17.0, P = 0.01), any exposure to tobacco smoke (smoker or passive exposure; OR 2.3; 95% CI 1.1-4.8, P = 0.02), passive exposure to tobacco smoke (OR 2.4; 95% CI 1.0-5.6, P = 0.03) and recent upper respiratory tract infection (OR 1.9, 95% CI 0.9-4.1, P = 0.06). Children who were breast-fed were less likely to develop IMD (OR 0.3; 95% CI 0.1-1.1, P = 0.04). Attendance at a childcare centre was not associated with an increased risk of IMD. In multivariate analysis, IMD was associated with children under 6 years of age who shared a bedroom with two or more people (OR 7.4; 95% CI 1.5-36.1, P = 0.01) or who had a primary carer who smoked (OR 9.1; 95% CI 2.1-39.9, P = 0.003). This is the second Australian study that identifies links between risk of IMD and exposure to cigarette smoke. The risk of IMD in young children could be further reduced if primary caregivers did not smoke. This information may contribute a new perspective to antismoking campaigns.

[Survey of Spanish Society of Internal Medicine on health care provision by internists in the public health system].

PubMed

Losa, J E; Zapatero, A; Barba, R; Marco, J; Plaza, S; Canora, J

2011-05-01

To know the organization of internal medicine departments (IMD) and the opinion of their heads of department. In 2008, a survey was mailed to 410 heads of department of the IMD of 313 Spanish public hospitals. It included a standardized structured questionnaire on staff, hospitalization, outpatients, consultation, research and teaching. The heads of departments were also asked for their opinion and suggestions on management, projects and future. Sixty-eight surveys (22%) were filled out. Internists are on call an average of 3 times a month and perform 200 discharges, 500 outpatient visits and 40 consultations in a year. The average IMD consists of 10 internists with one-fifth of the hospital beds. One third of hospitals have alternatives to inpatient care, the most frequent being palliative care. Infectious diseases accounts for the most common monographic outpatient visit, one-third of IMD lack a structured relationship with primary care and the emergency department is independent of IMD. Half of the IMD have at least one IM resident and 6 residents in other specialties; half are involved in at least two clinical trials and one-third train medical students. The heads of the IMD identify problems in their relationship with hospital managers, other specialties and local population. Excessive workload, aging and discouragement of staff and patients' social problems have negative effects. Even so, they want to initiate projects, are optimistic about the future and take an interest in clinical epidemiology research. Although the sample is small and heterogeneous, it permits a valuable panoramic view of the structure and standard operation of a Spanish IMD as well as their expectations and areas of improvement. Copyright © 2010 Elsevier España, S.L. All rights reserved.

FTY720-loaded poly(DL-lactide-co-glycolide) electrospun scaffold significantly increases microvessel density over 7 days in streptozotocin-induced diabetic C57b16/J mice: preliminary results.

PubMed

Bowers, D T; Chhabra, P; Langman, L; Botchwey, E A; Brayman, K L

2011-11-01

Nanofiber scaffolds could improve islet transplant success by physically mimicking the shape of extracellular matrix and by acting as a drug-delivery vehicle. Scaffolds implanted in alternate transplant sites must be prevascularized or very quickly vascularized following transplantation to prevent hypoxia-induced islet necrosis. The local release of the S1P prodrug FTY720 induces diameter enlargement and increases in length density. The objective of this preliminary study was to evaluate length and diameter differences between diabetic and nondiabetic animals implanted with FTY720-containing electrospun scaffolds using intravital imaging of dorsal skinfold window chambers. Electrospun mats of randomly oriented fibers we created from polymer solutions of PLAGA (50:50 LA:GA) with and without FTY720 loaded at a ratio of 1:200 (FTY720:PLAGA by wt). The implanted fiber mats were 4 mm in diameter and ∼0.2 mm thick. Increases in length density and vessel diameter were assessed by automated analysis of images over 7 days in RAVE, a Matlab program. Image analysis of repeated measures of microvessel metrics demonstrated a significant increase in the length density from day 0 to day 7 in the moderately diabetic animals of this preliminary study (P < .05). Furthermore, significant differences in length density at day 0 and day 3 were found between recently STZ-induced moderately diabetic and nondiabetic animals in response to FTY720 local release (P < .05, Student t test). Driving the islet revascularization process using local release of factors, such as FTY720, from biodegradable polymers makes an attractive system for the improvement of islet transplant success. Preliminary study results suggest that a recently induced moderately diabetic state may potentiate the mechanism by which local release of FTY720 from polymer fibers increases length density of microvessels. Therefore, local release of S1P receptor-targeted drugs is under further investigation for improvement of transplanted islet function. Copyright © 2011. Published by Elsevier Inc.

Innate immune signaling in Drosophila is regulated by transforming growth factor β (TGFβ)-activated kinase (Tak1)-triggered ubiquitin editing

PubMed Central

Chen, Li; Paquette, Nicholas; Mamoor, Shahan; Rus, Florentina; Nandy, Anubhab; Leszyk, John; Shaffer, Scott A.; Silverman, Neal

2017-01-01

Coordinated regulation of innate immune responses is necessary in all metazoans. In Drosophila the Imd pathway detects Gram-negative bacterial infections through recognition of diaminopimelic acid (DAP)-type peptidoglycan and activation of the NF-κB precursor Relish, which drives robust antimicrobial peptide gene expression. Imd is a receptor-proximal adaptor protein homologous to mammalian RIP1 that is regulated by proteolytic cleavage and Lys-63-polyubiquitination. However, the precise events and molecular mechanisms that control the post-translational modification of Imd remain unclear. Here, we demonstrate that Imd is rapidly Lys-63-polyubiquitinated at lysine residues 137 and 153 by the sequential action of two E2 enzymes, Ubc5 and Ubc13-Uev1a, in conjunction with the E3 ligase Diap2. Lys-63-ubiquitination activates the TGFβ-activated kinase (Tak1), which feeds back to phosphorylate Imd, triggering the removal of Lys-63 chains and the addition of Lys-48 polyubiquitin. This ubiquitin-editing process results in the proteasomal degradation of Imd, which we propose functions to restore homeostasis to the Drosophila immune response. PMID:28377500

IMD-4690, a novel specific inhibitor for plasminogen activator inhibitor-1, reduces allergic airway remodeling in a mouse model of chronic asthma via regulating angiogenesis and remodeling-related mediators.

PubMed

Tezuka, Toshifumi; Ogawa, Hirohisa; Azuma, Masahiko; Goto, Hisatsugu; Uehara, Hisanori; Aono, Yoshinori; Hanibuchi, Masaki; Yamaguchi, Yoichi; Fujikawa, Tomoyuki; Itai, Akiko; Nishioka, Yasuhiko

2015-01-01

Plasminogen activator inhibitor (PAI)-1 is the principal inhibitor of plasminogen activators, and is responsible for the degradation of fibrin and extracellular matrix. IMD-4690 is a newly synthesized inhibitor for PAI-1, whereas the effect on allergic airway inflammation and remodeling is still unclear. We examined the in vivo effects by using a chronic allergen exposure model of bronchial asthma in mice. The model was generated by an immune challenge for 8 weeks with house dust mite antigen, Dermatophagoides pteronyssinus (Dp). IMD-4690 was intraperitoneally administered during the challenge. Lung histopathology, hyperresponsiveness and the concentrations of mediators in lung homogenates were analyzed. The amount of active PAI-1 in the lungs was increased in mice treated with Dp. Administration with IMD-4690 reduced an active/total PAI-1 ratio. IMD-4690 also reduced the number of bronchial eosinophils in accordance with the decreased expressions of Th2 cytokines in the lung homogenates. Airway remodeling was inhibited by reducing subepithelial collagen deposition, smooth muscle hypertrophy, and angiogenesis. The effects of IMD-4690 were partly mediated by the regulation of TGF-β, HGF and matrix metalloproteinase. These results suggest that PAI-1 plays crucial roles in airway inflammation and remodeling, and IMD-4690, a specific PAI-1 inhibitor, may have therapeutic potential for patients with refractory asthma due to airway remodeling.

Epidemiology of vaccine-preventable invasive diseases in Catalonia in the era of conjugate vaccines

PubMed Central

Ciruela, Pilar; Martínez, Ana; Izquierdo, Conchita; Hernández, Sergi; Broner, Sonia; Muñoz-Almagro, Carmen; Domínguez, Àngela; of Catalonia Study Group, the Microbiological Reporting System

2013-01-01

We investigated the incidence and distribution of cases of invasive pneumococcal disease (IPD), invasive meningococcal disease (IMD) and invasive Hemophilus influenzae disease (IHiD) notified by hospital laboratories to the Microbiological Reporting System of Catalonia between 2005 and 2009. Incidence rates were compared using the rate ratio (RR) and 95% CI were calculated. A value of p < 0.05 was considered statistically significant. Of the 6,661 cases, 6,012 were IPD, 436 IMD and 213 IHiD. The global annual incidence per 105 inhabitants was 16.62 (95% CI 16.20–17.04) for IPD, 1.21 (95% CI 1.09–1.32) for IMD and 0.59 (95% CI 0.51–0.67) for IHiD. IPD increased in 2009 compared with 2005 (RR:1.55, 95%CI: 1.43–1.70) and IMD and IHiD remained stable. Pneumonia was the most-frequent clinical manifestation of IPD (75.6%) and IHiD (44.1%) and meningoencephalitis with or without sepsis for IMD (70.6%). The male:female ratio was 1.37 for IPD, 1.0 for IMD and 1.15 for IHiD. The age groups with the highest incidence were the ≤ 2 y and 2–4 y groups for IPD (66.40 and 50.66/100,000 persons-year) and IMD (14.88 and 7.26/100,000 persons-year) and the ≤ 2 y and ≥ 65 y groups for IHiD (1.88 and 1.89/100,000 persons-year). The most-frequent serotypes were serotype 1 (19.0%) in IPD and untypeable serotypes (60.8%) in IHiD. Serogroup B (78.3%) was the most frequent in IMD. S. pneumoniae is the most-frequent agent causing invasive disease in Catalonia. The main clinical manifestations were pneumonia in IPD and IHiD and meningitis in IMD. The main causative agent of meningitis was N. meningitidis in people aged < 20 y and S. pneumoniae in people aged ≥ 20 y. Vaccination with conjugate vaccines may reduce the risk of infectious disease in our setting. PMID:23303166

Detection and quantification of mast cell, vascular endothelial growth factor, and microvessel density in human inflammatory periapical cysts and granulomas.

PubMed

Fonseca-Silva, T; Santos, C C O; Alves, L R; Dias, L C; Brito, M; De Paula, A M B; Guimarães, A L S

2012-09-01

To identify and quantify mast cell (MC), vascular endothelial growth factor (VEGF) expression and microvessel density (MVD) in human periapical cysts and granulomas. Archived samples of cysts (n = 40) and granulomas (n = 28) were sectioned and stained with toluidine blue. MCs were identified and counted. Immunohistochemical reactions were employed to evaluate the tissue expression of VEGF and vessels. MVD was estimated by determining the areas of tissue labelled with CD31 antibody. The data were analysed using the Mann-Whitney test (P < 0.05). MCs were observed in the peripheral regions of both lesion types, whilst VEGF and MVD were distributed in the stroma. The presence of MCs was higher in cysts than in granulomas (P < 0.05). VEGF and MVD expression were similar in these lesions. The highest number of MCs was observed in cysts. Moreover, the identification of VEGF and MVD was consistent with the immune mechanisms involved in the lesions. © 2012 International Endodontic Journal.

[Inhibitory effect of taspine on mouse S180 sarcoma and its mechanism].

PubMed

Zhang, Yan-Min; He, Lang-Chong; Wang, Hong-Ying

2007-05-01

To study the inhibition effect of taspine on mouse S180 sarcoma and its mechanism. The mouse S180 sarcoma model was established and used to observe the antitumor activity of taspine. The microvessel density and protein expressing of the VEGF, bFGF, Bcl-2 and Bax in the tumor were measured by immunohistochemistry. Taspine showed antitumor activity on the mouse S180 sarcoma in a good dose-dependent manner. The inhibition rates on tumor of taspine at low, middle and high concentrations were 39.08% , 43.99% and 48.60%, respectively. The microvessel density and protein expressing of the VEGF, bFGF, Bcl-2 and Bax in the tumor were decreased compared with the negative control. The ratio of Bax to Bcl-2 was increased. Taspine has antitumor effect on the S180 sarcoma, and the mechanism may be through the way of decreasing the expressing of the VEGF, bFGF, Bcl-2 and Bax and inducing the vascular endothelial cell apoptosis.

Application of the WHOQOL-100 for the assessment of quality of life of adult patients with inherited metabolic diseases.

PubMed

Cazzorla, Chiara; Del Rizzo, Monica; Burgard, Peter; Zanco, Chiara; Bordugo, Andrea; Burlina, Alberto B; Burlina, Alessandro P

2012-05-01

As advances in neonatal and pediatric care for patients affected by inherited metabolic diseases (IMD) improve their outcome and allow for better survival rates, there is a growing interest in the quality of life (QoL) of patients reaching adulthood. In order to address this subject we designed a study to evaluate the QoL of a group of adult IMD patients who are receiving various treatments, in a comprehensive manner. A mixed-method study was conducted to assess the QoL in adult IMD patients. The multidimensional World Health Organization Quality of Life questionnaire (WHOQOL-100) was applied for quantitative evaluations, and an additional semi-standardized interview, was conducted for qualitative measurement of patients' perceptions of the impact of illness on their daily life, and the perceived adherence to their treatment recommendations. A total of 82 patients affected by IMD were enrolled. The inherited metabolic disorders included principally amino acids disorders, urea cycle defects, organic acidurias, carbohydrates disorders, and lysosomal disorders. The WHOQOL-100 and the semi-standardized interview were administered in a clinical setting to adult patients with IMD. The mean for the whole group indicates that adult patients with IMD can have a normal value of General QoL. Despite this value, the results of each domain show lower scores in the domains of perception of independence and quality of social relationships. We made a further analysis to compare the patients with dietary treatment with the patients with pharmacological treatment, and we observed a statistically significant difference in General QoL, in the Physical, Independence, Spiritual domains and in the facet of Medication. These results suggest that Global QoL measures might not be sufficient to assess the QoL for adult patients with IMD. Furthermore, the implementation of a qualitative semi-standardized interview, especially suitable for adult patients, added important features on illness perception and on perceived adherence to the treatment by adult IMD patients. In this study we underlined the importance of applying multidimensional instruments, like WHOQOL-100, to evaluate the quality of life of adult patients with IMD. The WHOQOL-100 has been demonstrated to be a valid instrument to measure the QoL of IMD patients. Moreover, the administration of a tailored psychometric instrument in combination with a qualitative interview may help us to better characterize special issues related to IMD. Indeed, other factors beyond the physical manifestations of the disease, such as psychological wellbeing, social behavior, illness perception and adherence to the treatment, strongly influence QoL and may serve as valid targets for intervention to improve patients' care. We believe this kind of approach is especially useful for adult patients with inherited metabolic diseases. Copyright © 2012 Elsevier Inc. All rights reserved.

The Drosophila imd signaling pathway.

PubMed

Myllymäki, Henna; Valanne, Susanna; Rämet, Mika

2014-04-15

The fruit fly, Drosophila melanogaster, has helped us to understand how innate immunity is activated. In addition to the Toll receptor and the Toll signaling pathway, the Drosophila immune response is regulated by another evolutionarily conserved signaling cascade, the immune deficiency (Imd) pathway, which activates NF-κB. In fact, the Imd pathway controls the expression of most of the antimicrobial peptides in Drosophila; thus, it is indispensable for normal immunity in flies. In this article, we review the current literature on the Drosophila Imd pathway, with special emphasis on its role in the (patho)physiology of different organs. We discuss the systemic response, as well as local responses, in the epithelial and mucosal surfaces and the nervous system.

Deconstructing Black Swans: An Introductory Approach to Inherited Metabolic Disorders in the Neonate.

PubMed

Mew, Nicholas Ah; Viall, Sarah; Kirmse, Brian; Chapman, Kimberly A

2015-08-01

Inherited metabolic disorders (IMDs) are individually rare but collectively common disorders that frequently require rapid or urgent therapy. This article provides a generalized approach to IMDs, as well as some investigations and safe therapies that may be initiated pending the metabolic consult. An overview of the research supporting management strategies is provided. In addition, the newborn metabolic screen is reviewed. Caring for infants with IMDs can seem difficult because each of the types is rarely seen; however, collectively the management can be seen as similar. When an IMD is suspected, a metabolic specialist should be consulted for expert advice regarding appropriate laboratory investigations and management. Because rapid intervention of IMDs before the onset of symptoms may prevent future irreversible sequelae, each abnormal newborn screen must be addressed promptly. Management can be difficult. Research in this area is limited and can be difficult without multisite coordination since sample sizes of any significance are difficult to achieve.

Anatomic distribution of nerves and microvascular density in the human anterior vaginal wall: prospective study.

PubMed

Li, Ting; Liao, Qinping; Zhang, Hong; Gao, Xuelian; Li, Xueying; Zhang, Miao

2014-01-01

The presence of the G-spot (an assumed erotic sensitive area in the anterior wall of the vagina) remains controversial. We explored the histomorphological basis of the G-spot. Biopsies were drawn from a 12 o'clock direction in the distal- and proximal-third areas of the anterior vagina of 32 Chinese subjects. The total number of protein gene product 9.5-immunoreactive nerves and smooth muscle actin-immunoreactive blood vessels in each specimen was quantified using the avidin-biotin-peroxidase assay. Vaginal innervation was observed in the lamina propria and muscle layer of the anterior vaginal wall. The distal-third of the anterior vaginal wall had significantly richer small-nerve-fiber innervation in the lamina propria than the proximal-third (p = 0.000) and in the vaginal muscle layer (p = 0.006). There were abundant microvessels in the lamina propria and muscle layer, but no small vessels in the lamina propria and few in the muscle layer. Significant differences were noted in the number of microvessels when comparing the distal- with proximal-third parts in the lamina propria (p = 0.046) and muscle layer (p = 0.002). Significantly increased density of nerves and microvessels in the distal-third of the anterior vaginal wall could be the histomorphological basis of the G-spot. Distal anterior vaginal repair could disrupt the normal anatomy, neurovascular supply and function of the G-spot, and cause sexual dysfunction.

Influence of imbalance on distortion in optical push-pull frontends

NASA Astrophysics Data System (ADS)

Hagensen, Morten

1995-04-01

The influence of imbalance on second-order inter-modulation distortion (IMD2) in optical push-pull frontends for Subcarrier Multiplex CATV applications is investigated theoretically and experimentally. The investigation focuses on imbalance introduced in either the photodiode, the push-pull amplifier, or the output balun, and expressions describing the overall IMD2 cancellation efficiency are derived. The developed theory is used to predict the IMD2 cancellation behavior of an optical push-pull fronted. Commercially available PIN photodiodes for CATV purposes and ferrite core transformers are characterised for phase and amplitude balance up to 1 GHz. The overall IMD2 cancellation efficiency of an optical push-pull frontend based on the best of these devices is calculated. The theory is finally verified experimentally with an optical push-pull frontend designed with the characterised photodiode and transformer. The improvement in IMD2 suppression obtained with the push-pull structure relative to a single-ended structure is in average 29 dB across the band from 47-862 MHz. The total IMD2 suppression obtained for the frontend is between 60 dBc and 79 dBc at an average optical input power of 1 mW and with an optical modulation index (OMI) of 35% per carrier in a two-tone setup.

Antimicrobial peptide gene induction, involvement of Toll and IMD pathways and defense against bacteria in the red flour beetle, Tribolium castaneum.

PubMed

Yokoi, Kakeru; Koyama, Hiroaki; Minakuchi, Chieka; Tanaka, Toshiharu; Miura, Ken

2012-01-01

Using Tribolium castaneum, we quantitatively investigated the induction of nine antimicrobial peptide (AMP) genes by live gram-negative bacteria (Escherichia coli and Enterobacter cloacae), gram-positive bacteria (Micrococcus luteus and Bacillus subtilis) and the budding yeast (Saccharomyces cerevisiae). Then, five representative AMP genes were selected, and the involvement of the Toll and IMD pathways in their induction by E. coli, M. luteus and S. cerevisiae was examined by utilizing RNA interference of either MyD88 or IMD. Results indicated: Robust and acute induction of three genes by the two bacterial species was mediated mainly by the IMD pathway; slow and sustained induction of one gene by the two bacteria was mediated mainly by the Toll pathway; induction of the remaining one gene by the two bacteria was mediated by both pathways; induction of the five genes by the yeast was mediated by the Toll and/or IMD pathways depending on respective genes. These results suggest that more promiscuous activation and usage of the two pathways may occur in T. castaneum than in Drosophila melanogaster. In addition, the IMD pathway was revealed to dominantly contribute to defense against two bacterial species, gram-negative E. cloacae and gram-positive B. subtilis that possesses DAP-type peptidoglycan.

Biocompatible ionic liquid-biopolymer electrolyte-enabled thin and compact magnesium-air batteries.

PubMed

Jia, Xiaoteng; Yang, Yang; Wang, Caiyun; Zhao, Chen; Vijayaraghavan, R; MacFarlane, Douglas R; Forsyth, Maria; Wallace, Gordon G

2014-12-10

With the surge of interest in miniaturized implanted medical devices (IMDs), implantable power sources with small dimensions and biocompatibility are in high demand. Implanted battery/supercapacitor devices are commonly packaged within a case that occupies a large volume, making miniaturization difficult. In this study, we demonstrate a polymer electrolyte-enabled biocompatible magnesium-air battery device with a total thickness of approximately 300 μm. It consists of a biocompatible polypyrrole-para(toluene sulfonic acid) cathode and a bioresorbable magnesium alloy anode. The biocompatible electrolyte used is made of choline nitrate (ionic liquid) embedded in a biopolymer, chitosan. This polymer electrolyte is mechanically robust and offers a high ionic conductivity of 8.9 × 10(-3) S cm(-1). The assembled battery delivers a maximum volumetric power density of 3.9 W L(-1), which is sufficient to drive some types of IMDs, such as cardiac pacemakers or biomonitoring systems. This miniaturized, biocompatible magnesium-air battery may pave the way to a future generation of implantable power sources.

Reduction in Neisseria meningitidis infection in Italy after Meningococcal C conjugate vaccine introduction: A time trend analysis of 1994–2012 series

PubMed Central

de Waure, Chiara; Miglietta, Alessandro; Nedovic, Darko; Mereu, Giovanna; Ricciardi, Walter

2016-01-01

The incidence of invasive meningococcal disease (IMD) in Italy is among the lowest in Europe. Meningococcal C conjugate vaccine (MCC) was introduced in 2005 for 12 months old infants. The aim of this study was to describe the epidemiology of IMD in Italy from 1994 to 2012 and to evaluate the impact of MCC introduction. Data about Neisseria meningitidis (N. meningitidis) cases were drawn from the National Surveillance of Invasive Bacterial Diseases. The average incidence of IMD during 1994–2012 in Italy was 0.36 per 100,000 (95%CI 0.30; 0.40). N. meningitidis B was the most frequent serogroup and infants less than 12 months old were the most affected. Joinpoint analysis showed a statistically significant reduction in the incidence of N. meningitidis C related IMD after MCC introduction: the Annual Percentage Change declined from 21.8 (95%CI 15.1; 28.9) in 1994–2005 to −19.9 (95%CI −28.2; −10.7) afterwards. No changes were observed with respect to N. meningitidis B related IMD. Poisson regression showed a statistically significant reduction in the incidence of IMD both associated to N. meningitidis C (Incidence Rate Ratio 0.33; 95%CI 0.29; 0.37) and due to all serogroups (Incidence Rate Ratio 0.70; 95%CI 0.65; 0.75) in the post-vaccination period compared to the pre-vaccination one. On the other hand, the incidence of N. meningitidis B related IMD did not decrease. Our results suggest that MCC had an impact in decreasing the incidence of N. meningitidis C related IMD. However, data on typing are incomplete and efforts are needed to make them available for studying the need and the impact of other meningococcal vaccines. PMID:26308192

The New Zealand Indices of Multiple Deprivation (IMD): A new suite of indicators for social and health research in Aotearoa, New Zealand

PubMed Central

2017-01-01

For the past 20 years, the New Zealand Deprivation Index (NZDep) has been the universal measure of area-based social circumstances for New Zealand (NZ) and often the key social determinant used in population health and social research. This paper presents the first theoretical and methodological shift in the measurement of area deprivation in New Zealand since the 1990s and describes the development of the New Zealand Index of Multiple Deprivation (IMD). We briefly describe the development of Data Zones, an intermediary geographical scale, before outlining the development of the New Zealand Index of Multiple Deprivation (IMD), which uses routine datasets and methods comparable to current international deprivation indices. We identified 28 indicators of deprivation from national health, social development, taxation, education, police databases, geospatial data providers and the 2013 Census, all of which represented seven Domains of deprivation: Employment; Income; Crime; Housing; Health; Education; and Geographical Access. The IMD is the combination of these seven Domains. The Domains may be used individually or in combination, to explore the geography of deprivation and its association with a given health or social outcome. Geographic variations in the distribution of the IMD and its Domains were found among the District Health Boards in NZ, suggesting that factors underpinning overall deprivation are inconsistent across the country. With the exception of the Access Domain, the IMD and its Domains were statistically and moderately-to-strongly associated with both smoking rates and household poverty. The IMD provides a more nuanced view of area deprivation circumstances in Aotearoa NZ. Our vision is for the IMD and the Data Zones to be widely used to inform research, policy and resource allocation projects, providing a better measurement of area deprivation in NZ, improved outcomes for Māori, and a more consistent approach to reporting and monitoring the social climate of NZ. PMID:28771596

The New Zealand Indices of Multiple Deprivation (IMD): A new suite of indicators for social and health research in Aotearoa, New Zealand.

PubMed

Exeter, Daniel John; Zhao, Jinfeng; Crengle, Sue; Lee, Arier; Browne, Michael

2017-01-01

For the past 20 years, the New Zealand Deprivation Index (NZDep) has been the universal measure of area-based social circumstances for New Zealand (NZ) and often the key social determinant used in population health and social research. This paper presents the first theoretical and methodological shift in the measurement of area deprivation in New Zealand since the 1990s and describes the development of the New Zealand Index of Multiple Deprivation (IMD). We briefly describe the development of Data Zones, an intermediary geographical scale, before outlining the development of the New Zealand Index of Multiple Deprivation (IMD), which uses routine datasets and methods comparable to current international deprivation indices. We identified 28 indicators of deprivation from national health, social development, taxation, education, police databases, geospatial data providers and the 2013 Census, all of which represented seven Domains of deprivation: Employment; Income; Crime; Housing; Health; Education; and Geographical Access. The IMD is the combination of these seven Domains. The Domains may be used individually or in combination, to explore the geography of deprivation and its association with a given health or social outcome. Geographic variations in the distribution of the IMD and its Domains were found among the District Health Boards in NZ, suggesting that factors underpinning overall deprivation are inconsistent across the country. With the exception of the Access Domain, the IMD and its Domains were statistically and moderately-to-strongly associated with both smoking rates and household poverty. The IMD provides a more nuanced view of area deprivation circumstances in Aotearoa NZ. Our vision is for the IMD and the Data Zones to be widely used to inform research, policy and resource allocation projects, providing a better measurement of area deprivation in NZ, improved outcomes for Māori, and a more consistent approach to reporting and monitoring the social climate of NZ.

Country, Sex, EDSS Change and Therapy Choice Independently Predict Treatment Discontinuation in Multiple Sclerosis and Clinically Isolated Syndrome

PubMed Central

Jokubaitis, Vilija G.; Trojano, Maria; Izquierdo, Guillermo; Grand’Maison, François; Oreja-Guevara, Celia; Boz, Cavit; Lugaresi, Alessandra; Girard, Marc; Grammond, Pierre; Iuliano, Gerardo; Fiol, Marcela; Cabrera-Gomez, Jose Antonio; Fernandez-Bolanos, Ricardo; Giuliani, Giorgio; Lechner-Scott, Jeannette; Cristiano, Edgardo; Herbert, Joseph; Petkovska-Boskova, Tatjana; Bergamaschi, Roberto; van Pesch, Vincent; Moore, Fraser; Vella, Norbert; Slee, Mark; Santiago, Vetere; Barnett, Michael; Havrdova, Eva; Young, Carolyn; Sirbu, Carmen-Adella; Tanner, Mary; Rutherford, Michelle; Butzkueven, Helmut

2012-01-01

Objectives We conducted a prospective study, MSBASIS, to assess factors leading to first treatment discontinuation in patients with a clinically isolated syndrome (CIS) and early relapsing-remitting multiple sclerosis (RRMS). Methods The MSBASIS Study, conducted by MSBase Study Group members, enrols patients seen from CIS onset, reporting baseline demographics, cerebral magnetic resonance imaging (MRI) features and Expanded Disability Status Scale (EDSS) scores. Follow-up visits report relapses, EDSS scores, and the start and end dates of MS-specific therapies. We performed a multivariable survival analysis to determine factors within this dataset that predict first treatment discontinuation. Results A total of 2314 CIS patients from 44 centres were followed for a median of 2.7 years, during which time 1247 commenced immunomodulatory drug (IMD) treatment. Ninety percent initiated IMD after a diagnosis of MS was confirmed, and 10% while still in CIS status. Over 40% of these patients stopped their first IMD during the observation period. Females were more likely to cease medication than males (HR 1.36, p = 0.003). Patients treated in Australia were twice as likely to cease their first IMD than patients treated in Spain (HR 1.98, p = 0.001). Increasing EDSS was associated with higher rate of IMD cessation (HR 1.21 per EDSS unit, p<0.001), and intramuscular interferon-β-1a (HR 1.38, p = 0.028) and subcutaneous interferon-β-1a (HR 1.45, p = 0.012) had higher rates of discontinuation than glatiramer acetate, although this varied widely in different countries. Onset cerebral MRI features, age, time to treatment initiation or relapse on treatment were not associated with IMD cessation. Conclusion In this multivariable survival analysis, female sex, country of residence, EDSS change and IMD choice independently predicted time to first IMD cessation. PMID:22768046

Intermedin improves cardiac function and sympathetic neural remodeling in a rat model of post myocardial infarction heart failure

PubMed Central

Xu, Bin; Xu, Hao; Cao, Heng; Liu, Xiaoxiao; Qin, Chunhuan; Zhao, Yanzhou; Han, Xiaolin; Li, Hongli

2017-01-01

Emerging evidence has suggested that intermedin (IMD), a novel member of the calcitonin gene-related peptide (CGRP) family, has a wide range of cardioprotective effects. The present study investigated the effects of long-term administration of IMD on cardiac function and sympathetic neural remodeling in heart failure (HF) rats, and studied potential underlying mechanism. HF was induced in rats by myocardial infarction (MI). Male Sprague Dawley rats were randomly assigned to either saline or IMD (0.6 µg/kg/h) treatment groups for 4 weeks post-MI. Another group of sham-operated rats served as controls. Cardiac function was assessed by echocardiography, cardiac catheterization and plasma level of B-type natriuretic peptide (BNP). Cardiac sympathetic neural remodeling was assessed by immunohistochemistical study of tyrosine hydroxylase (TH) and growth associated protein 43 (GAP43) immunoreactive nerve fibers. The protein expression levels of nerve growth factor (NGF), TH and GAP43 in the ventricular myocardium were studied by western blotting. Ventricular fibrillation threshold (VFT) was determined to evaluate the incidence of ventricular arrhythmia. Oxidative stress was assessed by detecting the activity of superoxide dismutase and the level of malondialdehyde. Compared with rats administrated with saline, IMD significantly improved cardiac function, decreased the plasma BNP level, attenuated sympathetic neural remodeling, increased VFT and suppressed oxidative stress. In conclusion, these results indicated that IMD prevents ventricle remodeling and improves the performance of a failing heart. In addition, IMD attenuated sympathetic neural remodeling and reduced the incidence of ventricular arrhythmia, which may contribute to its anti-oxidative property. These results implicate IMD as a potential therapeutic agent for the treatment of HF. PMID:28627670

The influence of deprivation on malnutrition risk in outpatients with chronic obstructive pulmonary disease (COPD).

PubMed

Collins, P F; Elia, M; Kurukulaaratchy, R J; Stratton, R J

2018-02-01

The social gradient in chronic obstructive pulmonary disease (COPD) is considerable, but the influence of deprivation on common clinical risk factors such as malnutrition is unclear. This study aimed to explore the relationship between COPD disease-severity, deprivation and malnutrition. 424 outpatients with a confirmed diagnosis of COPD were routinely screened for malnutrition risk using the 'Malnutrition Universal Screening Tool' ('MUST') while attending respiratory clinics across two hospitals; a large city hospital (site A) and a smaller community hospital (site B). Deprivation was assessed for each outpatient according to their address (postcode) using the English governments' index of multiple deprivation (IMD) and related to malnutrition risk. Each postcode was attributed to both an IMD score and IMD rank, where a higher IMD score and a lower IMD ranking indicated increased deprivation. Overall prevalence of malnutrition was 22% (95% CI 18-26%; 9% medium risk, 13% high risk). It was significantly higher at site A (28% vs 17%; p = 0.004) where patients were also significantly more likely to reside in areas of more deprivation than those at site B (IMD rank: 15,510 SD 8137 vs 22,877 SD 6827; p < 0.001). COPD disease-severity was positively associated with malnutrition (p < 0.001) whilst a higher rank IMD was negatively associated with malnutrition (p = 0.014). Deprivation is a significant independent risk factor for malnutrition in outpatients with COPD. Consideration of deprivation is important in the identification of malnutrition and the nutritional management of patients with COPD. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

Fixed-flexion knee radiography using a new positioning device produced highly repeatable measurements of joint space width: ELSA-Brasil Musculoskeletal Study (ELSA-Brasil MSK).

PubMed

Telles, Rosa Weiss; Costa-Silva, Luciana; Machado, Luciana A C; Reis, Rodrigo Citton Padilha Dos; Barreto, Sandhi Maria

To describe the performance of a non-fluoroscopic fixed-flexion PA radiographic protocol with a new positioning device, developed for the assessment of knee osteoarthritis (OA) in Brazilian Longitudinal Study of Adult Health Musculoskeletal Study (ELSA-Brasil MSK). A test-retest design including 19 adults (38 knee images) was conducted. Feasibility of the radiographic protocol was assessed by image quality parameters and presence of radioanatomic alignment according to intermargin distance (IMD) values. Repeatability was assessed for IMD and joint space width (JSW) measured at three different locations. Approximately 90% of knee images presented excellent quality. Frequencies of nearly perfect radioanatomic alignment (IMD ≤1mm) ranged from 29% to 50%, and satisfactory alignment was found in up to 71% and 76% of the images (IMD ≤1.5mm and ≤1.7mm, respectively). Repeatability analyses yielded the following results: IMD [SD of mean difference=1.08; coefficient of variation (%CV)=54.68%; intraclass correlation coefficient (ICC) (95%CI)=0.59 (0.34-0.77)]; JSW [SD of mean difference=0.34-0.61; %CV=4.48%-9.80%; ICC (95%CI)=0.74 (0.55-0.85)-0.94 (0.87-0.97)]. Adequately reproducible measurements of IMD and JSW were found in 68% and 87% of the images, respectively. Despite the difficulty in achieving consistent radioanatomic alignment between subsequent radiographs in terms of IMD, the protocol produced highly repeatable JSW measurements when these were taken at midpoint and 10mm from the medial extremity of the medial tibial plateau. Therefore, measurements of JSW at these locations can be considered adequate for the assessment of knee OA in ELSA-Brasil MSK. Copyright © 2016. Published by Elsevier Editora Ltda.

Intermedin protects against myocardial ischemia-reperfusion injury in diabetic rats

PubMed Central

2013-01-01

Background Diabetic patients, through incompletely understood mechanisms, endure exacerbated ischemic heart injury compared to non-diabetic patients. Intermedin (IMD) is a novel calcitonin gene-related peptide (CGRP) superfamily member with established cardiovascular protective effects. However, whether IMD protects against diabetic myocardial ischemia/reperfusion (MI/R) injury is unknown. Methods Diabetes was induced by streptozotocin in Sprague–Dawley rats. Animals were subjected to MI via left circumflex artery ligation for 30 minutes followed by 2 hours R. IMD was administered formally 10 minutes before R. Outcome measures included left ventricular function, oxidative stress, cellular death, infarct size, and inflammation. Results IMD levels were significantly decreased in diabetic rats compared to control animals. After MI/R, diabetic rats manifested elevated intermedin levels, both in plasma (64.95 ± 4.84 pmol/L, p < 0.05) and myocardial tissue (9.8 ± 0.60 pmol/L, p < 0.01) compared to pre-MI control values (43.62 ± 3.47 pmol/L and 4.4 ± 0.41). IMD administration to diabetic rats subjected to MI/R decreased oxidative stress product generation, apoptosis, infarct size, and inflammatory cytokine release (p < 0.05 or p < 0.01). Conclusions By reducing oxidative stress, inflammation, and apoptosis, IMD may represent a promising novel therapeutic target mitigating diabetic ischemic heart injury. PMID:23777472

A Quantitative RNAi Screen for JNK Modifiers Identifies Pvr as a Novel Regulator of Drosophila Immune Signaling

PubMed Central

Bond, David; Foley, Edan

2009-01-01

Drosophila melanogaster responds to gram-negative bacterial challenges through the IMD pathway, a signal transduction cassette that is driven by the coordinated activities of JNK, NF-κB and caspase modules. While many modifiers of NF-κB activity were identified in cell culture and in vivo assays, the regulatory apparatus that determines JNK inputs into the IMD pathway is relatively unexplored. In this manuscript, we present the first quantitative screen of the entire genome of Drosophila for novel regulators of JNK activity in the IMD pathway. We identified a large number of gene products that negatively or positively impact on JNK activation in the IMD pathway. In particular, we identified the Pvr receptor tyrosine kinase as a potent inhibitor of JNK activation. In a series of in vivo and cell culture assays, we demonstrated that activation of the IMD pathway drives JNK-dependent expression of the Pvr ligands, Pvf2 and Pvf3, which in turn act through the Pvr/ERK MAP kinase pathway to attenuate the JNK and NF-κB arms of the IMD pathway. Our data illuminate a poorly understood arm of a critical and evolutionarily conserved innate immune response. Furthermore, given the pleiotropic involvement of JNK in eukaryotic cell biology, we believe that many of the novel regulators identified in this screen are of interest beyond immune signaling. PMID:19893628

Nonlinear intermodulation distortion suppression in coherent analog fiber optic link using electro-optic polymeric dual parallel Mach-Zehnder modulator.

PubMed

Kim, Seong-Ku; Liu, Wei; Pei, Qibing; Dalton, Larry R; Fetterman, Harold R

2011-04-11

A linearized dual parallel Mach-Zehnder modulator (DPMZM) based on electro-optic (EO) polymer was both fabricated, and experimentally used to suppress the third-order intermodulation distortion (IMD3) in a coherent analog fiber optic link. This optical transmitter design was based on a new EO chromophore called B10, which was synthesized for applications dealing with the fiber-optic communication systems. The chromophore was mixed with amorphous polycarbonate (APC) to form the waveguide's core material. The DPMZM was configured with two MZMs, of different lengths in parallel, with unbalanced input and output couplers and a phase shifter in one arm. In this configuration each of the MZMs carried a different optical power, and imposed a different depth of optical modulation. When the two optical beams from the MZMs were combined to generate the transmitted signal it was possible to set the IMD3 produced by each modulator to be equal in amplitude but 180° out of phase from the other. Therefore, the resulting IMD3 of the DPMZM transmitter was effectively canceled out during two-tone experiments. A reduction of the IMD3 below the noise floor was observed while leaving fifth-order distortion (IMD5) as the dominant IMD product. This configuration has the capability of broadband operation and shot-noise limited operation simultaneously. © 2011 Optical Society of America

Cell-Specific Imd-NF-κB Responses Enable Simultaneous Antibacterial Immunity and Intestinal Epithelial Cell Shedding upon Bacterial Infection.

PubMed

Zhai, Zongzhao; Boquete, Jean-Philippe; Lemaitre, Bruno

2018-05-03

Intestinal infection triggers potent immune responses to combat pathogens and concomitantly drives epithelial renewal to maintain barrier integrity. Current models propose that epithelial renewal is primarily driven by damage caused by reactive oxygen species (ROS). Here we found that in Drosophila, the Imd-NF-κB pathway controlled enterocyte (EC) shedding upon infection, via a mechanism independent of ROS-associated apoptosis. Mechanistically, the Imd pathway synergized with JNK signaling to induce epithelial cell shedding specifically in the context of bacterial infection, requiring also the reduced expression of the transcription factor GATAe. Furthermore, cell-specific NF-κB responses enabled simultaneous production of antimicrobial peptides (AMPs) and epithelial shedding in different EC populations. Thus, the Imd-NF-κB pathway is central to the intestinal antibacterial response by mediating both AMP production and the maintenance of barrier integrity. Considering the similarities between Drosophila Imd signaling and mammalian TNFR pathway, our findings suggest the existence of an evolutionarily conserved genetic program in immunity-induced epithelial shedding. Copyright © 2018 Elsevier Inc. All rights reserved.

Where Are Socioeconomically Deprived Immigrants Located in Chile? A Spatial Analysis of Census Data Using an Index of Multiple Deprivation from the Last Three Decades (1992-2012).

PubMed

Vasquez, Andrea; Cabieses, Baltica; Tunstall, Helena

2016-01-01

Immigrants in Chile have diverse characteristics and include socioeconomically deprived populations. The location of socioeconomically deprived immigrants is important for the development of public policy intelligence at the local and national levels but their areas of residence have not been mapped in Chile. This study explored the spatial distribution of socioeconomic deprivation among immigrants in Chile, 1992-2012, and compared it to the total population. Areas with socioeconomically deprived populations were identified with a deprivation index which we developed modelled upon the Index of Multiple Deprivation (IMD) for England. Our IMD was based upon the indicators of unemployment, low educational level (primary) and disability from Census data at county level for the three decades 1992, 2002 and 2012, for 332, 339 and 343 counties respectively. We developed two versions of the IMD one based on disadvantage among the total population and another focused upon the circumstances of immigrants only. We generated a spatial representation of the IMD using GIS, for the overall IMD score and for each dimension of the index, separately. We also compared the immigrants´ IMD to the total population´s IMD using Pearson´s correlation test. Results showed that socioeconomically deprived immigrants tended to be concentrated in counties in the northern and central area of Chile, in particular within the Metropolitan Region of Santiago. These were the same counties where there was the greatest concentration of socioeconomic deprivation for the total population during the same time periods. Since 1992 there have been significant change in the location of the socioeconomically deprived populations within the Metropolitan Region of Santiago with the highest IMD scores for both the total population and immigrants becoming increasingly concentrated in the central and eastern counties of the Region. This is the first study analysing the spatial distribution of socioeconomic deprivation among international immigrants and the total population in a Latin American country. Findings could inform policy makers about location of areas of higher need of social protection in Chile, for both immigrants and the total resident population in the country.

A comparative analysis of the impact of a positive list system on new chemical entity drugs and incrementally modified drugs in South Korea.

PubMed

Ha, DongMun; Choi, Yong; Kim, Dae Up; Chung, Kyu Hyuck; Lee, Eui-Kyung

2011-07-01

Medical costs in South Korea have risen, in part due to increased demand and consumption of pharmaceutical products by an aging population and also because of the introduction of newer, more expensive drugs. In an effort to stabilize the financing of health insurance and alleviate the financial burden on individuals, the government implemented a policy changing the national health insurance drug-listing system from a negative list system to a positive list system (PLS). The goal of this study was to compare differences in drug-listing rates for new chemical entities (NCEs) and incrementally modified drugs (IMDs) after South Korea introduced the PLS in December 2006. Parameters significantly affecting NCE and IMD listings were also identified. New drug-listing data for 2007 and 2008 were obtained from the databases of the Health Insurance Review Agency and the Ministry of Health and Welfare. Descriptive analyses on the reimbursement rate and logistic regression analysis were conducted. Statistical significance was tested for all results, and P < 0.05 was considered statistically significant. A total of 150 reimbursement applications (79 for NCEs, 71 for IMDs) were examined for this study. The overall drug-listing rate was lower than before the introduction of the PLS. Drug reimbursement rates for NCEs (50.6%) were lower than those for IMDs (74.6%) (P = 0.0025). However, the price negotiation rate was 85.0% for NCEs compared with 73.6% for IMDs (P = 0.1847). The time required for both reimbursement and drug pricing was significantly longer for NCE than for IMD listings (P < 0.05). Cost-effectiveness and budget impact were 2 significant variables affecting the listing of NCEs. However, no significant variable was identified for IMDs. The PLS challenges the drug-listing system by decreasing the drug-listing rate and lengthening the period for reimbursement determinations. These effects were more pronounced for NCE listings than for IMD listings. Crown Copyright © 2011. Published by EM Inc USA. All rights reserved.

Imidacloprid transport and sorption nonequilibrium in single and multilayered columns of Immokalee fine sand

PubMed Central

Nkedi-Kizza, Peter; Morgan, Kelly T.; Kadyampakeni, Davie M.

2017-01-01

Imidacloprid (IMD) is a neonicotinoid pesticide soil-drenched to many crops to control piercing-sucking insects such as the Asian citrus psyllid (ACP). Neonicotinoids are persistent in the environment and transport analyses are helpful estimate leaching potential from soils that could result in groundwater pollution. The objective of this study was to analyze IMD breakthrough under saturated water flow in soil columns packed with three horizons (A, E, Bh) of Immokalee Fine Sand (IFS). Also, we used the dimensionless form of the convective-dispersive model (CD-Model) to compare the optimized transport parameters from each column experiment (retardation factor, R; fraction of instantaneous-to-total retardation, β; and mass transfer coefficient, ω) with the parameters obtained from sorption batch equilibria and sorption kinetics. The tracer (Cl-) breakthrough curves (BTCs) were symmetrical and properly described by the CD-Model. IMD BTCs from A, Bh, and multilayered [A+E+Bh] soil columns showed steep fronts and tailing that were well described by the one-site nonequilibrium (OSNE) model, which was an evidence of non-ideal transport due to IMD mass transfer into the soil organic matter. In general, IMD was weakly-sorbed in the A and Bh horizons (R values of 3.72 ± 0.04 and 3.08 ± 0.07, respectively), and almost no retardation was observed in the E horizon (R = 1.20 ± 0.02) due to its low organic matter content (0.3%). Using the HYDRUS-1D package, optimized parameters (R, β, ω) from the individual columns successfully simulated IMD transport in a multilayered column mimicking an IFS soil profile. These column studies and corresponding simulations agreed with previous findings from batch sorption equilibria and kinetics experiments, where IMD showed one-site kinetic mass transfer between soil surfaces and soil solution. Ideally, sandy soils should be maintained unsaturated by crop irrigation systems and rainfall monitoring during and after soil-drench application. The unsaturated soil will increase IMD retardation factors and residence time for plant uptake, lowering leaching potential from soil layers with low sorption capacity, such as the E horizon. PMID:28837702

Angiogenesis extent and macrophage density increase simultaneously with pathological progression in B-cell non-Hodgkin's lymphomas

PubMed Central

Vacca, A; Ribatti, D; Ruco, L; Giacchetta, F; Nico, B; Quondamatteo, F; Ria, R; Iurlaro, M; Dammacco, F

1999-01-01

Node biopsies of 30 benign lymphadenopathies and 71 B-cell non-Hodgkin's lymphomas (B-NHLs) were investigated for microvessel and macrophage counts using immunohistochemistry and morphometric analysis. Both counts were significantly higher in B-NHL. Moreover, when these were grouped into low-grade and high-grade lymphomas, according to the Kiel classification and Working Formulation (WF), statistically significant higher counts were found in the high-grade tumours. Immunohistochemistry and electron microscopy revealed a close spatial association between microvessels and macrophages. Overall, the results suggest that, in analogy to what has already been shown in solid tumours, angiogenesis occurring in B-NHLs increases with tumour progression, and that macrophages promote the induction of angiogenesis via the release of their angiogenic factors. © 1999 Cancer Research Campaign PMID:10070898

Structural and functional bases of laser-microvessels interaction

NASA Astrophysics Data System (ADS)

Kozlov, Valentine I.; Terman, Oleg A.; Builin, Vitalij; Lebedeva, Natalia A.; Samoilov, Nickolai

1993-07-01

Structural and functional microcirculatory changes in tissues and organs (muscles, liver, derma, epinephros, brain cortex) under various dosages and powers of laser irradiation in the red (633 nm) and near infrared (890 nm) spectrum regions have been studied in experiments and clinic. In case of nonsensitized tissues the `photoactivation' range of power densities and doses of laser irradiation has been established. We have identified a short-term reaction of microvessels and a long-term reaction (adaptation). The former consists of intensification of microcirculation and metabolism rise in parenchymatous cells; the latter is connected with neoangiogenesis acceleration. The intensification of the blood microcirculation includes a dilation of microvessels of all orders, an amplification of arteriolar vasomotions and an opening of `reserved' capillaries. Data on the structural reconstruction of myocytes and endotheliocytes have shown that the high differential parenchymatous cells and its membrane structures are sensitive to low energy laser irradiation and, on the other hand, under low energy laser irradiation there is an activation of synthetic processes in the cells. Thus, during the laser-tissue interaction in such complex system as human organism the microcirculation plays the key role among the other systems.

Expression and localization of the vascular endothelial growth factor and changes of microvessel density during hair follicle development of Liaoning cashmere goats.

PubMed

Zhang, Q L; Li, J P; Li, Y M; Chang, Q; Chen, Y; Jiang, H Z; Zhao, Z H; Guo, D

2013-12-10

Vascular endothelial growth factors (VEGFs) play important roles in neovascularization, tissue development, and angiogenesis. In this study, changes in VEGF expression patterns and microvessel density (MVD), and their correlations, were investigated during hair follicle development in epidermal appendages of Liaoning cashmere goats. Polyclonal antibodies to VEGF and microvessels were used for monthly immunohistochemical examinations of normal skin specimens from adult female goats for one year. VEGF was expressed in the hair bulb of primary and secondary hair follicles, the outer and inner root sheaths, sebaceous glands (ductal and secretory portions), eccrine sweat glands (ductal and secretory portions), and the epidermis. Abundant expression of VEGF was observed in the follicular basement membrane zone surrounding the bulb matrix and in ductal and secretory portions of eccrine sweat glands. The change in VEGFs in primary hair follicles showed a bimodal pattern, with the first peak observed from March to May, and the second in August. Maximal expression in secondary hair follicles occurred in May and August. Therefore, VEGF expression in primary and secondary hair follicles is synchronized throughout the year, and is correlated to hair development. In the later telogen and anagen phases, VEGF expression was higher in the secondary, compared to the primary, hair follicle. Changes in MVD also showed a bimodal pattern with peaks in May and August. VEGF expression and MVD showed moderate and strongly positive correlation in the primary and secondary hair follicles, respectively. Therefore, MVD and VEGF are closely related to the processes involved in hair cycle regulation.

Growth inhibition of malignant melanoma by intermediate frequency alternating electric fields, and the underlying mechanisms.

PubMed

Chen, H; Liu, R; Liu, J; Tang, J

2012-01-01

This study investigated the antitumour effects of intermediate frequency alternating electric fields (IF-AEF) in a murine melanoma cell line (B16F10) and a mouse tumour model. IF-AEF was applied at 100 kHz. Proliferation of B16F10 cells in vitro was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. IF-AEF was applied in vivo to mice bearing B16F10 tumours. Terminal deoxy nucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assay for apoptosis, and immunohistochemical detection of CD34 and vascular endothelial growth factor (VEGF), were performed. IF-AEF inhibited the proliferation of B16F10 cells in an electrical intensity and time-dependent manner. Treatment with IF-AEF for 7 days significantly inhibited the growth of tumours compared with untreated controls. IF-AEF induced apoptosis in vivo and reduced CD34-positive cell numbers; CD34 is a special marker of microvessel density. IF-AEF reduced microvessel density related to tumour growth and may serve as a therapeutic strategy for cancer treatment.

Does Dexamethasone Helps in Meningococcal Sepsis?

PubMed

Tolaj, Ilir; Ramadani, Hamdi; Mehmeti, Murat; Gashi, Hatixhe; Kasumi, Arbana; Gashi, Visar; Jashari, Haki

2017-06-01

Prompt recognition and aggressive early treatment are the only effective measures against invasive meningococcal disease (IMD). Anti-inflammatory adjunctive treatment remains controversial and difficult to assess in patients with IMD. The purpose of this study was to evaluate the effect of dexamethasone (DXM) as adjunctive treatment in different clinical forms of IMD, and attempt to answer if DXM should be routinely used in the treatment of IMD. In this non-interventional clinical study (NIS), 39 patients with meningococcal septicaemia with or without of meningitis were included, and compared regarding the impact of dexamethasone (DXM), as an adjunctive treatment, on the outcome of IMD. SPSS statistics is used for statistical processing of data. Thirty (76.9%) patients with IMD had sepsis and meningitis, and 9 (23.1%) of them had sepsis alone. Dexamethasone was used in 24 (61.5%) cases, in both clinical groups. The overall mortality rate was 10.3%. Pneumonia was diagnosed in 6 patients (15.4%), arthritis in 3 of them (7.7%), and subdural effusion in one patient (2.6%). The data showed a significant statistical difference on the length of hospitalization, and WBC normalization in groups of patients treated with DXM. The use of DXM as adjunctive therapy in invasive meningococcal disease has a degree of proven benefits and no harmful effects. In fighting this very dangerous and complex infection, even a limited benefit is sufficient to recommend the use of DXM as adjunctive treatment in invasive meningococcal disease.

Does Dexamethasone Helps in Meningococcal Sepsis?

PubMed Central

Tolaj, Ilir; Ramadani, Hamdi; Mehmeti, Murat; Gashi, Hatixhe; Kasumi, Arbana; Gashi, Visar; Jashari, Haki

2017-01-01

Purpose: Prompt recognition and aggressive early treatment are the only effective measures against invasive meningococcal disease (IMD). Anti-inflammatory adjunctive treatment remains controversial and difficult to assess in patients with IMD. The purpose of this study was to evaluate the effect of dexamethasone (DXM) as adjunctive treatment in different clinical forms of IMD, and attempt to answer if DXM should be routinely used in the treatment of IMD. Methods: In this non-interventional clinical study (NIS), 39 patients with meningococcal septicaemia with or without of meningitis were included, and compared regarding the impact of dexamethasone (DXM), as an adjunctive treatment, on the outcome of IMD. SPSS statistics is used for statistical processing of data. Results: Thirty (76.9%) patients with IMD had sepsis and meningitis, and 9 (23.1%) of them had sepsis alone. Dexamethasone was used in 24 (61.5%) cases, in both clinical groups. The overall mortality rate was 10.3%. Pneumonia was diagnosed in 6 patients (15.4%), arthritis in 3 of them (7.7%), and subdural effusion in one patient (2.6%). The data showed a significant statistical difference on the length of hospitalization, and WBC normalization in groups of patients treated with DXM. Conclusion: The use of DXM as adjunctive therapy in invasive meningococcal disease has a degree of proven benefits and no harmful effects. In fighting this very dangerous and complex infection, even a limited benefit is sufficient to recommend the use of DXM as adjunctive treatment in invasive meningococcal disease. PMID:28974828

Can immunosuppressive therapy facilitate the diagnosis and affect the clinical signs of canine scabies? A retrospective study of 79 cases.

PubMed

Souza, Clarissa P; Torres, Sheila M F; Koch, Sandra N; Rendahl, Aaron; Verocai, Guilherme G

2016-06-01

Scabies infestation is one of the most pruritic dermatoses of dogs. It is often misdiagnosed and dogs are treated with immunomodulatory drugs (IMD) to relieve pruritus. The primary goals of this study were to determine the impact of IMD on skin scraping results, pruritus level and extent of skin lesions, and to evaluate whether disease duration is associated with positive skin scrapings and contagion. Seventy nine dogs with a final diagnosis of scabies. Inclusion in this retrospective study required a positive skin scraping for scabies or a clinical response to an acaricidal treatment trial. The average pruritus score of dogs that received IMD (8.71) was significantly higher than those that did not (7.43; P = 0.03). However, there were no significant differences in either the rates of positive skin scrapings (79.6% versus 59.1%; P = 0.13) or the mean number of body sites affected (3.8 versus 3.4; P = 0.30) between dogs that received IMD and those that did not. Neither skin scraping status nor duration of clinical signs were correlated with a report of contagion within the household. IMD was associated with a significant increase in the pruritus level, but not with the mean number of lesional body sites. Dogs exposed to IMD had a 20.5% higher rate of positive skin scrapings. This difference could be clinically relevant and lack of statistical significance may indicate an underpowered study. © 2016 ESVD and ACVD.

Net mass balance calculations for the Shirase Drainage Basin, east Antarctica, using the mass budget method

NASA Astrophysics Data System (ADS)

Nakamura, Kazuki; Yamanokuchi, Tsutomu; Doi, Koichiro; Shibuya, Kazuo

2016-06-01

We quantify the mass budget of the Shirase drainage basin (SHI), Antarctica, by separately estimating snow accumulation (surface mass balance; SMB) and glacier ice mass discharge (IMD). We estimated the SMB in the SHI, using a regional atmospheric climate model (RACMO2.1). The SMB of the mainstream A flow region was 12.1 ± 1.5 Gt a-1 for an area of 1.985 × 105 km2. Obvious overestimation of the model round the coast, ∼0.5 Gt a-1, was corrected for. For calculating the IMD, we employed a 15-m resolution Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) with a digital elevation model (DEM) to determine the heights at the grounding line (GL), after comparison with the interpolated Bamber DEM grid heights; the results of this are referred to as the measured heights. Ice thickness data at the GL were inferred by using a free-board relationship between the measured height and the ice thickness, and considering the measured firn depth correction (4.2 m with the reference ice density of 910 kg m-3) for the nearby blue-ice area. The total IMD was estimated to be 14.0 ± 1.8 Gt a-1. Semi-empirical firn densification model gives the estimate within 0.1-0.2 Gt a-1 difference. The estimated net mass balance, -1.9 Gt a-1, has a two-σ uncertainty of ±3.3 Gt a-1, and probable melt water discharge strongly suggests negative NMB, although the associated uncertainty is large.

Invasive meningococcal disease--improving management through structured review of cases in the Hunter New England area, Australia.

PubMed

Guimont, Chantal; Hullick, Carolyn; Durrheim, David; Ryan, Nick; Ferguson, John; Massey, Peter

2010-03-01

Invasive meningococcal disease (IMD) is the most common infectious cause of death in childhood in developed countries. This disease may cause severe disability or death if a patient is sub-optimally managed. An audit was performed in Australia of all 2005-06 notified IMD cases to elicit correctable issues. Over the 2 year period, 24 cases were notified in the Hunter New England Health area. These cases were reviewed by an expert panel to highlight key correctable issues in recognition and management of IMD. The 24 patients were aged between 1 month and 70 years. Thirteen (54%) were children and 14 (58%) were women. Six (25%) cases developed complications, two being severe (one death, one limb amputations). These patients had risk factors for IMD. The emergency department average delay between assessment and administration of antibiotics was 57.8 min. There were avoidable factors identified in both patients with a poor outcome. Length of delay in initiating antibiotic therapy has been associated with poor outcome, thus the delay in our series is of concern. The audit highlighted many potentially correctable issues in the medical, laboratory and public health management of IMD cases.

Phase II Study of Neoadjuvant Bevacizumab and Radiotherapy for Resectable Soft Tissue Sarcomas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yoon, Sam S., E-mail: syoon@partners.org; Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, PA; Duda, Dan G.

Purpose: Numerous preclinical studies have demonstrated that angiogenesis inhibitors can increase the efficacy of radiotherapy (RT). We sought to examine the safety and efficacy of bevacizumab (BV) and RT in soft tissue sarcomas and explore biomarkers to help determine the treatment response. Methods and Materials: Patients with {>=}5 cm, intermediate- or high-grade soft tissue sarcomas at significant risk of local recurrence received neoadjuvant BV alone followed by BV plus RT before surgical resection. Correlative science studies included analysis of the serial blood and tumor samples and serial perfusion computed tomography scans. Results: The 20 patients had a median tumor sizemore » of 8.25 cm, with 13 extremity, 1 trunk, and 6 retroperitoneal/pelvis tumors. The neoadjuvant treatment was well tolerated, with only 4 patients having Grade 3 toxicities (hypertension, liver function test elevation). BV plus RT resulted in {>=}80% pathologic necrosis in 9 (45%) of 20 tumors, more than double the historical rate seen with RT alone. Three patients had a complete pathologic response. The median microvessel density decreased 53% after BV alone (p <.05). After combination therapy, the median tumor cell proliferation decreased by 73%, apoptosis increased 10.4-fold, and the blood flow, blood volume, and permeability surface area decreased by 62-72% (p <.05). Analysis of gene expression microarrays of untreated tumors identified a 24-gene signature for treatment response. The microvessel density and circulating progenitor cells at baseline and the reduction in microvessel density and plasma soluble c-KIT with BV therapy also correlated with a good pathologic response (p <.05). After a median follow-up of 20 months, only 1 patient had developed local recurrence. Conclusions: The results from the present exploratory study indicated that BV increases the efficacy of RT against soft tissue sarcomas and might reduce the incidence of local recurrence. Thus, this regimen warrants additional investigation. Gene expression profiles and other tissue and circulating biomarkers showed promising correlations with treatment response.« less

Dapsone protects brain microvascular integrity from high-fat diet induced LDL oxidation.

PubMed

Zhan, Rui; Zhao, Mingming; Zhou, Ting; Chen, Yue; Yu, Weiwei; Zhao, Lei; Zhang, Tao; Wang, Hecheng; Yang, Huan; Jin, Yinglan; He, Qihua; Yang, Xiaoda; Guo, Xiangyang; Willard, Belinda; Pan, Bing; Huang, Yining; Chen, Yingyu; Chui, Dehua; Zheng, Lemin

2018-06-07

Atherosclerosis was considered to induce many vascular-related complications, such as acute myocardial infarction and stroke. Abnormal lipid metabolism and its peroxidation inducing blood-brain barrier (BBB) leakage were associated with the pre-clinical stage of stroke. Dapsone (DDS), an anti-inflammation and anti-oxidation drug, has been found to have protective effects on vascular. However, whether DDS has a protective role on brain microvessels during lipid oxidation had yet to be elucidated. We investigated brain microvascular integrity in a high-fat diet (HFD) mouse model. We designed this study to explore whether DDS had protective effects on brain microvessels under lipid oxidation and tried to explain the underlying mechanism. In our live optical study, we found that DDS significantly attenuated brain microvascular leakage through reducing serum oxidized low-density lipoprotein (oxLDL) in HFD mice (p < 0.001), and DDS significantly inhibited LDL oxidation in vitro (p < 0.001). Our study showed that DDS protected tight junction proteins: ZO-1 (p < 0.001), occludin (p < 0.01), claudin-5 (p < 0.05) of microvascular endothelial cells in vivo and in vitro. DDS reversed LAMP1 aggregation in cytoplasm, and decreased the destruction of tight junction protein: ZO-1 in vitro. We first revealed that DDS had a protective role on cerebral microvessels through preventing tight junction ZO-1 from abnormal degradation by autophagy and reducing lysosome accumulation. Our findings suggested the significance of DDS in protecting brain microvessels under lipid metabolic disorders, which revealed a novel potential therapeutic strategy in brain microvascular-related diseases.

Interleukin 35 Expression Correlates With Microvessel Density in Pancreatic Ductal Adenocarcinoma, Recruits Monocytes, and Promotes Growth and Angiogenesis of Xenograft Tumors in Mice.

PubMed

Huang, Chongbiao; Li, Zengxun; Li, Na; Li, Yang; Chang, Antao; Zhao, Tiansuo; Wang, Xiuchao; Wang, Hongwei; Gao, Song; Yang, Shengyu; Hao, Jihui; Ren, He

2018-02-01

Cells of the monocyte lineage contribute to tumor angiogenesis. Interleukin 35 (IL35) is a member of the IL12 family produced by regulatory, but not effector, T cells. IL35 is a dimer comprising the IL12 alpha and IL27 beta chains, encoded by IL12A and EBI3, respectively. Expression of IL35 is increased in pancreatic ductal adenocarcinomas (PDACs) compared with normal pancreatic tissues, and promotes metastasis. We investigated the role of IL35 in monocyte-induced angiogenesis of PDAC in mice. We measured levels of IL35 protein, microvessel density, and numbers of monocytes in 123 sequential PDAC tissues from patients who underwent surgery in China in 2010. We performed studies with the human PDAC cell lines CFPAC-1, BxPC-3, Panc-1, MIA-PaCa-2, and mouse PDAC cell line Pan02. Monocyte subsets were isolated by flow cytometry from human peripheral blood mononuclear cells. Fused human or mouse IL12A and EBI3 genes were overexpressed in PDAC cells or knocked down using small hairpin RNAs. Cells were grown as xenograft tumors in SCID mice; some mice were given injections of an IL35-neutralizing antibody and tumor growth was monitored. We performed chemotaxis assays to measure the ability of IL35 to recruit monocytes. We analyzed mRNA sequences of 179 PDACs in the Cancer Genome Atlas to identify correlations between expression of IL12A and EBI3 and monocyte markers. Monocytes incubated with IL35 or PDAC cell supernatants were analyzed in tube formation and endothelial migration assays. In PDAC samples from patients, levels of IL35 mRNA and protein correlated with microvessel density and infiltration of monocyte lineage cells. In cells and mice with xenograft tumors, IL35 increased recruitment of monocytes into PDAC tumors, which required CCL5. Upon exposure to IL35, monocytes increased expression of genes whose products promote angiogenesis (CXCL1 and CXCL8). IL35 activated transcription of CCL5, CXCL1, and CXCL8 by inducing GP130 signaling, via IL12RB2 and phosphorylation of STAT1 and STAT4. A combination of a neutralizing antibody against IL35 and gemcitabine significantly decreased monocyte infiltration, microvessel density, and volume of xenograft tumors grown from PDAC cells in mice. PDAC cells produce IL35 to recruit monocytes via CCL5 and induce macrophage to promote angiogenesis via expression of CXCL1 and CXCL8. IL35 signaling promotes angiogenesis and growth of xenograft tumors from PDAC cells in mice. IL35 might serve as a therapeutic target for patients with pancreatic cancer. Copyright © 2018. Published by Elsevier Inc.

Impact of Enteral Nutrition with an Immunomodulating Diet Enriched with Hydrolyzed Whey Peptide on Infection After Liver Transplantation.

PubMed

Kamo, Naoko; Kaido, Toshimi; Hamaguchi, Yuhei; Uozumi, Ryuji; Okumura, Shinya; Kobayashi, Atsushi; Shirai, Hisaya; Yagi, Shintaro; Okajima, Hideaki; Uemoto, Shinji

2018-05-21

Infection is a leading cause of death after liver transplantation (LT). Therefore, prevention of infection is crucial for improving outcomes after LT. We examined the impact of early enteral nutrition with an immunomodulating diet (IMD) enriched with hydrolyzed whey peptide (HWP) formulation on infection after living donor LT (LDLT), focusing on sarcopenia. This study enrolled 279 consecutive patients who underwent primary LDLT at our institute between January 2008 and April 2015. Early enteral nutrition with the IMD enriched with HWP formulation and a conventional elemental diet were started within the first 24 h after surgery for 164 (IMD-HWP) and 115 (conventional) patients. Sequential changes in nutritional parameters, and the incidences of acute cellular rejection (ACR) and bacteremia were compared between the IMD-HWP and control groups. The comparison was made between those members of each group that did or did not exhibit sarcopenia. Risk factors for post-transplant bacteremia were also assessed. Postoperative nutritional parameters and the incidence of ACR were comparable between the groups, except for the prealbumin level. The incidence of bacteremia was significantly lower in the IMD-HWP group, and among patients without sarcopenia in the IMD-HWP group compared with the conventional group (24.4 vs. 41.7%; P = 0.002 and 20.8 vs. 39.0%; P = 0.040, respectively). Independent risk factor for bacteremia comprised bleeding ≥10,000 mL (P = 0.025). In contrast, enteral nutrition without HWP formulation was not significantly associated with bacteremia. However, enteral nutrition without HWP formulation (P = 0.080), MELD scores (P = 0.097), and ABO incompatibility (P = 0.088) showed a trend toward increased incidence of bacteremia, although they did not reach statistical significance in the multivariate analysis. Postoperative immunonutrition with an IMD enriched with HWP formulation was closely involved with post-transplant bacteremia.

Multidisciplinary analysis of invasive meningococcal disease as a framework for continuous quality and safety improvement in regional Australia

PubMed Central

Taylor, Kathryn A; Durrheim, David N; Merritt, Tony; Massey, Peter; Ferguson, John; Ryan, Nick; Hullick, Carolyn

2018-01-01

Background System factors in a regional Australian health district contributed to avoidable care deviations from invasive meningococcal disease (IMD) management guidelines. Traditional root cause analysis (RCA) is not well-suited to IMD, focusing on individual cases rather than system improvements. As IMD requires complex care across healthcare silos, it presents an opportunity to explore and address system-based patient safety issues. Context Baseline assessment of IMD cases (2005–2006) identified inadequate triage, lack of senior clinician review, inconsistent vital sign recording and laboratory delays as common issues, resulting in antibiotic administration delays and inappropriate or premature discharge. Methods Clinical governance, in partnership with clinical and public health services, established a multidisciplinary Meningococcal Reference Group (MRG) to routinely review management of all IMD cases. The MRG comprised representatives from primary care, acute care, public health, laboratory medicine and clinical governance. Baseline data were compared with two subsequent evaluation points (2011–2012 and 2013–2015). Interventions Phase I involved multidisciplinary process mapping and development of a standardised audit tool from national IMD management guidelines. Phase II involved formalisation of group processes and advocacy for operational change. Phase III focused on dissemination of findings to clinicians and managers. Results Greatest care improvements were observed in the final evaluation. Median antibiotic delay decreased from 72 to 42 min and proportion of cases triaged appropriately improved from 38% to 75% between 2013 and 2015. Increasing fatal outcomes were attributed to the emergence of more virulent meningococcal serotypes. Conclusions The MRG was a key mechanism for identifying system gaps, advocating for change and enhancing communication and coordination across services. Employing IMD case review as a focus for district-level process reflection presents an innovative patient safety approach, combining the strengths of prospective hazard analysis with more traditional RCA methodologies. PMID:29527576

Where Are Socioeconomically Deprived Immigrants Located in Chile? A Spatial Analysis of Census Data Using an Index of Multiple Deprivation from the Last Three Decades (1992-2012)

PubMed Central

2016-01-01

Introduction and Purpose of the Study Immigrants in Chile have diverse characteristics and include socioeconomically deprived populations. The location of socioeconomically deprived immigrants is important for the development of public policy intelligence at the local and national levels but their areas of residence have not been mapped in Chile. This study explored the spatial distribution of socioeconomic deprivation among immigrants in Chile, 1992–2012, and compared it to the total population. Material and Methods Areas with socioeconomically deprived populations were identified with a deprivation index which we developed modelled upon the Index of Multiple Deprivation (IMD) for England. Our IMD was based upon the indicators of unemployment, low educational level (primary) and disability from Census data at county level for the three decades 1992, 2002 and 2012, for 332, 339 and 343 counties respectively. We developed two versions of the IMD one based on disadvantage among the total population and another focused upon the circumstances of immigrants only. We generated a spatial representation of the IMD using GIS, for the overall IMD score and for each dimension of the index, separately. We also compared the immigrants´ IMD to the total population´s IMD using Pearson´s correlation test. Results Results showed that socioeconomically deprived immigrants tended to be concentrated in counties in the northern and central area of Chile, in particular within the Metropolitan Region of Santiago. These were the same counties where there was the greatest concentration of socioeconomic deprivation for the total population during the same time periods. Since 1992 there have been significant change in the location of the socioeconomically deprived populations within the Metropolitan Region of Santiago with the highest IMD scores for both the total population and immigrants becoming increasingly concentrated in the central and eastern counties of the Region. Conclusion This is the first study analysing the spatial distribution of socioeconomic deprivation among international immigrants and the total population in a Latin American country. Findings could inform policy makers about location of areas of higher need of social protection in Chile, for both immigrants and the total resident population in the country. PMID:26756869

Clinical study of contrast-enhanced digital mammography and the evaluation of blood and lymphatic microvessel density

PubMed Central

Cruz-Bastida, Juan P; Rosado-Méndez, Iván M; Villaseñor-Navarro, Yolanda; Pérez-Ponce, Héctor; Galván, Héctor A; Trujillo-Zamudio, Flavio E; Sánchez-Suárez, Patricia; Benítez-Bribiesca, Luis

2016-01-01

Objective: To correlate image parameters in contrast-enhanced digital mammography (CEDM) with blood and lymphatic microvessel density (MVD). Methods: 18 Breast Imaging-Reporting and Data System (BI-RADS)-4 to BI-RADS-5 patients were subjected to CEDM. Craniocaudal views were acquired, two views (low and high energy) before iodine contrast medium (CM) injection and four views (high energy) 1–5 min afterwards. Processing included registration and two subtraction modalities, traditional single-energy temporal (high-energy) and “dual-energy temporal with a matrix”, proposed to improve lesion conspicuity. Images were calibrated into iodine thickness, and iodine uptake, contrast, time–intensity and time–contrast kinetic curves were quantified. Image indicators were compared with MVD evaluated by anti-CD105 and anti-podoplanin (D2-40) immunohistochemistry. Results: 11 lesions were cancerous and 7 were benign. CEDM subtraction strongly increased conspicuity of lesions enhanced by iodine uptake. A strong correlation was observed between lymphatic vessels and blood vessels; all benign lesions had <30 blood microvessels per field, and all cancers had more than this value. MVD showed no correlation with iodine uptake, nor with contrast. The most frequent curve was early uptake followed by plateau for uptake and contrast in benign and malignant lesions. The positive-predictive value of uptake dynamics was 73% and that of contrast was 64%. Conclusion: CEDM increased lesion visibility and showed additional features compared with conventional mammography. Lack of correlation between image parameters and MVD is probably due to tumour tissue heterogeneity, mammography projective nature and/or dependence of extracellular iodine irrigation on tissue composition. Advances in knowledge: Quantitative analysis of CEDM images was performed. Image parameters and MVD showed no correlation. Probably, this is indication of the complex dependence of CM perfusion on tumour microenvironment. PMID:27376457

Erythropoietin promotes network formation of transplanted adipose tissue-derived microvascular fragments.

PubMed

Karschnia, P; Scheuer, C; Heß, A; Später, T; Menger, M D; Laschke, M W

2018-05-09

The seeding of tissue constructs with adipose tissue-derived microvascular fragments (ad-MVF) is an emerging pre-vascularisation strategy. Ad-MVF rapidly reassemble into new microvascular networks after in vivo implantation. Herein it was analysed whether this process was improved by erythropoietin (EPO). Ad-MVF were isolated from green fluorescent protein (GFP)+ as well as wild-type C57BL/6 mice and cultivated for 24 h in medium supplemented with EPO (20 IU/mL) or vehicle. Freshly isolated, non-cultivated ad-MVF served as controls. Protein expression, cell viability and proliferation of ad-MVF were assessed by proteome profiler array and fluorescence microscopy. GFP+ ad-MVF were seeded on collagen-glycosaminoglycan matrices, which were implanted into dorsal skinfold chambers of C57BL/6 mice, to analyse their vascularisation over 14 d by intravital fluorescence microscopy, histology and immunohistochemistry. Cultivation up-regulated the expression of pro- and anti-angiogenic factors within both vehicle- and EPO-treated ad-MVF when compared with non-cultivated controls. Moreover, EPO treatment suppressed cultivation-associated apoptosis and significantly increased the number of proliferating endothelial cells in ad-MVF when compared with vehicle-treated and non-cultivated ad-MVF. Accordingly, implanted matrices seeded with EPO-treated ad-MVF exhibited an improved vascularisation, as indicated by a significantly higher functional microvessel density. The matrices of the three groups contained a comparably large fraction of GFP+ microvessels originating from the ad-MVF, whereas the tissue surrounding the matrices seeded with EPO-treated ad-MVF exhibited a significantly increased microvessel density when compared with the other two groups. These findings indicated that EPO represents a promising cytokine to further boost the excellent vascularisation properties of ad-MVF in tissue-engineering applications.

Meningitis Vaccination, Knowledge, and Awareness Among YMSM in Chicago.

PubMed

Phillips, Gregory; Johnson, Amy K; Adames, Christian N; Mustanski, Brian

2018-01-01

Serogroup C invasive meningococcal disease (IMD) outbreaks in men who have sex with men (MSM) have been occurring with greater frequency in urban areas across the United States. An effective vaccine for IMD is available and is recommended for MSM in outbreak settings. Particular subgroups of MSM have been disproportionately represented in outbreaks, specifically young, Black, and HIV-positive MSM. As little is known about the knowledge, awareness, and vaccination status of young MSM, we sought to describe this and explore racial/ethnic differences. Data were collected from an established cohort study-RADAR-of 16- to 29-year-old MSM recruited through previous cohort studies and/or by being a partner or peer of a current study member. A total of 486 young MSM (YMSM) responded to 13 IMD-related questions. Approximately half of the sample correctly identified how IMD is spread and 58.6% accurately responded that vaccination was the best prevention method; however, more than 60% of participants felt they were at no risk of getting meningitis and only 49% self-reported vaccination. Additionally, White YMSM were significantly more likely to be vaccinated and to have accurate knowledge and risk perception of IMD compared with Black YMSM. Findings have important implications for disease control, outbreak management, and intervention development.

A Web-based searchable system to confirm magnetic resonance compatibility of implantable medical devices in Japan: a preliminary study.

PubMed

Fujiwara, Yasuhiro; Fujioka, Hitoshi; Watanabe, Tomoko; Sekiguchi, Maiko; Murakami, Ryuji

2017-09-01

Confirmation of the magnetic resonance (MR) compatibility of implanted medical devices (IMDs) is mandatory before conducting magnetic resonance imaging (MRI) examinations. In Japan, few such confirmation methods are in use, and they are time-consuming. This study aimed to develop a Web-based searchable MR safety information system to confirm IMD compatibility and to evaluate the usefulness of the system. First, MR safety information for intravascular stents and stent grafts sold in Japan was gathered by interviewing 20 manufacturers. These IMDs were categorized based on the descriptions available on medical package inserts as: "MR Safe," "MR Conditional," "MR Unsafe," "Unknown," and "No Medical Package Insert Available". An MR safety information database for implants was created based on previously proposed item lists. Finally, a Web-based searchable system was developed using this database. A questionnaire was given to health-care personnel in Japan to evaluate the usefulness of this system. Seventy-nine datasets were collected using information provided by 12 manufacturers and by investigating the medical packaging of the IMDs. Although the datasets must be updated by collecting data from other manufacturers, this system facilitates the easy and rapid acquisition of MR safety information for IMDs, thereby improving the safety of MRI examinations.

Risk of subsequent ischemic and hemorrhagic stroke in patients hospitalized for immune-mediated diseases: a nationwide follow-up study from Sweden

PubMed Central

2012-01-01

Background Certain immune-mediated diseases (IMDs) have been associated with increased risk for cardiovascular disorders. The aim of the present study was to examine whether there is an association between 32 different IMDs and first hospitalization for ischemic or hemorrhagic stroke. Methods All individuals in Sweden hospitalized with a main diagnosis of IMD (without previous or coexisting stroke), between January 1, 1987 and December 31, 2008 (n = 216,291), were followed for first hospitalization for ischemic or hemorrhagic stroke. The reference population was the total population of Sweden. Adjusted standardized incidence ratios (SIRs) for ischemic and hemorrhagic stroke were calculated. Results Totally 20 and 15 of the 32 IMDs studied, respectively, were associated with an increased risk of ischemic and hemorrhagic stroke during the follow-up. The overall risks of ischemic and hemorrhagic stroke during the first year after hospitalization for IMD were 2.02 (95% CI 1.90–2.14) and 2.65 (95% CI 2.27–3.08), respectively. The overall risk of ischemic or hemorrhagic stroke decreased over time, to 1.50 (95% CI 1.46–1.55) and 1.83 (95% CI 1.69–1.98), respectively, after 1–5 years, and 1.29 (95% CI 1.23–1.35) and 1.47 (95% CI 1.31–1.65), respectively, after 10+ years. The risk of hemorrhagic stroke was ≥2 during the first year after hospitalization for seven IMDs: ankylosing spondylitis (SIR = 8.11), immune thrombocytopenic purpura (SIR = 8.60), polymyalgia rheumatica (SIR = 2.06), psoriasis (SIR = 2.88), rheumatoid arthritis (SIR = 3.27), systemic lupus erythematosus (SIR = 8.65), and Wegener´s granulomatosis (SIR = 5.83). The risk of ischemic stroke was ≥2 during the first year after hospitalization for twelve IMDs: Addison’s disease (SIR = 2.71), Crohn´s disease (SIR = 2.15), Grave´s disease (SIR = 2.15), Hashimoto´s thyroiditis (SIR = 2.99), immune thrombocytopenic purpura (SIR = 2.35), multiple sclerosis (SIR = 3.05), polymyositis/dermatomyositis (SIR = 3.46), rheumatic fever (SIR = 3.91), rheumatoid arthritis (SIR = 2.08), Sjögren’s syndrome (SIR = 2.57), systemic lupus erythematosus (SIR = 2.21), and ulcerative colitis (SIR = 2.15). Conclusions Hospitalization for many IMDs is associated with increased risk of ischemic or hemorrhagic stroke. The findings suggest that several IMDs are linked to cerebrovascular disease. PMID:22708578

Arachidonic acid and prostaglandin endoperoxide metabolism in isolated rabbit and coronary microvessels and isolated and cultivated coronary microvessel endothelial cells.

PubMed Central

Gerritsen, M E; Cheli, C D

1983-01-01

Isolated microvessels and isolated and cultured microvessel endothelial cells were prepared from rabbit cardiac muscle. Pathways of arachidonic acid metabolism were determined by measurement of exogenous substrate utilization [( 1-14C]arachidonic acid incorporation and release from intact tissue and cells; [1-14C]prostaglandin H2 (PGH2) metabolism by broken cell preparations) and by quantification of endogenous products (immunoreactive 6-keto-prostaglandin F1 alpha (PGF1 alpha) and prostaglandin E (PGE) release) by selective radioimmunoassay. Rabbit coronary microvessels and derived microvascular endothelial cells (RCME cells) synthesized two major products of the cyclooxygenase pathway: 6-keto-PGF1 alpha (hydrolytic product of prostaglandin I2) and PGE2. A reduced glutathione requiring PGH-E isomerase was demonstrated in coronary microvessels and RCME cells, but not in rabbit circumflex coronary artery or aorta. In addition, a minor amount of a compound exhibiting similar characteristics to 6-keto-PGE1 was found to be produced by microvessels and RCME cells. Measurement of endogenously released prostaglandins indicated that under basal and stimulated conditions, PGE release exceeded that of 6-keto-PGF1 alpha. Microvessels and microvessel endothelial cells derived from cardiac muscle of rabbit exhibit pathways of arachidonate metabolism that are different from those of many large blood vessels and derived endothelial cells. Images PMID:6415116

SH3-domain binding protein 1 in the tumor microenvironment promotes hepatocellular carcinoma metastasis through WAVE2 pathway

PubMed Central

Tao, Yiming; Hu, Kuan; Tan, Fengbo; Zhang, Sai; Zhou, Ming; Luo, Jia; Wang, Zhiming

2016-01-01

SH3-domain binding protein-1 (SH3BP1) specifically inactivating Rac1 and its target WAVE2 is required for cell motility. The present study shows SH3BP1 expression patterns in human HCC tissues and cell lines were examined. The regulation of SH3BP1 on HCC cell migration and invasion related to Rac1-WAVE2 signaling was characterized using in vitro and in vivo models. SH3BP1 overexpressed in HCC tissues and highly metastatic HCC cells was significantly associated vascular invasion (VI). SH3BP1 promoted VEGF secretion via Rac1-WAVE2 signaling, so as to exert an augmentation on cell invasion and microvessel formation. In three study cohorts with a total of 516 HCC patients, high SH3BP1 expression combined with high microvessel density (MVD) was confirmed as a powerful independent predictor of HCC prognosis in both training cohorts and validation cohort. Being an important angiogenic factor of HCC through Rac1-WAVE2 signaling, SH3BP1 promotes tumor invasion and microvessel formation contributing to HCC metastasis and recurrence. SH3BP1 is a novel WAVE2 regulator, a prognostic marker and a potential therapeutic target of HCC. PMID:26933917

SH3-domain binding protein 1 in the tumor microenvironment promotes hepatocellular carcinoma metastasis through WAVE2 pathway.

PubMed

Tao, Yiming; Hu, Kuan; Tan, Fengbo; Zhang, Sai; Zhou, Ming; Luo, Jia; Wang, Zhiming

2016-04-05

SH3-domain binding protein-1 (SH3BP1) specifically inactivating Rac1 and its target WAVE2 is required for cell motility. The present study shows SH3BP1 expression patterns in human HCC tissues and cell lines were examined. The regulation of SH3BP1 on HCC cell migration and invasion related to Rac1-WAVE2 signaling was characterized using in vitro and in vivo models. SH3BP1 overexpressed in HCC tissues and highly metastatic HCC cells was significantly associated vascular invasion (VI). SH3BP1 promoted VEGF secretion via Rac1-WAVE2 signaling, so as to exert an augmentation on cell invasion and microvessel formation. In three study cohorts with a total of 516 HCC patients, high SH3BP1 expression combined with high microvessel density (MVD) was confirmed as a powerful independent predictor of HCC prognosis in both training cohorts and validation cohort. Being an important angiogenic factor of HCC through Rac1-WAVE2 signaling, SH3BP1 promotes tumor invasion and microvessel formation contributing to HCC metastasis and recurrence. SH3BP1 is a novel WAVE2 regulator, a prognostic marker and a potential therapeutic target of HCC.

Infection-derived lipids elicit a novel immune deficiency circuitry in arthropods

USDA-ARS?s Scientific Manuscript database

The insect Immune Deficiency (IMD) pathway resembles the tumor necrosis factor receptor network in mammals and senses diaminopimelic-type peptidoglycans present in Gram-negative bacteria. Whether unidentified chemical moieties elicit the IMD signaling cascade remains unknown. Here, we disclose thoug...

Predictive tool for estimating the potential effect of water fluoridation on dental caries.

PubMed

Foster, G R K; Downer, M C; Lunt, M; Aggarwal, V; Tickle, M

2009-03-01

To provide a tool for public health planners to estimate the potential improvement in dental caries in children that might be expected in a region if its water supply were to be fluoridated. Recent BASCD (British Association for the Study of Community Dentistry) dental epidemiological data for caries in 5- and 11-year-old children in English primary care trusts in fluoridated and non-fluoridated areas were analysed to estimate absolute and relative improvement in dmft/DMFT and caries-free measures observed in England. Where data were sufficient for testing significance this analysis included the effect of different levels of deprivation. A table of observed improvements was produced, together with an example of how that table can be used as a tool for estimating the expected improvement in caries in any specific region of England. Observed absolute improvements and 95% confidence intervals were: for 5-year-olds reduction in mean dmft 0.56 (0.38, 0.74) for IMD 12, 0.73 (0.60, 0.85) for IMD 20, and 0.94 (0.76, 1.12) for IMD 30, with 12% (9%, 14%) more children free of caries; for 11-year-olds reduction in mean DMFT 0.12 (0.04, 0.20) for IMD 12, 0.19 (0.13, 0.26) for IMD 20, 0.29 (0.18, 0.40) and for IMD 30, with 8% (5%, 11%) more children free from caries. The BASCD data taken together with a deprivation measure are capable of yielding an age-specific, 'intention to treat' model of water fluoridation that can be used to estimate the potential effect on caries levels of a notional new fluoridation scheme in an English region.

Need for Optimisation of Immunisation Strategies Targeting Invasive Meningococcal Disease in the Netherlands.

PubMed

Bousema, Josefien Cornelie Minthe; Ruitenberg, Joost

2015-09-13

Invasive meningococcal disease (IMD) is a severe bacterial infectious disease with high mortality and morbidity rates worldwide. In recent years, industrialised countries have implemented vaccines targeting IMD in their National Immunisation Programmes (NIPs). In 2002, the Netherlands successfully implemented a single dose of meningococcal serogroup C conjugate vaccine at the age of 14 months and performed a single catch-up for children ≤18 years of age. Since then the disease disappeared in vaccinated individuals. Furthermore, herd protection was induced, leading to a significant IMD reduction in non-vaccinated individuals. However, previous studies revealed that the current programmatic immunisation strategy was insufficient to protect the population in the foreseeable future. In addition, vaccines that provide protection against additional serogroups are now available. This paper describes to what extent the current strategy to prevent IMD in the Netherlands is still sufficient, taking into account the burden of disease and the latest scientific knowledge related to IMD and its prevention. In particular, primary MenC immunisation seems not to provide long-term protection, indicating a risk for possible recurrence of the disease. This can be combatted by implementing a MenC or MenACWY adolescent booster vaccine. Additional health benefits can be achieved by replacing the primary MenC by a MenACWY vaccine. By implementation of a recently licensed MenB vaccine for infants in the NIP, the greatest burden of disease would be targeted. This paper shows that optimisation of the immunisation strategy targeting IMD in the Netherlands should be considered and contributes to create awareness concerning prevention optimisation in other countries. © 2015 by Kerman University of Medical Sciences.

Phenyl-imidazolo-cytidine analogues: structure-photophysical activity relationship and ability to detect single DNA mismatch.

PubMed

Kovaliov, Marina; Weitman, Michal; Major, Dan Thomas; Fischer, Bilha

2014-08-01

To expand the arsenal of fluorescent cytidine analogues for the detection of genetic material, we synthesized para-substituted phenyl-imidazolo-cytidine ((Ph)ImC) analogues 5a-g and established a relationship between their structure and fluorescence properties. These analogues were more emissive than cytidine (λem 398-420 nm, Φ 0.009-0.687), and excellent correlation was found between Φ of 5a-g and σp(-) of the substituent on the phenyl-imidazolo moiety (R(2) = 0.94). Calculations suggested that the dominant tautomer of (Ph)ImC in methanol solution is identical to that of cytidine. DFT calculations of the stable tautomer of selected (Ph)ImC analogues suggested a relationship between the HOMO-LUMO gap and Φ and explained the loss of fluorescence in the nitro analogue. Incorporation of the CF3-(Ph)ImdC analogue into a DNA probe resulted in 6-fold fluorescence quenching of the former. A 17-fold reduction of fluorescence was observed for the G-matched duplex vs ODN(CF3-(Ph)ImdC), while for A-mismatched duplex, only a 2-fold decrease was observed. Furthermore, since the quantum yield of ODN(CF3-(Ph)ImdC):ODN(G) was reduced 17-fold vs that of a single strand, whereas that of ODN(CF3-(Ph)ImdC):ORN(G) was reduced only 3.8-fold, ODN(CF3-(Ph)ImdC) appears to be a DNA-selective probe. We conclude that the ODN(CF3-(Ph)ImdC) probe, exhibiting emission sensitivity upon single nucleotide replacement, may be potentially useful for DNA single nucleotide polymorphism (SNP) typing.

Evaluation of leaching potential of three systemic neonicotinoid insecticides in vineyard soil

NASA Astrophysics Data System (ADS)

Kurwadkar, Sudarshan; Wheat, Remington; McGahan, Donald G.; Mitchell, Forrest

2014-12-01

Dinotefuran (DNT), imidacloprid (IMD), and thiamethoxam (THM) are commonly used neonicotinoid insecticides in a variety of agriculture operations. Although these insecticides help growers control pest infestation, the residual environmental occurrence of insecticides may cause unintended adverse ecological consequences to non-target species. In this study, the leaching behavior of DNT, IMD, and THM was investigated in soils collected from an active AgriLife Research Extension Center (AREC) vineyard. A series of column experiments were conducted to evaluate the leaching potential of insecticides under two experimental scenarios: a) individual pulse mode, and b) mixed pulse mode. In both scenarios, the breakthrough pattern of the insecticides in the mostly acidic to neutral vineyard soil clearly demonstrates medium to high leachability. Of the three insecticides studied for leaching, DNT has exhibited high leaching potential and exited the column with fewer pore volumes, whereas IMD was retained for longer, indicating lower leachability. Relative differences in leaching behavior of neonicotinoids could be attributed to their solubility with the leaching pattern IMD < THM < DNT showing strong correlation with increasing aqueous solubility 610 mg/L < 4100 mg/L < 39,830 mg/L. Triplicate column study experiments were conducted to evaluate the consistency of the breakthrough pattern of these insecticides. The repeatability of the breakthrough curves shows that both DNT and IMD are reproducible between runs, whereas, THM shows some inconsistency. Leaching behavior of neonicotinoid insecticides based on the leachability indices such as groundwater ubiquity score, relative leaching potential, and partitioning between different environmental matrices through a fugacity-based equilibrium criterion model clearly indicates that DNT may pose a greater threat to aquatic resources compared to IMD and THM.

Childhood disadvantage and emergency admission rates for common presentations in London: an exploratory analysis.

PubMed

Kyle, Richard G; Kukanova, Marina; Campbell, Malcolm; Wolfe, Ingrid; Powell, Peter; Callery, Peter

2011-03-01

To determine whether emergency hospital admission rates (EAR) for common paediatric conditions in Greater London are associated with measures of child well-being and deprivation. Retrospective analysis of hospital episode statistics and secondary analysis of the Index of Multiple Deprivation (IMD) 2007 and Local Index of Child Well-Being (CWI) 2009. 31 Greater London primary care trusts (PCTs). EAR in PCTs for breathing difficulty, feverish illness and/or diarrhoea. 24,481 children under 15 years of age were discharged following emergency admission for breathing difficulty, feverish illness and/or diarrhoea during 2007/2008. The EAR for breathing difficulty was associated with the IMD (Spearman's rho 0.59, p<0.001) and IMD indicators of: overcrowding (Spearman's rho 0.62, p<0.001), houses in poor condition (Spearman's rho 0.55, p=0.001), air quality (Spearman's rho 0.53, p=0.002), homelessness (Spearman's rho 0.44, p=0.013), and domains of the CWI: housing (Spearman's rho 0.64, p<0.001), children in need (Spearman's rho 0.62, p<0.001), material (Spearman's rho 0.58, p=0.001) and environment (Spearman's rho 0.53, p=0.002). There were no statistically significant relationships between the EAR of children admitted for feverish illness and diarrhoea or aged under 1 year for any condition, and the IMD, either IMD indicators or CWI domains. Housing and environmental factors are associated with children's demand for hospital admission for breathing difficulty. Some associations are stronger with the CWI than the IMD. The CWI has potential to identify priority PCTs for housing and environment interventions that could have specific public health benefits for respiratory conditions.

Relations of Digital Vascular Function, Cardiovascular Risk Factors, and Arterial Stiffness: The Brazilian Longitudinal Study of Adult Health (ELSA‐Brasil) Cohort Study

PubMed Central

Brant, Luisa C. C.; Hamburg, Naomi M.; Barreto, Sandhi M.; Benjamin, Emelia J.; Ribeiro, Antonio L. P.

2014-01-01

Background Vascular dysfunction is an early expression of atherosclerosis and predicts cardiovascular (CV) events. Peripheral arterial tonometry (PAT) evaluates basal pulse amplitude (BPA), endothelial function (PAT ratio), and wave reflection (PAT‐AIx) in the digital microvessels. In Brazilian adults, we investigated the correlations of PAT responses to CV risk factors and to carotid‐femoral pulse wave velocity (PWV), a measure of arterial stiffness. Methods and Results In a cross‐sectional study, 1535 participants of the ELSA‐Brasil cohort underwent PAT testing (52±9 years; 44% women). In multivariable analyses, more‐impaired BPA and PAT ratios were associated with male sex, higher body mass index (BMI), and total cholesterol/high‐density lipoprotein. Higher age and triglycerides were related to higher BPA, whereas lower systolic blood pressure, hypertension (HTN) treatment, and prevalent CV disease (CVD) were associated with lower PAT ratio. PAT‐AIx correlated positively with female sex, advancing age, systolic and diastolic blood pressures, and smoking and inversely to heart rate, height, BMI, and prevalent CVD. Black race was associated with lower BPA, higher PAT ratio, and PAT‐AIx. Microvessel vasodilator function was not associated with PWV. Higher PAT‐AIx was modestly correlated to higher PWV and PAT ratio and inversely correlated to BPA. Conclusion Metabolic risk factors are related to impaired microvessel vasodilator function in Brazil. However, in contrast to studies from the United States, black race was not associated with an impaired microvessel vasodilator response, implying that vascular function may vary by race across populations. PAT‐AIx relates to HTN, may be a valid measure of wave reflection, and provides distinct information from arterial stiffness. PMID:25510401

Prenatal alcohol exposure affects vasculature development in the neonatal brain.

PubMed

Jégou, Sylvie; El Ghazi, Faiza; de Lendeu, Pamela Kwetieu; Marret, Stéphane; Laudenbach, Vincent; Uguen, Arnaud; Marcorelles, Pascale; Roy, Vincent; Laquerrière, Annie; Gonzalez, Bruno José

2012-12-01

In humans, antenatal alcohol exposure elicits various developmental disorders, in particular in the brain. Numerous studies focus on the deleterious effects of alcohol on neural cells. Although recent studies suggest that alcohol can affect angiogenesis in adults, the impact of prenatal alcohol exposure on brain microvasculature remains poorly understood. We used a mouse model to investigate effects of prenatal alcohol exposure on the cortical microvascular network in vivo and ex vivo and the action of alcohol, glutamate, and vascular endothelial growth factor A (VEGF) on activity, plasticity, and survival of microvessels. We used quantitative reverse transcriptase polymerase chain reaction, Western blot, immunohistochemistry, calcimetry, and videomicroscopy. We characterized the effect of prenatal alcohol exposure on the cortical microvascular network in human controls and fetal alcohol syndrome (FAS)/partial FAS (pFAS) patients at different developmental stages. In mice, prenatal alcohol exposure induced a reduction of cortical vascular density, loss of the radial orientation of microvessels, and altered expression of VEGF receptors. Time-lapse experiments performed on brain slices revealed that ethanol inhibited glutamate-induced calcium mobilization in endothelial cells, affected plasticity, and promoted death of microvessels. These effects were prevented by VEGF. In humans, we evidenced a stage-dependent alteration of the vascular network in the cortices of fetuses with pFAS/FAS. Whereas no modification was observed from gestational week 20 (WG20) to WG22, the radial organization of cortical microvessels was clearly altered in pFAS/FAS patients from WG30 to WG38. Prenatal alcohol exposure affects cortical angiogenesis both in mice and in pFAS/FAS patients, suggesting that vascular defects contribute to alcohol-induced brain abnormalities. Copyright © 2012 American Neurological Association.

Implantable Medical Device Website Efficacy in Informing Consumers Weighing Benefits/Risks of Health Care Options.

PubMed

Wagner, Teresa; Lindstadt, Calandra; Jeon, Yongwoog; Mackert, Michael

2016-01-01

As more individuals turn to the Internet for health-related information and technology increases the availability and use of implantable medical devices (IMDs), the websites marketing these devices will increase. Healthy People 2020 mandates increased understandability and usability of health-related websites. This project used social cognitive theory (SCT) and health literacy constructs from the Institute of Medicine and National Institutes of Health to analyze eight IMD websites. Despite current recommendations, none of the websites considered for this study offered content of an appropriate reading level in conjunction with the United States average of eighth grade, and 75% of the sites failed to satisfy more than one health literacy construct. Most of the websites lacked many of the SCT constructs. More attention is needed to improve the usability of these and future IMD websites to simultaneously meet the goal of marketing IMDs and the Healthy People 2020 goals to educate patients and promote public health.

EASApprox® skin-stretching system: A secure and effective method to achieve wound closure.

PubMed

Song, Mingzhi; Zhang, Zhen; Liu, Tao; Liu, Song; Li, Gang; Liu, Zhaochang; Huang, Jingyang; Chen, Song; Li, Linan; Guo, Li; Qiu, Yang; Wan, Jiajia; Liu, Yuejian; Wu, Tao; Wang, Xiaoyong; Lu, Ming; Wang, Shouyu

2017-07-01

Large skin defects are commonly observed in the clinic and have attracted much attention recently. Therefore, finding an effective solution for large skin defects is a global problem. The objective of the present study was to assess the effectiveness of the EASApprox ® skin-stretching system for closing large skin defects. Skin defects (5×5 cm) were created on the forearms of 9 Bama miniature pigs, which were randomly divided into the following three groups: Direct suture, the new EASApprox ® skin-stretching device and Kirschner wires. Microcirculation was assessed before surgery and after wound closure. Following the different treatments, the defects were sutured, and wound healing was assessed based on a clinical score. Furthermore, microscopic and ultramicroscopic structures were evaluated, including collagen, elastic fibers and the microvessel density. Significant differences in the clinical score and microvessel density were observed among the groups. Additionally, the mean length obtained for elastic fibers was larger than that obtained for the other two groups. Finally, the new EASApprox ® skin-stretching device resulted in successful wound management and with only minor side effects on skin histology and microcirculation. Therefore, this method has the potential to be used for healing large skin defects.

Histopathological vascular investigation of the peritumoral brain zone of glioblastomas.

PubMed

Tamura, Ryota; Ohara, Kentaro; Sasaki, Hikaru; Morimoto, Yukina; Yoshida, Kazunari; Toda, Masahiro

2018-01-01

To date, no histopathological vascular investigation focusing on peritumoral brain zone (PBZ) has been reported for glioblastoma. We analyzed 10 newly diagnosed cases of glioblastomas. For these PBZs, histopathological investigation was performed by hematoxylin-eosin (H&E) staining and immunohistochemistry was analyzed for CD31, CD34, Factor VIII, VEGF, VEGFR-1/2, Ki67, p53 and nestin. Although it was difficult to identify PBZ by H&E, Ki67 and p53 staining, there were apparent differences in nestin staining among PBZ, tumor core (TC), and normal zone (NZ). Therefore, in this study, we divided PBZ from TC and NZ by nestin staining. Differences in histological features, microvessel density, expression of VEGF and its receptors were assessed for PBZ, TC and NZ. The microvessel density, as determined by counting CD31, CD34 and VEGF receptors, and VEGF-A expression were lower in PBZ than TC. The expression patterns for CD31, CD34 and VEGF receptors in vessels show dissociation in PBZ. In addition, the vascular characteristics of the PBZ may correlate with findings of radiographic imaging. We provide the first clinicopathological evidence that PBZ exhibits unique angiogenic characteristics. These in situ observations will help to elucidate the mechanisms of tumor recurrence.

IFATS Collection: Adipose-Derived Stromal Cells Improve the Foreign Body Response

PubMed Central

Prichard, Heather L.; Reichert, William; Klitzman, Bruce

2015-01-01

Many implanted devices fail due to the formation of an avascular capsule surrounding the device. Additionally, fat has long been known to promote healing and vascularization. The goals of this study were to identify potential mechanisms of the provascular actions of adipose-derived stromal cells (ASCs) and to improve implant biocompatibility. First, adult ASCs and fibroblasts from rats were attached to polyurethane and polystyrene in vitro and their cytokine secretion profile was analyzed. Secretion of vascular endothelial growth factor (VEGF) from ASCs was 10 –70 times higher than fibroblasts after 3 and 6 days. Next, polyurethane, bare and with cellular coatings, was implanted subcutaneously in rats. The fibrous capsule surrounding bare polyurethane implants was 17%–32% thicker and the amount of collagen was 27% greater than the capsule surrounding ASC-coated implants. Finally, the microvessel density adjacent to ASC-coated polyurethane was approximately 50%–80% higher than bare polyurethane. In summary, ASCs attached to polyurethane have a dramatically increased VEGF production compared with fibroblasts in vitro, and these cells also produce an increased microvessel density in the surrounding tissue when implanted subcutaneously in rats. PMID:18436858

National Centers for Environmental Prediction

Science.gov Websites

Statistics Observational Data Processing Data Assimilation Monsoon Desk Model Transition Seminars Seminar Installation at IMD July, 2011 - IMD in New Delhi, India The Hurricane Weather Research and Forecasting (HWRF ) 5830 University Research Court College Park, MD 20740 Page Author: EMC Webmaster Page generated:Sunday

Climate Verification Using Running Mann Whitney Z Statistics

USDA-ARS?s Scientific Manuscript database

A robust method previously used to detect observed intra- to multi-decadal (IMD) climate regimes was adapted to test whether climate models could reproduce IMD variations in U.S. surface temperatures during 1919-2008. This procedure, called the running Mann Whitney Z (MWZ) method, samples data ranki...

[Invasive meningococcal disease in the Czech Republic - analysis of the epidemiological situation and vaccination strategy recommendations].

PubMed

Křížová, Pavla; Vacková, Zuzana; Musílek, Martin; Kozáková, Jana

2013-12-01

Analysis of invasive meningococcal disease (IMD) surveillance data including molecular epidemio-logy data. Vaccination strategy recommendations based on the current epidemiological situation of IMD in the Czech Republic and availability of meningococcal vaccines. IMD surveillance data are compiled by the National Reference Laboratory for Meningococcal Disease (NRL) from routinely reported data and NRL data after clearing out duplicate data. Neisseria meningitidis (N.m.) isolates referred to the NRL are confirmed and characterized in detail according to internationally validated methods. The current epidemiological situation of IMD is relatively favourable - the incidence rates have been below 1/100,000 population for several years, but show a slightly upward trend over more than 40-year period (1970-2012). A return to the typical prevalence of serogroup B accounting for up to 75% of cases has recently been shown. In this context, the upward trend in IMD caused by serogroup Y associated with a high case fatality rate in the Czech Republic cannot be overseen or even underestimated. The hypervirulent clonal complex cc11 characteristic of N.m.C:2a:P1.2,5 prevailed in this country between 1993 and 2004, but decreased in the following years and currently, hypervirulent clonal complexes characteristic of N.m.B (cc18, cc32, cc41/44, and cc269) are the most common in the Czech Republic. The average overall case fatality rate in the Czech Republic is 10%, but varies between causative serogroups: the highest case fatality rate has been caused by serogroup Y (16.7% ), followed by serogroup C (12.3%), and serogroup W135 (11.7%), while serogroup B only accounts for a case fatality rate of 7.8%. In the age group under one year, the incidence of IMD caused by serogroup B remains three to five times as high as in the age groups 1-4 years and 15-19 years throughout the surveillance period. The highest numbers of IMD cases caused by serogroup B have been reported in 3-7-month-olds. Based on the IMD surveillance data from the Czech Republic, the NRL recommends a vaccination strategy to provide an adequate protection to individuals. To induce an immune response as wide as possible, the tetravalent meningococcal conjugate vaccine A,C,Y,W135 in combination with the newly registered MenB vaccine designed by reverse vaccinology should be given. To maintain immunity, subsequent booster doses are required at intervals depending on the primary vaccination age.

Low-frequency ultrasound-mediated microvessel disruption combined with docetaxel to treat prostate carcinoma xenografts in nude mice: A novel type of chemoembolization

PubMed Central

Yang, Yu; Bai, Wenkun; Chen, Yini; Nan, Shuliang; Lin, Yanduan; Ying, Tao; Hu, Bing

2016-01-01

The aim of the present study was to investigate whether low-frequency ultrasound (US)-mediated microvessel disruption combined with docetaxel (DTX) can be used as a novel type of chemoembolization. Mice were assigned to four groups: i) The USMB group, treated with low-frequency US combined with microbubbles (USMB); ii) the DTX group, treated with DTX; iii) the USMB + DTX group, treated with combined therapy; and iv) the control group, which was untreated. Immediately after the first treatment, the average peak intensity (API) on contrast-enhanced US was calculated, and tumors were excised for hematoxylin and eosin (HE) staining. At 2 weeks post-treatment, the tumor volumes and wet weights were calculated, and tumors were excised for immunohistochemistry to calculate apoptotic index (AI), proliferative index (PI) and microvessel density (MVD) values. Immediately after the first treatment, in the DTX and control groups, the tumors demonstrated abundant perfusion enhancement, while in the USMB + DTX and USMB groups, blood perfusion of the tumors was interrupted. Compared with that of the control group, the API was significantly lower in the USMB + DTX USMB groups (all P<0.001). HE staining showed that tumor microvasculature was disrupted into flaky hematomas and severely dilated microvessels in the USMB + DTX and USMB groups. In the DTX and control groups, there was no distinct evidence of the disruption and dilation of blood microvessels. At the end of the treatment, the mean tumor inhibition ratio was 73.33, 46.67 and 33.33% for the USMB + DTX, DTX and USMB groups, respectively. The USMB + DTX group had the highest AI, and the lowest PI and MVD compared with the other groups, although the difference between the USMB + DTX and DTX groups with regard to PI and MVD was not significant (USMB + DTX vs. DTX group, P=0.345 and P=0.059, respectively). In conclusion, as a novel type of chemoembolization, USMB combined with DTX is more effective than USMB or DTX alone in inhibiting tumor growth via the enhancement of apoptosis, and the suppression of proliferation and angiogenesis. PMID:27446386

Bees prefer foods containing neonicotinoid pesticides

NASA Astrophysics Data System (ADS)

Kessler, Sébastien C.; Tiedeken, Erin Jo; Simcock, Kerry L.; Derveau, Sophie; Mitchell, Jessica; Softley, Samantha; Stout, Jane C.; Wright, Geraldine A.

2015-05-01

The impact of neonicotinoid insecticides on insect pollinators is highly controversial. Sublethal concentrations alter the behaviour of social bees and reduce survival of entire colonies. However, critics argue that the reported negative effects only arise from neonicotinoid concentrations that are greater than those found in the nectar and pollen of pesticide-treated plants. Furthermore, it has been suggested that bees could choose to forage on other available flowers and hence avoid or dilute exposure. Here, using a two-choice feeding assay, we show that the honeybee, Apis mellifera, and the buff-tailed bumblebee, Bombus terrestris, do not avoid nectar-relevant concentrations of three of the most commonly used neonicotinoids, imidacloprid (IMD), thiamethoxam (TMX), and clothianidin (CLO), in food. Moreover, bees of both species prefer to eat more of sucrose solutions laced with IMD or TMX than sucrose alone. Stimulation with IMD, TMX and CLO neither elicited spiking responses from gustatory neurons in the bees' mouthparts, nor inhibited the responses of sucrose-sensitive neurons. Our data indicate that bees cannot taste neonicotinoids and are not repelled by them. Instead, bees preferred solutions containing IMD or TMX, even though the consumption of these pesticides caused them to eat less food overall. This work shows that bees cannot control their exposure to neonicotinoids in food and implies that treating flowering crops with IMD and TMX presents a sizeable hazard to foraging bees.

Bees prefer foods containing neonicotinoid pesticides

PubMed Central

Simcock, Kerry L.; Derveau, Sophie; Mitchell, Jessica; Softley, Samantha; Stout, Jane C.; Wright, Geraldine A.

2015-01-01

The impact of neonicotinoid insecticides on insect pollinators is highly controversial. Sublethal concentrations alter the behaviour of social bees and reduce survival of entire colonies1-3. However, critics argue that the reported negative effects only arise from neonicotinoid concentrations that are greater than those found in the nectar and pollen of pesticide-treated plants4. Furthermore, it has been suggested that bees could choose to forage on other available flowers and hence avoid or dilute exposure4,5. Here, using a two-choice feeding assay, we show that the honeybee, Apis mellifera, and the buff-tailed bumblebee, Bombus terrestris, do not avoid nectar-relevant concentrations of three of the most commonly-used neonicotinoids, imidacloprid (IMD), thiamethoxam (TMX), and clothianidin (CLO) in food. Moreover, bees of both species prefer to eat more of sucrose solutions laced with IMD or TMX than sucrose alone. Stimulation with IMD, TMX, and CLO neither elicited spiking responses from gustatory neurons in the bees’ mouthparts nor inhibited the responses of sucrose-sensitive neurons. Our data indicate that bees cannot taste neonicotinoids and are not repelled by them. Instead, bees preferred solutions containing IMD or TMX even though the consumption of these pesticides caused them to eat less food overall. This work shows that bees cannot control their exposure to neonicotinoids in food and implies that treating flowering crops with IMD and TMX presents a significant hazard to foraging bees. PMID:25901684

EpiHosp: A web-based visualization tool enabling the exploratory analysis of complications of implantable medical devices from a nationwide hospital database.

PubMed

Ficheur, Grégoire; Ferreira Careira, Lionel; Beuscart, Régis; Chazard, Emmanuel

2015-01-01

Administrative data can be used for the surveillance of the outcomes of implantable medical devices (IMDs). The objective of this work is to build a web-based tool allowing for an exploratory analysis of time-dependent events that may occur after the implementation of an IMD. This tool should enable a pharmacoepidemiologist to explore on the fly the relationship between a given IMD and a potential outcome. This tool mine the French nationwide database of inpatient stays from 2008 to 2013. The data are preprocessed in order to optimize the queries. A web tool is developed in PHP, MySQL and Javascript. The user selects one or a group of IMD from a tree, and can filter the results using years and hospital names. Four result pages describe the selected inpatient stays: (1) temporal and demographic description, (2) a description of the geographical location of the hospital, (3) a description of the geographical place of residence of the patient and (4) a table showing the rehospitalization reasons by decreasing order of frequency. Then, the user can select one readmission reason and display dynamically the probability of readmission by mean of a Kaplan-Meier curve with confidence intervals. This tool enables to dynamically monitor the occurrence of time-dependent complications of IMD.

TLR and IMD signaling pathways from Caligus rogercresseyi (Crustacea: Copepoda): in silico gene expression and SNPs discovery.

PubMed

Valenzuela-Muñoz, V; Gallardo-Escárate, C

2014-02-01

The Toll and IMD signaling pathways represent one of the first lines of innate immune defense in invertebrates like Drosophila. However, for crustaceans like Caligus rogercresseyi, there is very little genomic information and, consequently, understanding of immune mechanisms. Massive sequencing data obtained for three developmental stages of C. rogercresseyi were used to evaluate in silico the expression patterns and presence of SNPs variants in genes involved in the Toll and IMD pathways. Through RNA-seq analysis, which used 20 contigs corresponding to relevant genes of the Toll and IMD pathways, an overexpression of genes linked to the Toll pathway, such as toll3 and Dorsal, were observed in the copepod stage. For the chalimus and adult stages, overexpression of genes in both pathways, such as Akirin and Tollip and IAP and Toll9, respectively, were observed. On the other hand, PCA statistical analysis inferred that in the chalimus and adult stages, the immune response mechanism was more developed, as evidenced by a relation between these two stages and the genes of both pathways. Moreover, 136 SNPs were identified for 20 contigs in genes of the Toll and IMD pathways. This study provides transcriptomic information about the immune response mechanisms of Caligus, thus providing a foundation for the development of new control strategies through blocking the innate immune response. Copyright © 2013 Elsevier Ltd. All rights reserved.

Designing of fluorescent and magnetic imprinted polymer for rapid, selective and sensitive detection of imidacloprid via activators regenerated by the electron transfer-atom transfer radical polymerization (ARGET-ATRP) technique

NASA Astrophysics Data System (ADS)

Kumar, Sunil; Karfa, Paramita; Madhuri, Rashmi; Sharma, Prashant K.

2018-05-01

In this work, we report on a dual-behavior electrochemical/optical sensor for sensitive determination of Imidacloprid by fluorescent dye (fluorescein, FL) and imprinted polymer modified europium doped superparamagnetic iron oxide nanoparticles (FL@SPIONs@MIP). The imidacloprid (IMD)-imprinted polymer was directly synthesized on the Eu-SPIONs surface via Activators regenerated by the electron transfer-atom transfer radical polymerization (ARGET-ATRP) technique. Preparation, characterization and application of the prepared FL@SPIONs@MIP were systematically investigated using scanning electron microscopy (SEM), X-ray diffraction (XRD), vibrating sample magnetometer (VSM), fluorescence spectroscopy and electrochemical techniques. The electrochemical experiments exhibited a remarkable selectivity of the prepared sensor towards IMD. Determination of IMD by the square wave stripping voltammetry method represented a wide linear range of 0.059-0.791 μg L-1 with a detection limit of 0.0125 μg L-1. In addition, the fluorescence method shows a linear range of 0.039-0.942 μg L-1 and LOD of 0.0108 μg L-1. The fluorescence property of prepared FL@SPIONs@MIP was used for rapid, on-spot but selective detection of IMD in real samples. The proposed electrode displayed excellent repeatability and long-term stability and was successfully applied for quantitative and trace level determination of IMD in several real samples.

Serogroup and Clonal Characterization of Czech Invasive Neisseria meningitidis Strains Isolated from 1971 to 2015

PubMed Central

Jandova, Zuzana; Musilek, Martin; Vackova, Zuzana; Kozakova, Jana; Krizova, Pavla

2016-01-01

Background This study presents antigenic and genetic characteristics of Neisseria meningitidis strains recovered from invasive meningococcal disease (IMD) in the Czech Republic in 1971–2015. Material and Methods A total of 1970 isolates from IMD, referred to the National Reference Laboratory for Meningococcal Infections in 1971–2015, were studied. All isolates were identified and characterized by conventional biochemical and serological tests. Most isolates (82.5%) were characterized by multilocus sequence typing method. Results In the study period 1971–2015, the leading serogroup was B (52.4%), most often assigned to clonal complexes cc32, cc41/44, cc18, and cc269. A significant percentage of strains were of serogroup C (41.4%), with high clonal homogeneity due to hyperinvasive complex cc11, which played an important role in IMD in the Czech Republic in the mid-1990s. Serogroup Y isolates, mostly assigned to cc23, and isolates of clonally homogeneous serogroup W have also been recovered more often over the last years. Conclusion The incidence of IMD and distribution of serogroups and clonal complexes of N. meningitidis in the Czech Republic varied over time, as can be seen from the long-term monitoring, including molecular surveillance data. Data from the conventional and molecular IMD surveillance are helpful in refining the antimeningococcal vaccination strategy in the Czech Republic. PMID:27936105

Bees prefer foods containing neonicotinoid pesticides.

PubMed

Kessler, Sébastien; Tiedeken, Erin Jo; Simcock, Kerry L; Derveau, Sophie; Mitchell, Jessica; Softley, Samantha; Stout, Jane C; Wright, Geraldine A

2015-05-07

The impact of neonicotinoid insecticides on insect pollinators is highly controversial. Sublethal concentrations alter the behaviour of social bees and reduce survival of entire colonies. However, critics argue that the reported negative effects only arise from neonicotinoid concentrations that are greater than those found in the nectar and pollen of pesticide-treated plants. Furthermore, it has been suggested that bees could choose to forage on other available flowers and hence avoid or dilute exposure. Here, using a two-choice feeding assay, we show that the honeybee, Apis mellifera, and the buff-tailed bumblebee, Bombus terrestris, do not avoid nectar-relevant concentrations of three of the most commonly used neonicotinoids, imidacloprid (IMD), thiamethoxam (TMX), and clothianidin (CLO), in food. Moreover, bees of both species prefer to eat more of sucrose solutions laced with IMD or TMX than sucrose alone. Stimulation with IMD, TMX and CLO neither elicited spiking responses from gustatory neurons in the bees' mouthparts, nor inhibited the responses of sucrose-sensitive neurons. Our data indicate that bees cannot taste neonicotinoids and are not repelled by them. Instead, bees preferred solutions containing IMD or TMX, even though the consumption of these pesticides caused them to eat less food overall. This work shows that bees cannot control their exposure to neonicotinoids in food and implies that treating flowering crops with IMD and TMX presents a sizeable hazard to foraging bees.

Noise Equalization for Ultrafast Plane Wave Microvessel Imaging.

PubMed

Song, Pengfei; Manduca, Armando; Trzasko, Joshua D; Chen, Shigao

2017-11-01

Ultrafast plane wave microvessel imaging significantly improves ultrasound Doppler sensitivity by increasing the number of Doppler ensembles that can be collected within a short period of time. The rich spatiotemporal plane wave data also enable more robust clutter filtering based on singular value decomposition. However, due to the lack of transmit focusing, plane wave microvessel imaging is very susceptible to noise. This paper was designed to: 1) study the relationship between ultrasound system noise (primarily time gain compensation induced) and microvessel blood flow signal and 2) propose an adaptive and computationally cost-effective noise equalization method that is independent of hardware or software imaging settings to improve microvessel image quality.

Letters: Noise Equalization for Ultrafast Plane Wave Microvessel Imaging

PubMed Central

Song, Pengfei; Manduca, Armando; Trzasko, Joshua D.

2017-01-01

Ultrafast plane wave microvessel imaging significantly improves ultrasound Doppler sensitivity by increasing the number of Doppler ensembles that can be collected within a short period of time. The rich spatiotemporal plane wave data also enables more robust clutter filtering based on singular value decomposition (SVD). However, due to the lack of transmit focusing, plane wave microvessel imaging is very susceptible to noise. This study was designed to: 1) study the relationship between ultrasound system noise (primarily time gain compensation-induced) and microvessel blood flow signal; 2) propose an adaptive and computationally cost-effective noise equalization method that is independent of hardware or software imaging settings to improve microvessel image quality. PMID:28880169

Downregulation of MicroRNA-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension.

PubMed

Potus, François; Ruffenach, Grégoire; Dahou, Abdellaziz; Thebault, Christophe; Breuils-Bonnet, Sandra; Tremblay, Ève; Nadeau, Valérie; Paradis, Renée; Graydon, Colin; Wong, Ryan; Johnson, Ian; Paulin, Roxane; Lajoie, Annie C; Perron, Jean; Charbonneau, Eric; Joubert, Philippe; Pibarot, Philippe; Michelakis, Evangelos D; Provencher, Steeve; Bonnet, Sébastien

2015-09-08

Right ventricular (RV) failure is the most important factor of both morbidity and mortality in pulmonary arterial hypertension (PAH). However, the underlying mechanisms resulting in the failed RV in PAH remain unknown. There is growing evidence that angiogenesis and microRNAs are involved in PAH-associated RV failure. We hypothesized that microRNA-126 (miR-126) downregulation decreases microvessel density and promotes the transition from a compensated to a decompensated RV in PAH. We studied RV free wall tissues from humans with normal RV (n=17), those with compensated RV hypertrophy (n=8), and patients with PAH with decompensated RV failure (n=14). Compared with RV tissues from patients with compensated RV hypertrophy, patients with decompensated RV failure had decreased miR-126 expression (quantitative reverse transcription-polymerase chain reaction; P<0.01) and capillary density (CD31(+) immunofluorescence; P<0.001), whereas left ventricular tissues were not affected. miR-126 downregulation was associated with increased Sprouty-related EVH1 domain-containing protein 1 (SPRED-1), leading to decreased activation of RAF (phosphorylated RAF/RAF) and mitogen-activated protein kinase (MAPK); (phosphorylated MAPK/MAPK), thus inhibiting the vascular endothelial growth factor pathway. In vitro, Matrigel assay showed that miR-126 upregulation increased angiogenesis of primary cultured endothelial cells from patients with decompensated RV failure. Furthermore, in vivo miR-126 upregulation (mimic intravenous injection) improved cardiac vascular density and function of monocrotaline-induced PAH animals. RV failure in PAH is associated with a specific molecular signature within the RV, contributing to a decrease in RV vascular density and promoting the progression to RV failure. More importantly, miR-126 upregulation in the RV improves microvessel density and RV function in experimental PAH. © 2015 American Heart Association, Inc.

Lymphangiogenesis and angiogenesis in oral cavity and lower lip squamous cell carcinoma.

PubMed

Alaeddini, Mojgan; Etemad-Moghadam, Shahroo

2016-01-01

Tumors of the lip and oral cavity differ in various aspects; therefore a clarification of the distinctions among these sites may help to better understand the biologic behavior of neoplasms occurring in these locations. Considering that angiogenesis and lymphangiogenesis are two major elements that can influence various aspects of tumor biology, we aimed to compare these factors between squamous cell carcinoma of the lower lip and oral cavity. A total of 84 primary squamous cell carcinomas including 45 oral and 39 lower lip tumors were selected and immunohistochemically stained with monoclonal antibody against D2-40 and CD105. Mean microvessel density was assessed in tumoral tissue, while lymphatic vessel density was calculated in both neoplastic tissue and invasion front. Data were statistically analyzed using t-test and p-values of <0.05 were considered significant. We found a mean microvessel density±standard deviation of 31.94±18.9 in oral cavity and 27.54±20.8 in lower lip squamous cell carcinomas, with no significant difference (p=0.32). Mean lymphatic vessel density±standard deviation was 13.05±8.2 and 16.57±10.79 in of oral cavity and lower lip neoplastic tissue, respectively. The corresponding values were 9.94±5.59 and 12.50±7.8 in the invasive front. Significant differences were not observed in either of the lymphatic vessel density variables between the two sites. According to our results, it seems that the search for additional factors other than those related to the vasculature should continue, to help clarify the differences in biologic behavior between lower lip and oral cavity squamous cell carcinomas. Copyright © 2015 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

Histomorphometric Analysis of Angiogenesis using CD31 Immunomarker and Mast Cell Density in Oral Premalignant and Malignant Lesions: A Pilot Study.

PubMed

Jyothsna, M; Rammanohar, M; Kumar, Kiran

2017-01-01

Mast cells have been implicated in promoting angiogenesis in malignant tumors of lung, oesophagus and breast, but there are few studies on Oral Squamous Cell Carcinomas (OSCC). Most oral squamous cell carcinomas arise from pre-existing precancerous lesions exhibiting epithelial dysplasia. The present pilot study attempts to compare Mast Cell Density (MCD), Microvessel Density (MVD), Microvessel Area (MVA) histomorphometrically between normal buccal mucosa, severe epithelial dysplasia and OSCC and to correlate the role of mast cells and angiogenesis in tumor progression. The retrospective study was conducted on eight cases of OSCC, eight cases of severe epithelial dysplasia and five cases of normal buccal mucosa. Immunohistochemical staining with anti CD-31, to demonstrate angiogenesis and toluidine blue staining for mast cells were employed. MVA, MVD and MCD were calculated using the measurement tools of the image analysis software and compared between the groups. One way ANOVA (Analysis of Variance) was used for comparing the parameter for multiple groups followed by Games Howell test. To assess the relationship between micro vessel density and mast cell density, Karl Pearson's correlation was used. MCD and MVD increased with disease progression and were statistically higher in OSCC than in severe epithelial dysplasia and normal buccal mucosa (p<0.001). MVA increased from normal to severe dysplasia and decreased from dysplasia to OSCC, may be due to revascularization of tumor tissue. A positive correlation was observed between MCD and MVD in OSCC and dysplasia, though were not statistically significant. These findings suggest that mast cells may up regulate angiogenesis in OSCC. MCD and MVD may be used as indicators for disease progression.

Investigation on vascular cytotoxicity and extravascular transport of cationic polymer nanoparticles using perfusable 3D microvessel model.

PubMed

Ahn, Jungho; Cho, Chong-Su; Cho, Seong Woo; Kang, Joo H; Kim, Sung-Yon; Min, Dal-Hee; Song, Joon Myong; Park, Tae-Eun; Jeon, Noo Li

2018-05-25

Vascular networks are the first sites exposed to cationic polymer nanoparticles (NPs) administered intravenously, and thus function as a barrier for NPs reaching the target organ. While cationic polymer NPs have been intensively studied as non-viral delivery systems, their biological effects in human microvessels have been poorly investigated due to a lack of appropriate in vitro systems. Here, we employed a three-dimensional microvessel on a chip, which accurately models in vivo conditions. An open and perfused microvessel surrounded by pericytes was shown to reproduce the important features of living vasculature, including barrier function and biomarkers. Using this microvessel chip, we observed contraction of the microvascular lumen induced by perfused polyethylenimine (PEI)/DNA NPs. We demonstrated that the oxidative stress present when microvessels were exposed to PEI NPs led to rearrangement of microtubules resulting in microvessel contraction. Furthermore, the transcytotic behavior of PEI NPs was analyzed in the microvessel by monitoring the escape of PEI NPs from the microvascular lumen into the perivascular region, which was not possible in two-dimensional culture systems. With our new understanding of the different behaviors of cationic polymer NPs depending on their transcytotic route, we suggest that caveolae-mediated transcytosis is a powerful route for efficient extravascular transport. Microvascular networks are not only biological system constituting largest surface area in the body and but also first site exposed to nanoparticle in vivo. While cationic polymer NPs have been intensively studied as non-viral delivery systems, its biological effects in human microvessel have been poorly investigated due to lack of appropriate in vitro systems. Here, we microengineered an open and perfused 3D pericyte incorporated microvessel model which possesses same morphological characteristic of in vivo. Using the microengineered model, this study represents the first report of transcytotic behavior of NPs in 3D microvessel, and its effect on extravasation efficiency. Our study lays the groundwork for the integration of innovative technologies to examine blood vessel-nanoparticle interaction, which a critical but ill-defined phenomenon. Copyright © 2018. Published by Elsevier Ltd.

Pre-Service Teachers' Perceptions on Development of Their IMD Competencies through TPACK-Based Activities

ERIC Educational Resources Information Center

Tokmak, Hatice Sancar; Yelken, Tugba Yanpar; Konokman, Gamze Yavuz

2013-01-01

The current study investigated perceived development of pre-service teachers in their Instructional Material Design (IMD) competencies through the course "Instructional Technology and Material Design," which is based on a technological, pedagogical, and content knowledge (TPACK) framework. A total of 22 Elementary Education pre-service…

Peptidoglycan-Sensing Receptors Trigger the Formation of Functional Amyloids of the Adaptor Protein Imd to Initiate Drosophila NF-κB Signaling.

PubMed

Kleino, Anni; Ramia, Nancy F; Bozkurt, Gunes; Shen, Yanfang; Nailwal, Himani; Huang, Jing; Napetschnig, Johanna; Gangloff, Monique; Chan, Francis Ka-Ming; Wu, Hao; Li, Jixi; Silverman, Neal

2017-10-17

In the Drosophila immune response, bacterial derived diaminopimelic acid-type peptidoglycan binds the receptors PGRP-LC and PGRP-LE, which through interaction with the adaptor protein Imd leads to activation of the NF-κB homolog Relish and robust antimicrobial peptide gene expression. PGRP-LC, PGRP-LE, and Imd each contain a motif with some resemblance to the RIP Homotypic Interaction Motif (RHIM), a domain found in mammalian RIPK proteins forming functional amyloids during necroptosis. Here we found that despite sequence divergence, these Drosophila cryptic RHIMs formed amyloid fibrils in vitro and in cells. Amyloid formation was required for signaling downstream of Imd, and in contrast to the mammalian RHIMs, was not associated with cell death. Furthermore, amyloid formation constituted a regulatable step and could be inhibited by Pirk, an endogenous feedback regulator of this pathway. Thus, diverse sequence motifs are capable of forming amyloidal signaling platforms, and the formation of these platforms may present a regulatory point in multiple biological processes. Copyright © 2017 Elsevier Inc. All rights reserved.

Determination of imidocarb residues in bovine and ovine liver and milk by immunobiosensor.

PubMed

Traynor, I M; Thompson, C S; Armstrong, L; Fodey, T; Danaher, M; Jordan, K; Kennedy, D G; Crooks, S R H

2013-01-01

Imidocarb (IMD) is a veterinary drug that has been used for more than 30 years to treat and prevent parasitic diseases. Pharmacokinetic studies have shown that substantial levels of IMD residues are retained in the edible tissues and milk of cattle and sheep for up to 6 months after administration. This has led to concern regarding the potential adverse effects posed through human consumption of edible tissue or milk from treated animals if the recommended withdrawal periods for the drug are not properly implemented. While MRLs have been established by the European Union, it is important that analytical methods are available to monitor food samples for potentially violative levels of IMD residues. A qualitative biosensor-based immunoassay was developed to allow the detection of IMD at less than the European Union MRLs of 50 μg kg(-1) for milk and 2 mg kg(-1) for bovine and ovine liver. Validation of the developed methods provided a detection capability of <25 μg kg(-1) in milk and <0.75 mg kg(-1) in liver. A comparison study was undertaken, with IMD incurred milk and ovine liver samples analysed by the newly developed procedures and results compared with those obtained by LC-MS/MS. The newly developed screening method was applied to both incurred milk and liver samples. This faster, cheaper and reliable screening method has potential use in sample analysis to ensure compliance with legislative requirements.

Effects of Italian Mediterranean organic diet vs. low-protein diet in nephropathic patients according to MTHFR genotypes.

PubMed

Di Daniele, Nicola; Di Renzo, Laura; Noce, Annalisa; Iacopino, Leonardo; Ferraro, Pietro Manuel; Rizzo, Mariagiovanna; Sarlo, Francesca; Domino, Emidio; De Lorenzo, Antonino

2014-10-01

Several reports associate an Italian-style Mediterranean diet (IMD) with lower risk of cardiovascular disease and morbidity. The present study aimed to explore the effects of an Italian Mediterranean organic diet (IMOD) versus low-protein diet (LPD) in chronic kidney disease (CKD) patients, according to patients' carrier status for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism. A total of 40 male patients with CKD and stable renal function (Kidney Disease Outcomes Quality Initiative stages 2 and 3) were classified according to MTHFR polymorphism as carrier T(+) or non carrier T(-). At the time of enrolment (T0) patients' diet consisted of LPD; they were then administered IMD for 14 days (T1), thereupon IMOD for 14 days (T2). Patients underwent a complete medical history, body composition assessment and biochemical analysis. Baseline homocysteine levels were on average 8.24 mol/l higher (95 % confidence interval 6.47, 10.00) among T(+) than T(-) and the difference was statistically significant (p < 0.001). We found a significant interaction between MTHFR status and the effect of both the IMD and IMOD on homocysteine levels compared to LPD (p for interaction <0.001). Both the IMD and IMOD resulted in significant variations of anthropometric and laboratory measurements. IMD and IMOD diets could represent a viable alternative to LPD in CKD patients on conservative therapy. The effect of these diets seems to be influenced by MTHFR genotypes.

Stability, Visibility, and Histologic Analysis of a New Implanted Fiducial for Use as a Kilovoltage Radiographic or Radioactive Marker for Patient Positioning and Monitoring in Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Neustadter, David, E-mail: david.n@navotek.co; Tune, Michal; Zaretsky, Asaph

Purpose: To analyze the stability, visibility, and histology of a novel implantable soft-tissue marker (nonradioactive and radioactive) implanted in dog prostate and rabbit liver. Methods and Materials: A total of 34 nonradioactive and 35 radioactive markers were implanted in 1 dog and 16 rabbits. Stability was assessed by measuring intermarker distance (IMD) variation relative to IMDs at implantation. The IMDs were measured weekly for 4 months in the dog and biweekly for 2-4 weeks in the rabbits. Ultrasound and X-ray imaging were performed on all subjects. Computed tomography and MRI were performed on the dog. Histologic analysis was performed onmore » the rabbits after 2 or 4 months. Results: A total of 139 measurements had a mean ({+-} SD) absolute IMD variation of 1.1 {+-} 1.1 mm. These IMD variations are consistent with those reported in the literature as due to random organ deformation. The markers were visible, identifiable, and induced minimal or no image artifacts in all tested imaging modalities. Histologic analysis revealed that all pathologic changes were highly localized and not expected to be clinically significant. Conclusions: The markers were stable from the time of implantation. The markers were found to be compatible with all common medical imaging modalities. The markers caused no significant histologic effects. With respect to marker stability, visibility, and histologic analysis these implanted fiducials are appropriate for soft-tissue target positioning in radiotherapy.« less

Plasminogen activator inhibitor-1 is an independent prognostic factor of ovarian cancer and IMD-4482, a novel plasminogen activator inhibitor-1 inhibitor, inhibits ovarian cancer peritoneal dissemination.

PubMed

Nakatsuka, Erika; Sawada, Kenjiro; Nakamura, Koji; Yoshimura, Akihito; Kinose, Yasuto; Kodama, Michiko; Hashimoto, Kae; Mabuchi, Seiji; Makino, Hiroshi; Morii, Eiichi; Yamaguchi, Yoichi; Yanase, Takeshi; Itai, Akiko; Morishige, Ken-Ichirou; Kimura, Tadashi

2017-10-27

In the present study, the therapeutic potential of targeting plasminogen activator inhibitor-1 (PAI-1) in ovarian cancer was tested. Tissues samples from 154 cases of ovarian carcinoma were immunostained with anti-PAI-1 antibody, and the prognostic value was analyzed. Among the samples, 67% (104/154) showed strong PAI-1 expression; this was significantly associated with poor prognosis (progression-free survival: 20 vs. 31 months, P = 0.0033). In particular, among patients with stage II-IV serous adenocarcinoma, PAI-1 expression was an independent prognostic factor. The effect of a novel PAI-1 inhibitor, IMD-4482, on ovarian cancer cell lines was assessed and its therapeutic potential was examined using a xenograft mouse model of ovarian cancer. IMD-4482 inhibited in vitro cell adhesion to vitronectin in PAI-1-positive ovarian cancer cells, followed by the inhibition of extracellular signal-regulated kinase and focal adhesion kinase phosphorylation through dissociation of the PAI-urokinase receptor complex from integrin αVβ3. IMD-4482 caused G0/G1 cell arrest and inhibited the proliferation of PAI-1-positive ovarian cancer cells. In the xenograft model, IMD-4482 significantly inhibited peritoneal dissemination with the reduction of PAI-1 expression and the inhibition of focal adhesion kinase phosphorylation. Collectively, the functional inhibition of PAI-1 significantly inhibited ovarian cancer progression, and targeting PAI-1 may be a potential therapeutic strategy in ovarian cancer.

Plasminogen activator inhibitor-1 is an independent prognostic factor of ovarian cancer and IMD-4482, a novel plasminogen activator inhibitor-1 inhibitor, inhibits ovarian cancer peritoneal dissemination

PubMed Central

Nakatsuka, Erika; Sawada, Kenjiro; Nakamura, Koji; Yoshimura, Akihito; Kinose, Yasuto; Kodama, Michiko; Hashimoto, Kae; Mabuchi, Seiji; Makino, Hiroshi; Morii, Eiichi; Yamaguchi, Yoichi; Yanase, Takeshi; Itai, Akiko; Morishige, Ken-ichirou; Kimura, Tadashi

2017-01-01

In the present study, the therapeutic potential of targeting plasminogen activator inhibitor-1 (PAI-1) in ovarian cancer was tested. Tissues samples from 154 cases of ovarian carcinoma were immunostained with anti-PAI-1 antibody, and the prognostic value was analyzed. Among the samples, 67% (104/154) showed strong PAI-1 expression; this was significantly associated with poor prognosis (progression-free survival: 20 vs. 31 months, P = 0.0033). In particular, among patients with stage II-IV serous adenocarcinoma, PAI-1 expression was an independent prognostic factor. The effect of a novel PAI-1 inhibitor, IMD-4482, on ovarian cancer cell lines was assessed and its therapeutic potential was examined using a xenograft mouse model of ovarian cancer. IMD-4482 inhibited in vitro cell adhesion to vitronectin in PAI-1-positive ovarian cancer cells, followed by the inhibition of extracellular signal-regulated kinase and focal adhesion kinase phosphorylation through dissociation of the PAI-urokinase receptor complex from integrin αVβ3. IMD-4482 caused G0/G1 cell arrest and inhibited the proliferation of PAI-1-positive ovarian cancer cells. In the xenograft model, IMD-4482 significantly inhibited peritoneal dissemination with the reduction of PAI-1 expression and the inhibition of focal adhesion kinase phosphorylation. Collectively, the functional inhibition of PAI-1 significantly inhibited ovarian cancer progression, and targeting PAI-1 may be a potential therapeutic strategy in ovarian cancer. PMID:29163796

Background Paper for the update of meningococcal vaccination recommendations in Germany: use of the serogroup B vaccine in persons at increased risk for meningococcal disease.

PubMed

Hellenbrand, Wiebke; Koch, Judith; Harder, Thomas; Bogdan, Christian; Heininger, Ulrich; Tenenbaum, Tobias; Terhardt, Martin; Vogel, Ulrich; Wichmann, Ole; von Kries, Rüdiger

2015-11-01

In December 2013 Bexsero® became available in Germany for vaccination against serogroup B meningococci (MenB). In August 2015 the German Standing Committee on Vaccination (STIKO) endorsed a recommendation for use of this vaccine in persons at increased risk of invasive meningococcal disease (IMD). This background paper summarizes the evidence underlying the recommendation. Bexsero® is based on surface protein antigens expressed by about 80% of circulating serogroup B meningococci in Germany. The paper reviews available data on immunogenicity and safety of Bexsero® in healthy children and adolescents; data in persons with underlying illness and on the effectiveness in preventing clinical outcomes are thus far unavailable.STIKO recommends MenB vaccination for the following persons based on an individual risk assessment: (1) Persons with congenital or acquired immune deficiency or suppression. Among these, persons with terminal complement defects and properdin deficiency, including those under eculizumab therapy, are at highest risk with reported invasive meningococcal disease (IMD) incidences up 10,000-fold higher than in the general population. Persons with asplenia were estimated to have a ~ 20-30-fold increased risk of IMD, while the risk in individuals with other immune defects such as HIV infection or hypogammaglobulinaemia was estimated at no more than 5-10-fold higher than the background risk. (2) Laboratory staff with a risk of exposure to N. meningitidis aerosols, for whom an up to 271-fold increased risk for IMD has been reported. (3) Unvaccinated household (-like) contacts of a MenB IMD index case, who have a roughly 100-200-fold increased IMD risk in the year after the contact despite chemoprophylaxis. Because the risk is highest in the first 3 months and full protective immunity requires more than one dose (particularly in infants and toddlers), MenB vaccine should be administered as soon as possible following identification of the serogroup of the index case.

Invasive meningococcal disease in the Veneto region of Italy: a capture-recapture analysis for assessing the effectiveness of an integrated surveillance system.

PubMed

Baldovin, Tatjana; Lazzari, Roberta; Cocchio, Silvia; Furlan, Patrizia; Bertoncello, Chiara; Saia, Mario; Russo, Francesca; Baldo, Vincenzo

2017-05-02

Epidemiology of Neisseria meningitidis has been changing since the introduction of universal vaccination programmes against meningococcal serogroup C (MenC) and meningococcal serogroup B (MenB) has now become dominant. This study aimed to analyse the cases reported in institutional data recording systems to estimate the burden of invasive meningococcal diseases (IMDs) and assess the effectiveness of surveillance in Veneto region (Italy). Analysis was performed from 2007 to 2014 on data recorded in different systems: Mandatory Notification System, National Surveillance of Invasive Bacterial Diseases System and Laboratories Surveillance System (LSS), which were pooled into a combined surveillance system (CSS) and hospital discharge records (HDRs). A capture-recapture method was used and completeness of each source estimated. Number of cases with IMD by source of information and year, incidence of IMD by age group, case fatality rate (CFR) and distribution of meningococcal serogroups by year were also analysed. Combining the four data systems enabled the identification of 179 confirmed cases with IMD, achieving an overall sensitivity of 94.7% (95% CI: 90.8% to 98.8%), while it was 76.7% (95% CI: 73.6% to 80.1%) for CSS and 77.2% (95% CI: 74.1% to 80.6%) for HDRs. Typing of isolates was done in 80% of cases, and 95.2% of the typed cases were provided by LSS. Serogroup B was confirmed in 50.3% of cases. The estimated IMD notification rate (cases with IMD diagnosed and reported to the surveillance systems) was 0.48/100 000 population, and incidence peaked at 6.2/100 000 in children aged <1 year old (60.9% due to MenB), and increased slightly in the age group between 15 and 19 years (1.1/100 000). A CFR of 14% was recorded (8.7% in paediatric age). Quality of surveillance systems relies on case ascertainment based on serological characterisation of the circulating strains by microbiology laboratories. All available sources should be routinely combined to improve the epidemiology of IMD and the information used by public health departments to conduct timely preventive measures. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Evans blue dye-enhanced imaging of the brain microvessels using spectral focusing coherent anti-Stokes Raman scattering microscopy

PubMed Central

Lee, Bo-Ram; Joo, Kyung-Il; Choi, Eun Sook; Jahng, Junghoon; Kim, Hyunmin

2017-01-01

We performed dye-enhanced imaging of mouse brain microvessels using spectral focusing coherent anti-Stokes Raman scattering (SF-CARS) microscopy. The resonant signals from C-H stretching in forward CARS usually show high background intensity in tissues, which makes CARS imaging of microvessels difficult. In this study, epi-detection of back-scattered SF-CARS signals showed a negligible background, but the overall intensity of resonant CARS signals was too low to observe the network of brain microvessels. Therefore, Evans blue (EB) dye was used as contrasting agent to enhance the back-scattered SF-CARS signals. Breakdown of brain microvessels by inducing hemorrhage in a mouse was clearly visualized using backward SF-CARS signals, following intravenous injection of EB. The improved visualization of brain microvessels with EB enhanced the sensitivity of SF-CARS, detecting not only the blood vessels themselves but their integrity as well in the brain vasculature. PMID:29049299

The Challenges of Balancing Safety and Security in Implantable Medical Devices.

PubMed

Katzis, Konstantinos; Jones, Richard W; Despotou, George

2016-01-01

Modern Implantable Medical Devices (IMDs), implement capabilities that have contributed significantly to patient outcomes, as well as quality of life. The ever increasing connectivity of IMD's does raise security concerns though there are instances where implemented security measures might impact on patient safety. The paper discusses challenges of addressing both of these attributes in parallel.

Update on invasive meningococcal vaccination for Canadian children and youth.

PubMed

Robinson, Joan L

2018-02-01

Invasive meningococcal disease (IMD) is serious, often resulting in fulminant sepsis or meningitis. IMD in Canada is primarily attributable to serogroups B and C. There are routine programs for serogroup C vaccine at 12 months of age, with some jurisdictions routinely providing additional earlier doses. Adolescents routinely receive a booster dose of serogroup C vaccine or of a quadrivalent (serogroups A, C, W and Y) vaccine. Serogroup B vaccines are not recommended for routine use pending further data on the efficacy and duration of protection from the available vaccine. However, children at increased risk for IMD should start immunization for serogroups B and C as soon as possible, assuming that they are at least 2 months of age.

Rhamnazin, a novel inhibitor of VEGFR2 signaling with potent antiangiogenic activity and antitumor efficacy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Yao; Department of Endocrinology and Metabolism, The Third Hospital of Nanchang, Nanchang Key Laboratory of Diabetes, No.1 Qianjing Road, Xihu District, Nanchang 330009, Jiangxi Province; Cai, Wei

Anti-angiogenesis targeting vascular endothelial growth factor receptor 2 (VEGFR2) has emerged as an important tool for cancer therapy. The identification of new drugs from natural products has a long and successful history. In this study, we described a novel VEGFR2 inhibitor, rhamnazin, which inhibits tumor angiogenesis and growth. Rhamnazin significantly inhibited proliferation, migration and tube formation of human umbilical vascular endothelial cells (HUVECs) in vitro as well as inhibited sprouts formation of rat aorta ring. In addition, it inhibited vascular endothelial growth factor (VEGF)-induced phosphorylation of VEGFR2 and its downstream signaling regulator in HUVECs. Moreover, rhamnazin could directly inhibit proliferation ofmore » breast cancer cells MDA-MB-231 in vitro and in vivo. Oral administration of rhamnazin at a dose of 200 mg/kg/day could markedly inhibited human tumor xenograft growth and decreased microvessel densities (MVD) in tumor sections. Taken together, these preclinical evaluations suggest that rhamnazin inhibits angiogenesis and may be a promising anticancer drug candidate. - Highlights: • Rhamnazin inhibits the response of HUVECs to VEGF in vitro. • Rhamnazin inhibits VEGFR2 kinase activity and its downstream signaling. • Rhamnazin prevents the growth of MDA-MB-231 tumor and reduces micro-vessel density in vivo.« less

Immunohistochemical expression of vascular endothelial growth factor in canine oral squamous cell carcinomas.

PubMed

Martano, Manuela; Restucci, Brunella; Ceccarelli, Dora Maria; Lo Muzio, Lorenzo; Maiolino, Paola

2016-01-01

Angiogenesis is crucial for the growth and metastasis of malignant tumours, and various proangiogenic factors promote this process. One of these factors is vascular endothelial growth factor (VEGF), which appears to play a key role in tumour angiogenesis. The aim of the present study was to assess whether VEGF expression is associated with angiogenesis, disease progression and neoplastic proliferation in canine oral squamous cell carcinoma (OSCC) tissue. VEGF immunoreactivity was quantified by immunohistochemistry in 30 specimens, including normal oral mucosa and OSCC tissues graded as well, moderately or poorly differentiated. VEGF expression was correlated with tumour cell proliferation, as assessed using the proliferating cell nuclear antigen (PCNA) marker and microvessel density (data already published). The present results revealed that VEGF and PCNA expression increased significantly between normal oral tissue and neoplastic tissue, and between well and moderately/poorly differentiated tumours. In addition, VEGF expression was strongly correlated with PCNA expression and microvessel density. It was concluded that VEGF may promote angiogenesis through a paracrine pathway, stimulating endothelial cell proliferation and, similarly, may induce tumour cell proliferation through an autocrine pathway. The present results suggest that the evaluation of VEGF may be a useful additional criterion for estimating malignancy and growth potential in canine OSCCs.

Continuous representation of tumor microvessel density and detection of angiogenic hotspots in histological whole-slide images.

PubMed

Kather, Jakob Nikolas; Marx, Alexander; Reyes-Aldasoro, Constantino Carlos; Schad, Lothar R; Zöllner, Frank Gerrit; Weis, Cleo-Aron

2015-08-07

Blood vessels in solid tumors are not randomly distributed, but are clustered in angiogenic hotspots. Tumor microvessel density (MVD) within these hotspots correlates with patient survival and is widely used both in diagnostic routine and in clinical trials. Still, these hotspots are usually subjectively defined. There is no unbiased, continuous and explicit representation of tumor vessel distribution in histological whole slide images. This shortcoming distorts angiogenesis measurements and may account for ambiguous results in the literature. In the present study, we describe and evaluate a new method that eliminates this bias and makes angiogenesis quantification more objective and more efficient. Our approach involves automatic slide scanning, automatic image analysis and spatial statistical analysis. By comparing a continuous MVD function of the actual sample to random point patterns, we introduce an objective criterion for hotspot detection: An angiogenic hotspot is defined as a clustering of blood vessels that is very unlikely to occur randomly. We evaluate the proposed method in N=11 images of human colorectal carcinoma samples and compare the results to a blinded human observer. For the first time, we demonstrate the existence of statistically significant hotspots in tumor images and provide a tool to accurately detect these hotspots.

Apoptosis and microvessel density in gastric cancer: correlation with tumor stage and prognosis.

PubMed

Aurello, Paolo; Bellagamba, Riccardo; Rossi Del Monte, Simone; D'Angelo, Francesco; Nigri, Giuseppe; Cicchini, Claudia; Ravaioli, Matteo; Ramacciato, Giovanni

2009-12-01

Gastric cancer remains one of the most common human malignancies with a poor prognosis. Apoptosis is known to be a programmed cell death and its inhibition is involved in the unregulated cellular growth that leads to neoplasms. Microvessel density (MVD) has been investigated as a promoting factor for angiogenesis with conflicting results about its relation to survival. The aim of our study was to search a correlation between these factors and some clinicopathological features and prognosis. Identification of apoptotic cells was performed applying the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling technique and recorded as apoptotic index (A.I.), whereas monoclonal antibodies were used for the study of MVD. A significant correlation was found between low and high A.I. and the subgroup of patients in Stages I and II (P < 0.02); 20 per cent of patients with a low A.I. showed an overall survival longer than 5 years versus 44 per cent of patients with an high A.I. (P = 0.041). High MVD was significantly related to the T stage (P = 0.036) and to a poorer 5-year overall survival (P < 0.05). Further studies are required to confirm the role of apoptosis and MVD in the development and progression of gastric cancer.

Puerarin Attenuates Cerebral Damage by Improving Cerebral Microcirculation in Spontaneously Hypertensive Rats

PubMed Central

Wu, Xu-Dong; Wang, Chen; Zhang, Zhen-Ying; Fu, Yan; Liu, Feng-Ying; Liu, Xiu-Hua

2014-01-01

Puerariae Lobatae Radix (Gegen in Chinese) is the dried root of Pueraria lobata, a semiwoody, perennial, and leguminous vine native to China. Puerarin is one of the effective components of isoflavones isolated from the root of Pueraria lobata. Previous studies showed that extracts derived from the root of Pueraria lobata possessed antihypertensive effect. Our study is to investigate whether puerarin contributes to prevention of stroke by improving cerebral microcirculation in rats. Materials and Methods. Video microscopy and laser Doppler perfusion imaging on the pia mater were used to measure the diameter of microvessel and blood perfusion in 12-week old spontaneously hypertensive rats (SHRs) and age-matched normotensive WKY rats. Histological alterations were observed by hematoxylin and eosin staining, and microvessel density in cerebral tissue was measured by immunohistochemical analysis with anti-Factor VIII antibody. Cell proliferation was detected by [3H]-TdR incorporation, and activities of p42/44 mitogen activated protein kinases (p42/44 MAPKs) were detected by western blot analysis in cultured cerebral microvascular endothelial cells (MECs). Results. Intravenous injection of puerarin relaxed arterioles and increased the blood flow perfusion in the pia mater in SHRs. Puerarin treatment for 14 days reduced the blood pressure to a normal level in SHRs (P < 0.05) and increased the arteriole diameter in the pia mater significantly as compared with vehicle treatment. Arteriole remodeling, edema, and ischemia in cerebral tissue were attenuated in puerarin-treated SHRs. Microvessel density in cerebral tissue was greater with puerarin than with vehicle treatment. Puerarin-treated MECs showed greater proliferation and p42/44 MAPKs activities than vehicle treatment. Conclusions. Puerarin possesses effects of antihypertension and stroke prevention by improved microcirculation in SHRs, which results from the increase in cerebral blood perfusion both by arteriole relaxation and p42/44 MAPKs-mediated angiogenesis. PMID:24715930

Coronary Serum Obtained After Myocardial Infarction Induces Angiogenesis and Microvascular Obstruction Repair. Role of Hypoxia-inducible Factor-1A.

PubMed

Ríos-Navarro, César; Hueso, Luisa; Miñana, Gema; Núñez, Julio; Ruiz-Saurí, Amparo; Sanz, María Jesús; Cànoves, Joaquin; Chorro, Francisco J; Piqueras, Laura; Bodí, Vicente

2018-06-01

Microvascular obstruction (MVO) exerts deleterious effects following acute myocardial infarction (AMI). We investigated coronary angiogenesis induced by coronary serum and the role of hypoxia-inducible factor-1A (HIF-1A) in MVO repair. Myocardial infarction was induced in swine by transitory 90-minute coronary occlusion. The pigs were divided into a control group and 4 AMI groups: no reperfusion, 1minute, 1 week and 1 month after reperfusion. Microvascular obstruction and microvessel density were quantified. The proangiogenic effect of coronary serum drawn from coronary sinus on endothelial cells was evaluated using an in vitro tubulogenesis assay. Circulating and myocardial HIF-1A levels and the effect of in vitro blockade of HIF-1A was assessed. Compared with control myocardium, microvessel density decreased at 90-minute ischemia, and MVO first occurred at 1minute after reperfusion. Both peaked at 1 week and almost completely resolved at 1 month. Coronary serum exerted a neoangiogenic effect on coronary endothelial cells in vitro, peaking at ischemia and 1minute postreperfusion (32 ± 4 and 41 ± 9 tubes vs control: 3 ± 3 tubes; P < .01). Hypoxia-inducible factor-1A increased in serum during ischemia (5-minute ischemia: 273 ± 52 pg/mL vs control: 148 ± 48 pg/mL; P < .01) being present on microvessels of all AMI groups (no reperfusion: 67% ± 5% vs control: 15% ± 17%; P < .01). In vitro blockade of HIF-1A reduced the angiogenic response induced by serum. Coronary serum represents a potent neoangiogenic stimulus even before reperfusion; HIF-1A might be crucial. Coronary neoangiogenesis induced by coronary serum can contribute to understanding the pathophysiology of AMI. Copyright © 2017 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Strains Responsible for Invasive Meningococcal Disease in Patients With Terminal Complement Pathway Deficiencies.

PubMed

Rosain, Jérémie; Hong, Eva; Fieschi, Claire; Martins, Paula Vieira; El Sissy, Carine; Deghmane, Ala-Eddine; Ouachée, Marie; Thomas, Caroline; Launay, David; de Pontual, Loïc; Suarez, Felipe; Moshous, Despina; Picard, Capucine; Taha, Muhamed-Kheir; Frémeaux-Bacchi, Véronique

2017-04-15

Patients with terminal complement pathway deficiency (TPD) are susceptible to recurrent invasive meningococcal disease (IMD). Neisseria meningitidis (Nm) strains infecting these patients are poorly documented in the literature. We identified patients with TPD and available Nm strains isolated during IMD. We investigated the genetic basis of the different TPDs and the characteristics of the Nm strains. We included 56 patients with C5 (n = 8), C6 (n = 20), C7 (n = 18), C8 (n = 9), or C9 (n = 1) deficiency. Genetic study was performed in 47 patients and 30 pathogenic variants were identified in the genes coding for C5 (n = 4), C6 (n = 5), C7 (n = 12), C8 (n = 7), and C9 (n = 2). We characterized 61 Nm strains responsible for IMD in the 56 patients with TPD. The most frequent strains belonged to groups Y (n = 27 [44%]), B (n = 18 [30%]), and W (n = 8 [13%]). Hyperinvasive clonal complexes (CC11, CC32, CC41/44, and CC269) were responsible for 21% of IMD cases. The CC23 predominates and represented 26% of all invasive isolates. Eleven of the 15 clonal complexes identified fit to 12 different clonal complexes belonging to carriage strains. Unusual meningococcal strains with low level of virulence similar to carriage strains are most frequently responsible for IMD in patients with TPD. © The Author 217. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Widefield in vivo spectral and fluorescence imaging microscopy of microvessel blood supply and oxygenation

NASA Astrophysics Data System (ADS)

Lee, Jennifer; Kozikowski, Raymond; Wankhede, Mamta; Sorg, Brian S.

2011-02-01

Abnormal microvascular function and angiogenesis are key components of various diseases that can contribute to the perpetuation of the disease. Several skin diseases and ophthalmic pathologies are characterized by hypervascularity, and in cancer the microvasculature of tumors is structurally and functionally abnormal. Thus, the microvasculature can be an important target for treatment of diseases characterized by abnormal microvasculature. Motivated largely by cancer research, significant effort has been devoted to research on drugs that target the microvasculature. Several vascular targeting drugs for cancer therapy are in clinical trials and approved for clinical use, and several off-label uses of these drugs have been reported for non-cancer diseases. The ability to image and measure parameters related to microvessel function preclinically in laboratory animals can be useful for development and comparison of vascular targeting drugs. For example, blood supply time measurements give information related to microvessel morphology and can be measured with first-pass fluorescence imaging. Hemoglobin saturation measurements give an indication of microvessel oxygen transport and can be measured with spectral imaging. While each measurement individually gives some information regarding microvessel function, the measurements together may yield even more information since theoretically microvessel morphology can influence microvessel oxygenation, especially in metabolically active tissue like tumors. However, these measurements have not yet been combined. In this study, we report the combination of blood supply time imaging and hemoglobin saturation imaging of microvessel networks in tumors using widefield fluorescence and spectral imaging, respectively. The correlation between the measurements in a mouse mammary tumor is analyzed.

Identifying in vivo DCE MRI markers associated with microvessel architecture and gleason grades of prostate cancer.

PubMed

Singanamalli, Asha; Rusu, Mirabela; Sparks, Rachel E; Shih, Natalie N C; Ziober, Amy; Wang, Li-Ping; Tomaszewski, John; Rosen, Mark; Feldman, Michael; Madabhushi, Anant

2016-01-01

To identify computer extracted in vivo dynamic contrast enhanced (DCE) MRI markers associated with quantitative histomorphometric (QH) characteristics of microvessels and Gleason scores (GS) in prostate cancer. This study considered retrospective data from 23 biopsy confirmed prostate cancer patients who underwent 3 Tesla multiparametric MRI before radical prostatectomy (RP). Representative slices from RP specimens were stained with vascular marker CD31. Tumor extent was mapped from RP sections onto DCE MRI using nonlinear registration methods. Seventy-seven microvessel QH features and 18 DCE MRI kinetic features were extracted and evaluated for their ability to distinguish low from intermediate and high GS. The effect of temporal sampling on kinetic features was assessed and correlations between those robust to temporal resolution and microvessel features discriminative of GS were examined. A total of 12 microvessel architectural features were discriminative of low and intermediate/high grade tumors with area under the receiver operating characteristic curve (AUC) > 0.7. These features were most highly correlated with mean washout gradient (WG) (max rho = -0.62). Independent analysis revealed WG to be moderately robust to temporal resolution (intraclass correlation coefficient [ICC] = 0.63) and WG variance, which was poorly correlated with microvessel features, to be predictive of low grade tumors (AUC = 0.77). Enhancement ratio was the most robust (ICC = 0.96) and discriminative (AUC = 0.78) kinetic feature but was moderately correlated with microvessel features (max rho = -0.52). Computer extracted features of prostate DCE MRI appear to be correlated with microvessel architecture and may be discriminative of low versus intermediate and high GS. © 2015 Wiley Periodicals, Inc.

[Laboratory surveillance for invasive meningococcal disease in Chile, 2006-2012].

PubMed

Araya, Pamela; Díaz, Janepsy; Seoane, Mabel; Fernández, Jorge; Terrazas, Solana; Canals, Andrea; Vaquero, Alejandra; Barra, Gisselle; Hormazábal, Juan C; Pidal, Paola; Valenzuela, M Teresa

2014-08-01

Laboratory surveillance of Invasive Meningococcal Disease (IMD) is performed by the Institute of Public Health of Chile. It confirms identification, classifies in serogroups and analyzes the genetic profiles of Neisseria meningitidis isolates from laboratories throughout the country. To show the results of this surveillance from 2006 to 2012. A descriptive data analysis of the confirmed cases of IMD and serological characterization, susceptibility and genetic profiles of the isolates. The analysis was disaggregated by serogroup, age and region. From 2006 to 2012, 486 isolates of N. meningitidis were confirmed. In 2011 a rise in IMD rates was observed due to an increase in W serogroup cases, mainly affecting children aged 5 years or less. Serogroup W became the most prevalent during 2012 (58.3%), replacing the historically prevalent serogroup B. Predominating strains belonged to ST-32 complex/ET-5 complex (40, 4% of strains) and ST-41/44 complex/ Lineage 3 (45, 9% of strains). Laboratory surveillance has allowed the early detection of increasing IMD caused by serogroup W, which is emergent in Chile. This information has reinforced the daily monitoring of new cases, in collaboration with all the clinical laboratories of the country.

The impact of social deprivation on paranoia, hallucinations, mania and depression: the role of discrimination social support, stress and trust.

PubMed

Wickham, Sophie; Taylor, Peter; Shevlin, Mark; Bentall, Richard P

2014-01-01

The negative implications of living in a socially unequal society are now well documented. However, there is poor understanding of the pathways from specific environmental risk to symptoms. Here we examine the associations between social deprivation, depression, and psychotic symptoms using the 2007 Adult Psychiatric Morbidity Survey, a cross-sectional dataset including 7,353 individuals. In addition we looked at the mediating role of stress, discrimination, trust and lack of social support. We found that the participants' neighbourhood index of multiple deprivation (IMD) significantly predicted psychosis and depression. On inspection of specific psychotic symptoms, IMD predicted paranoia, but not hallucinations or hypomania. Stress and trust partially mediated the relationship between IMD and paranoid ideation. Stress, trust and a lack of social support fully mediated the relationship between IMD and depression. Future research should focus on the role deprivation and social inequalities plays in specific manifestations of psychopathology and investigate mechanisms to explain those associations that occur. Targeting the mediating mechanisms through appropriate psychological intervention may go some way to dampen the negative consequences of living in an unjust society; ameliorating economic injustice may improve population mental health.

The Impact of Social Deprivation on Paranoia, Hallucinations, Mania and Depression: The Role of Discrimination Social Support, Stress and Trust

PubMed Central

Wickham, Sophie; Taylor, Peter; Shevlin, Mark; Bentall, Richard P.

2014-01-01

The negative implications of living in a socially unequal society are now well documented. However, there is poor understanding of the pathways from specific environmental risk to symptoms. Here we examine the associations between social deprivation, depression, and psychotic symptoms using the 2007 Adult Psychiatric Morbidity Survey, a cross-sectional dataset including 7,353 individuals. In addition we looked at the mediating role of stress, discrimination, trust and lack of social support. We found that the participants' neighbourhood index of multiple deprivation (IMD) significantly predicted psychosis and depression. On inspection of specific psychotic symptoms, IMD predicted paranoia, but not hallucinations or hypomania. Stress and trust partially mediated the relationship between IMD and paranoid ideation. Stress, trust and a lack of social support fully mediated the relationship between IMD and depression. Future research should focus on the role deprivation and social inequalities plays in specific manifestations of psychopathology and investigate mechanisms to explain those associations that occur. Targeting the mediating mechanisms through appropriate psychological intervention may go some way to dampen the negative consequences of living in an unjust society; ameliorating economic injustice may improve population mental health. PMID:25162703

Breast milk feeding in infants with inherited metabolic disorders other than phenylketonuria - a 10-year single-center experience.

PubMed

Pichler, Karin; Michel, Miriam; Zlamy, Manuela; Scholl-Buergi, Sabine; Ralser, Elisabeth; Jörg-Streller, Monika; Karall, Daniela

2017-04-01

Published data on breast milk feeding in infants suffering from inherited metabolic disorders (IMDs) other than phenylketonuria (PKU) are limited and described outcome is variable. We aimed to evaluate retrospectively whether breastfeeding and/or breast milk feeding are feasible in infants with IMDs including organic acidemias, fatty acid oxidation disorders, urea cycle disorders, aminoacidopathies or disorders of galactose metabolism. Data on breastfeeding and breast milk feeding as well as monitoring and neurological outcome were collected retrospectively from our database of patients with the mentioned IMD, who were followed in our metabolic center within the last 10 years. Twenty patients were included in the study, who were either breast fed on demand or received expressed breast milk. All the infants were evaluated clinically and biochemically at 2-4-week intervals, with weight gain as the leading parameter to determine metabolic control. Good metabolic control and adequate neurological development were achieved in all patients but one, who experienced the only metabolic crisis observed within the study period. Breast milk feeding with close clinical and biochemical monitoring is feasible in most IMD and should be considered as it offers nutritional and immunological benefits.

Peptidoglycan recognition protein genes and their roles in the innate immune pathways of the red flour beetle, Tribolium castaneum.

PubMed

Koyama, Hiroaki; Kato, Daiki; Minakuchi, Chieka; Tanaka, Toshiharu; Yokoi, Kakeru; Miura, Ken

2015-11-01

We have previously demonstrated that the functional Toll and IMD innate immune pathways indeed exist in the model beetle, Tribolium castaneum while the beetle's pathways have broader specificity in terms of microbial activation than that of Drosophila. To elucidate the molecular basis of this broad microbial activation, we here focused on potential upstream sensors of the T. castaneum innate immune pathways, peptidoglycan recognition proteins (PGRPs). Our phenotype analyses utilizing RNA interference-based comprehensive gene knockdown followed by bacterial challenge suggested: PGRP-LA functions as a pivotal sensor of the IMD pathway for both Gram-negative and Gram-positive bacteria; PGRP-LC acts as an IMD pathway-associated sensor mainly for Gram-negative bacteria; PGRP-LE also has some roles in Gram-negative bacterial recognition of the IMD pathway. On the other hand, we did not obtain clear phenotype changes by gene knockdown of short-type PGRP genes, probably because of highly inducible nature of these genes. Our results may collectively account for the promiscuous bacterial activation of the T. castaneum innate immune pathways at least in part. Copyright © 2015 Elsevier Inc. All rights reserved.

Gene expression profiling provides insights into the immune mechanism of Plutella xylostella midgut to microbial infection.

PubMed

Lin, Junhan; Xia, Xiaofeng; Yu, Xiao-Qiang; Shen, Jinhong; Li, Yong; Lin, Hailan; Tang, Shanshan; Vasseur, Liette; You, Minsheng

2018-03-20

Insect gut immunity plays a key role in defense against microorganism infection. The knowledge of insect gut immunity has been obtained mostly from Drosophila melanogaster. Little is known about gut immunity in the diamondback moth, Plutella xylostella (L.), a pest destroying cruciferous crops worldwide. In this study, expressions of the immune-related genes in the midgut of P. xylostella orally infected with Staphylococcus aureus, Escherichia coli and Pichia pastoris were profiled by RNA-seq and qRT-PCR approaches. The results revealed that the Toll, IMD, JNK and JAK-STAT pathways and possibly the prophenoloxidase activation system in P. xylostella could be activated by oral infections, and moricins, gloverins and lysozyme2 might act as important effectors against microorganisms. Subsequent knock-down of IMD showed that this gene was involved in regulating the expression of down-stream genes in the IMD pathway. Our work indicates that the Toll, IMD, JNK and JAK-STAT pathways may synergistically modulate immune responses in the P. xylostella midgut, implying a complex and diverse immune system in the midgut of insects. Copyright © 2018 Elsevier B.V. All rights reserved.

Tortuous Microvessels Contribute to Wound Healing via Sprouting Angiogenesis.

PubMed

Chong, Diana C; Yu, Zhixian; Brighton, Hailey E; Bear, James E; Bautch, Victoria L

2017-10-01

Wound healing is accompanied by neoangiogenesis, and new vessels are thought to originate primarily from the microcirculation; however, how these vessels form and resolve during wound healing is poorly understood. Here, we investigated properties of the smallest capillaries during wound healing to determine their spatial organization and the kinetics of formation and resolution. We used intravital imaging and high-resolution microscopy to identify a new type of vessel in wounds, called tortuous microvessels. Longitudinal studies showed that tortuous microvessels increased in frequency after injury, normalized as the wound healed, and were closely associated with the wound site. Tortuous microvessels had aberrant cell shapes, increased permeability, and distinct interactions with circulating microspheres, suggesting altered flow dynamics. Moreover, tortuous microvessels disproportionately contributed to wound angiogenesis by sprouting exuberantly and significantly more frequently than nearby normal capillaries. A new type of transient wound vessel, tortuous microvessels, sprout dynamically and disproportionately contribute to wound-healing neoangiogenesis, likely as a result of altered properties downstream of flow disturbances. These new findings suggest entry points for therapeutic intervention. © 2017 The Authors.

Glucose Transporters are Abundant in Cells with "Occluding" Junctions at the Blood-Eye Barriers

NASA Astrophysics Data System (ADS)

Harik, Sami I.; Kalaria, Rajesh N.; Whitney, Paul M.; Andersson, Lars; Lundahl, Per; Ledbetter, Steven R.; Perry, George

1990-06-01

We studied the distribution of the "erythroid/brain" glucose transporter protein in the human and rat eye by immunocytochemistry with monoclonal and polyclonal antibodies to the C terminus of the human erythrocyte glucose transporter. We found intense immunocytochemical staining in the endothelium of microvessels of the retina, optic nerve, and iris but not in microvessels of the choroid, ciliary body, sclera, and other retro-orbital tissues. In addition, we found marked immunocytochemical staining of retinal pigment epithelium, ciliary body epithelium, and posterior epithelium of the iris. The common feature of all those endothelial and epithelial cells that stained intensely for the glucose transporter is the presence of "occluding" intercellular junctions, which constitute the anatomical bases of the blood-eye barriers. We propose that a high density of the glucose transporter is a biochemical concomitant of epithelial and endothelial cells with barrier characteristics, at least in tissues that have a high metabolic requirement for glucose.

Chitosan nanoparticles inhibit the growth of human hepatocellular carcinoma xenografts through an antiangiogenic mechanism.

PubMed

Xu, Yinglei; Wen, Zhengshun; Xu, Zirong

2009-12-01

Chitosan nanoparticles (CNP) have demonstrated anticancer activity in vitro and in vivo by a few recent researches. However, the mechanisms involved in their potential anticancer activity remain to be elucidated. In this study, the effects of CNP on tumor growth were investigated using a model of nude mice xenografted with human hepatocellular carcinoma (HCC) (BEL-7402) cells. The results demonstrated that the treatment of these nude mice with CNP significantly inhibited tumor growth and induced tumor necrosis. Furthermore, microvessel density (MVD) determination by counting immunohistologically stained tumor microvessels suggested that CNP dose-dependent tumor suppression was correlated with the inhibition of tumor angiogenesis. Mechanistically, immunohistochemical and quantitative real-time reverse transcription-polymerase reaction assays provided evidence that CNP-mediated inhibition of tumor angiogenesis was linked to impaired levels of vascular endothelial growth factor receptor 2 (VEGFR2). Due to their low or non-toxicity, CNP and their derivatives may represent a novel class of anti-cancer drug.

Non-Invasive Markers of Tumor Growth, Metastases, and Sensitivity to Anti-Neoplastic Therapy

DTIC Science & Technology

2009-01-01

angiogenic agents. Validation of the results of the treatment studies will be based on tumor growth, metastases, and microvessel density...detectable by NMR. DCE-MRI studies do not suggest differences in vascular parameters between slow and fast growing rat prostate tumors. The R3327AT...Introduction The primary goal of this study is to determine whether non-invasive magnetic resonance (MR) techniques can distinguish between slow and

COX-2 and Prostate Cancer Angiogenesis

DTIC Science & Technology

2001-03-01

the optimal dosing and timing of a COX-2 inhibitor (NS398) in an animal model of human prostate cancer, (2)and (3) the mechanisms underlying the...cancer tissues (14) and that a COX-2 inhibitor selectively induces apoptosis in a prostate cancer cell line (15). We also demonstrated that treatment of...human prostate tumor-bearing mice with a selective COX-2 inhibitor (NS-398) significantly reduces tumor size, microvessel density and levels of a

Local microcirculation disorders in uterus under laser tissue welding and their influence in the healing process

NASA Astrophysics Data System (ADS)

Kozlov, Valentine I.; Skobelkin, Oleg K.; Fatkullin, Ildar; Terman, Oleg A.; Chizhov, Gennadii; Gabidullina, Rushania

1994-12-01

To study the possibility of using Nd:YAG laser to weld the tissues of the uterus experiments in rats and dogs have been conducted. With the biomicroscopy and the laser Doppler flowmetry we have evaluated the microcirculation in the uterus wall under traditional suture and laser welding suture. As a model of the wound, the dissection of serosa and muscles of the organ wall have been used. In laser welding suture we have welded the zone of tissue about 1 mm3 with the laser (power density 270 W/cm2). Histological control has been fulfilled on various phases of the healing process. The investigation of the uterus wall demonstrates that there are zones of microcirculation disorders in tissues: (1) the zone of coagulation of microvessels and adjacent tissues (about 100 micrometers ); (2) the zone of stasis (150 - 200 micrometers ); (3) the zone of reactive-destructive changes of microvessels (300 micrometers ), (4) the zone of malfunctional microcirculatory changes (600 micrometers ). The coagulation of microvessels changes the character of inflammation and the healing process, decreases the exudation phase and the leucocyte infiltration of tissues, and accelerates the capillary growth. In contrast with traditional suture, in the case of laser welding suture the edema and hemorrhagic signs are less expressed. The complete restoration of microcirculation under laser welding suture has been observed by the fourteenth day of the healing process. Under the traditional suture method normalization of tissue nutritious blood flow has been achieved by 21 days.

Brain vascular image segmentation based on fuzzy local information C-means clustering

NASA Astrophysics Data System (ADS)

Hu, Chaoen; Liu, Xia; Liang, Xiao; Hui, Hui; Yang, Xin; Tian, Jie

2017-02-01

Light sheet fluorescence microscopy (LSFM) is a powerful optical resolution fluorescence microscopy technique which enables to observe the mouse brain vascular network in cellular resolution. However, micro-vessel structures are intensity inhomogeneity in LSFM images, which make an inconvenience for extracting line structures. In this work, we developed a vascular image segmentation method by enhancing vessel details which should be useful for estimating statistics like micro-vessel density. Since the eigenvalues of hessian matrix and its sign describes different geometric structure in images, which enable to construct vascular similarity function and enhance line signals, the main idea of our method is to cluster the pixel values of the enhanced image. Our method contained three steps: 1) calculate the multiscale gradients and the differences between eigenvalues of Hessian matrix. 2) In order to generate the enhanced microvessels structures, a feed forward neural network was trained by 2.26 million pixels for dealing with the correlations between multi-scale gradients and the differences between eigenvalues. 3) The fuzzy local information c-means clustering (FLICM) was used to cluster the pixel values in enhance line signals. To verify the feasibility and effectiveness of this method, mouse brain vascular images have been acquired by a commercial light-sheet microscope in our lab. The experiment of the segmentation method showed that dice similarity coefficient can reach up to 85%. The results illustrated that our approach extracting line structures of blood vessels dramatically improves the vascular image and enable to accurately extract blood vessels in LSFM images.

Establishing core outcome sets for phenylketonuria (PKU) and medium-chain Acyl-CoA dehydrogenase (MCAD) deficiency in children: study protocol for systematic reviews and Delphi surveys.

PubMed

Potter, Beth K; Hutton, Brian; Clifford, Tammy J; Pallone, Nicole; Smith, Maureen; Stockler, Sylvia; Chakraborty, Pranesh; Barbeau, Pauline; Garritty, Chantelle M; Pugliese, Michael; Rahman, Alvi; Skidmore, Becky; Tessier, Laure; Tingley, Kylie; Coyle, Doug; Greenberg, Cheryl R; Korngut, Lawrence; MacKenzie, Alex; Mitchell, John J; Nicholls, Stuart; Offringa, Martin; Schulze, Andreas; Taljaard, Monica

2017-12-19

Inherited metabolic diseases (IMD) are a large group of rare single-gene disorders that are typically diagnosed early in life. There are important evidence gaps related to the comparative effectiveness of therapies for IMD, which are in part due to challenges in conducting randomized controlled trials (RCTs) for rare diseases. Registry-based RCTs present a unique opportunity to address these challenges provided the registries implement standardized collection of outcomes that are important to patients and their caregivers and to clinical providers and healthcare systems. Currently there is no core outcome set (COS) for studies evaluating interventions for paediatric IMD. This protocol outlines a study that will establish COS for each of two relatively common IMD in children, phenylketonuria (PKU) and medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. This two-part study is registered with the Core Outcome Measures in Effectiveness Trials (COMET) initiative. Part 1 includes a rapid review and development of an evidence map to identify a comprehensive listing of outcomes reported in past studies of PKU and MCAD deficiency. The review follows established methods for knowledge synthesis, including a comprehensive search strategy, two stages of screening citations against inclusion/exclusion criteria by two reviewers working independently, and extraction of important data elements from eligible studies, including details of the outcomes collected and outcome measurement instruments. The review findings will inform part 2 of our study, a set of Delphi surveys to establish consensus on the highest priority outcomes for each condition. Healthcare providers, families of children with PKU or MCAD deficiency, and health system decision-makers will be invited to participate in two to three rounds of Delphi surveys. The design of the surveys will involve parents of children with IMD who are part of a family advisory forum. This protocol is a crucial step in developing the capacity to launch RCTs with meaningful outcomes that address comparative effectiveness questions in the field of paediatric IMD. Such trials will contribute high-quality evidence to inform decision-making by patients and their family members, clinicians, and policy-makers.

Sociodemographic predictors of variation in coverage of the national shingles vaccination programme in England, 2014/15.

PubMed

Ward, Charlotte; Byrne, Lisa; White, Joanne M; Amirthalingam, Gayatri; Tiley, Karen; Edelstein, Michael

2017-04-25

In September 2013, England introduced a shingles vaccination programme to reduce incidence and severity of shingles in the elderly. This study aims to assess variation in vaccine coverage with regards to selected sociodemographic factors to inform activities for improving equity of the programme. Eligible 70year-olds were identified from a national vaccine coverage dataset in 2014/15 that includes 95% of GPs in England. NHS England Local Team (LT) and index of multiple deprivation (IMD) scores were assigned to patients based on GP-postcode. Vaccine coverage (%) with 95% confidence intervals (CIs), were calculated overall and by LT, ethnicity and IMD, using binomial regression. Of 502,058 eligible adults, 178,808 (35.6%) had ethnicity recorded. Crude vaccine coverage was 59.5% (95%CI: 59.3-59.7). Coverage was lowest in London (49.6% coverage, 95%CI: 49.0-50.2), and compared to this coverage was significantly higher in all other LTs (+6.3 to +10.4, p<0.001) after adjusting for ethnicity and IMD. Coverage decreased with increasing deprivation and was 8.2% lower in the most deprived (95%CI: 7.3-9.1) compared with the least deprived IMD quintile (64.1% coverage, 95%CI: 63.6-64.6), after adjustment for ethnicity and LT. Compared with White-British (60.7% coverage, 95%CI: 60.5-61.0), other ethnic groups had between 4.0% (Indian) and 21.8% (Mixed: White and Black African) lower coverage. After adjusting for IMD and LT, significantly lower coverage by ethnicity persisted in all groups, except in Mixed: Other, Indian and Bangladeshi compared with White-British. After taking geography and deprivation into account, shingles vaccine coverage varied by ethnicity. White-British, Indian and Bangladeshi groups had highest coverage; Mixed: White and Black African, and Black-other ethnicities had the lowest. Patients' ethnicity and IMD are predictors of coverage which contribute to, but do not wholly account for, geographical variation coverage. Interventions to address service-related, sociodemographic and ethnic inequalities in shingles vaccine coverage are required. Copyright © 2017 Elsevier Ltd. All rights reserved.

Growth of arterioles in chronically stimulated adult rat skeletal muscle.

PubMed

Hansen-Smith, F; Egginton, S; Hudlicka, O

1998-01-01

The purpose of this study was to test the hypothesis that capillary growth induced by chronic electrical stimulation of skeletal muscle is accompanied by the growth of small arterioles. Lower limb flexor muscles of Sprague-Dawley rats were stimulated by electrodes implanted in the vicinity of the peroneal nerve at 10 Hz for 8 h/d for 2 and 7 days. Cryostat sections from the proximal, middle, and distal regions of the extensor digitorum longus muscle (EDL) were fluorescently immunolabeled with alpha-smooth muscle actin (alpha SMA) and myosin heavy chain (MHC) to identify mature (alpha SMA and MHC-positive) and immature (alpha SMA-positive, MHC-negative) arterioles. The fluorescent derivative of the lectin Griffonia simplicifolia I (GSI) was used to identify all microvessels, including arterioles, capillaries, and venules. The number of vessels positive for GSI or alpha SMA surrounding muscle fibers was similar in all three muscle regions (proximal, middle, distal). The mean values +/- SEM for GSI-positive vessels from all regions were similar in control (4.3 +/- 0.07) and 2-day stimulated (4.7 +/- 0.08) but higher in 7-day stimulated muscles (6.7 +/- 0.1, p < 0.05), thus confirming the previous findings on capillary growth. A similar increase was found in the number of alpha SMA positive vessels < or = 10 microns outer diameter (1.3 +/- 0.09 versus 0.4 +/- 0.03 around muscle fibers in controls). The density of terminal arterioles (< or = 10 microns) was slightly but not significantly higher after 2 days of stimulation (19.5 +/- 4 versus 15.6 +/- 2 profiles/mm2 in control muscles) and significantly higher after 7 days (33 +/- 7). While a similar increase was observed in the density of preterminal arterioles > 10 microns (17 +/- 3 control, 22 +/- 3 at 2 days and 40 +/- 5 at 7 days), the density of MHC-positive vessels muscles stimulated for 7 days was unchanged. Seven-day stimulated muscle also had a fivefold higher density of microvessel profiles < or = 10 microns that were only partially surrounded by alpha SMA. This considerably exceeds the relative increase in the number of capillaries and thus supports the concept of arteriolar growth by transformation from capillaries. Chronic electrical stimulation results in an early increase in the number of immature (MHG-negative), but not mature (MHC-positive) arterioles, a process that accompanies the increase in capillarization. The great increase in the number of microvessels only partially covered by alpha SMA suggests arteriolization of capillaries as a contributing mechanism in this growth.

Moving beyond average values: assessing the night-to-night instability of sleep and arousal in DSM-IV-TR insomnia subtypes.

PubMed

Sánchez-Ortuño, M Montserrat; Carney, Colleen E; Edinger, Jack D; Wyatt, James K; Harris, Andrea

2011-04-01

We explored differences between individuals with DSM-IV-TR diagnoses of primary insomnia (PI) and insomnia related to a mental disorder (IMD) by using serial measurements of self-reported sleep variables (sleep onset latency, SOL; wake after sleep onset, WASO; total sleep time, TST; sleep efficiency, SE), and visual analogue scale ratings of 2 forms of bedtime arousal (cognitive and emotional). Furthermore, we sought to examine the relationship between sleep and arousal within each diagnostic subgroup. Between-group and within-group comparisons. Duke and Rush University Medical Centers, USA. One hundred eighty-seven insomnia sufferers (126 women, average age 47.15 years) diagnosed by sleep specialists at 2 sleep centers as PI patients (n=126) and IMD patients (n=61). N/A. Multilevel models for sleep measures indicated that IMD displayed significantly more instability across nights in their TST (i.e., larger changes) than did PI patients. With respect to pre-sleep arousal, IMD patients exhibited higher mean levels of emotional arousal, as well as more instability on the nightly ratings of this measure. Within the PI group, correlational analyses revealed a moderate relationship between the 2 arousal variables and SOL (r values 0.29 and 0.26), whereas the corresponding correlations were negligible and statistically nonsignificant in the IMD group. We found a number of differences on nighttime variables between those diagnosed with primary insomnia and those diagnosed with insomnia related to a mental disorder. These differences imply different perpetuating mechanisms involved in their ongoing sleep difficulties. Additionally, they support the categorical distinctiveness and the concurrent validity of these insomnia subtypes.

Virus-associated apoptosis of blood neutrophils as a risk factor for invasive meningococcal disease

PubMed Central

Smith, Harry; Rogers, Sharon L; Smith, Helen V; Gillis, David; Siskind, Victor; Smith, Judith A

2013-01-01

Aims To quantify a range of haematological indicators of viral infection (leucocyte apoptosis, cytopenia of normal lymphocytes, reactive lymphocyte increase, neutropenia) in patients with recent onset invasive meningococcal disease (IMD), with a view to test the association of viral infection with IMD and identify possible haematological risk factors for its development. Subjects and methods 88 patients with recent onset IMD, classified on clinical severity as fatal (n=14), septic shock survived (n=26) and no shock (n=48), and 50 healthy controls were studied. Blood film microscopy and leucocyte counts were used to quantify the virus-associated indicators. Cocci-containing neutrophils were also quantified. Results All viral parameters were significantly more frequent or higher in patients than controls, with leucocyte apoptosis found only in the patients. A significant gradient in accord with clinical severity was found for neutrophil and lymphocyte apoptosis, neutropenia and cocci-containing neutrophils. Crucially, apoptotic neutrophils did not contain cocci, and cocci-containing neutrophils were not apoptotic. Conclusions The correlation between magnitude of neutrophil apoptosis and severity of IMD suggests a cause–effect relationship. We propose that neutrophil apoptosis is more likely a facilitator rather than an effect of IMD for these reasons: (1) apoptotic neutrophils did not contain cocci and cocci-containing neutrophils were not apoptotic, (2) leucocyte apoptosis is a recognised viral effect and (3) Neisseria meningitidis is incapable of producing a Panton–Valentine type leucocidin. The lymphocyte apoptosis which accompanies neutrophil death may contribute to risk by impairing the generation of microbicidal antibody. Leucocyte apoptosis is a morphological expression of viral immunosuppression and, we suggest, is a likely contributor to a range of viral effects. PMID:23801496

Targeting Inhibitor of κB Kinase β Prevents Inflammation-Induced Preterm Delivery by Inhibiting IL-6 Production from Amniotic Cells.

PubMed

Toda, Aska; Sawada, Kenjiro; Fujikawa, Tomoyuki; Wakabayashi, Atsuko; Nakamura, Koji; Sawada, Ikuko; Yoshimura, Akihiko; Nakatsuka, Erika; Kinose, Yasuto; Hashimoto, Kae; Mabuchi, Seiji; Tokuhira, Atsushi; Nakayama, Masahiro; Itai, Akiko; Kurachi, Hirohisa; Kimura, Tadashi

2016-03-01

Preterm delivery (PTD) remains a serious challenge in perinatology. Intrauterine infection and/or inflammation, followed by increased inflammatory cytokines, represented by IL-6, are involved in this pathology. Our aim was to identify IL-6-producing cells in the placenta and to analyze the potential of targeting IκB kinase β (IKKβ) signaling to suppress IL-6 production for the treatment of PTD. Immunohistochemical analyses using placentas complicated with severe chorioamnionitis revealed that IL-6 is mainly expressed in human amniotic mesenchymal stromal cells (hAMSCs). Primary hAMSCs were collected, and strong IL-6 expression was confirmed. In hAMSCs, the treatment of tumor necrosis factor-α or IL-1β drastically induced IL-6 production, followed by the phosphorylation of IKKs. A novel IKKβ inhibitor, IMD-0560, almost completely inhibited IL-6 production from hAMSCs. Using an experimental lipopolysaccharide-induced PTD mouse model, the therapeutic potential of IMD-0560 was examined. IMD-0560 was delivered vaginally 4 hours before lipopolysaccharide administration. Mice in the IMD-0560 (30 mg/kg, twice a day) group had a significantly lower rate of PTD [10 of 22 (45%)] without any apparent adverse events on the mice and their pups. In uteri collected from mice, IMD-0560 inhibited not only IL-6 production but also production of related cytokines, such as keratinocyte-derived protein chemokine/CXCL1, macrophage inflammatory protein-2/CXCL2, and monocyte chemoattractant protein-1/chemokine ligand 2. Targeting IKKβ signaling shows promising effects through the suppression of these cytokines and can be explored as a future option for the prevention of PTD. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

IKKβ Regulates VEGF Expression and Is a Potential Therapeutic Target for Ovarian Cancer as an Antiangiogenic Treatment.

PubMed

Kinose, Yasuto; Sawada, Kenjiro; Makino, Hiroshi; Ogura, Tomonori; Mizuno, Tomoko; Suzuki, Noriko; Fujikawa, Tomoyuki; Morii, Eiichi; Nakamura, Koji; Sawada, Ikuko; Toda, Aska; Hashimoto, Kae; Isobe, Aki; Mabuchi, Seiji; Ohta, Tsuyoshi; Itai, Akiko; Morishige, Ken-ichirou; Kurachi, Hirohisa; Kimura, Tadashi

2015-04-01

The prolongation of progression-free survival (PFS) in patients with advanced ovarian cancer by antiangiogenic therapy has been shown in several clinical trials. However, although an anti-VEGF antibody (bevacizumab) is the only option currently available, its efficacy is limited and it is not cost effective for use in all patients. Therefore, the development of a novel antiangiogenic drug, especially composed of small-molecule compounds, could be a powerful armament for ovarian cancer treatment. As NF-κB signaling has the potential to regulate VEGF expression, we determined to identify whether VEGF expression is associated with NF-κB activation and to investigate the possibility of a novel IKKβ inhibitor, IMD-0354 (IMMD Inc.), as an antiangiogenic drug. Tissue microarrays from 94 ovarian cancer tissues were constructed and immunohistochemical analyses performed. We revealed that IKK phosphorylation is an independent prognostic factor (PFS: 26.1 vs. 49.8 months, P = 0.011), and is positively correlated with high VEGF expression. In in vitro analyses, IMD-0354 robustly inhibited adhesive and invasive activities of ovarian cancer cells without impairing cell viabilities. IMD-0354 significantly suppressed VEGF production from cancer cells, which led to the inhibition of angiogenesis. In a xenograft model, the treatment of IMD-0354 significantly inhibited peritoneal dissemination with a marked reduction of intratumoral blood vessel formation followed by the inhibition of VEGF expression from cancer cells. IMD-0354 is a stable small-molecule drug and has already been administered safely to humans in other trials. Antiangiogenic therapy targeting IKKβ is a potential future option to treat ovarian cancer. ©2015 American Association for Cancer Research.

Imidazenil prevention of alprazolam-induced acquisition deficit in patas monkeys is devoid of tolerance

PubMed Central

Auta, James; Guidotti, Alessandro; Costa, Erminio

2000-01-01

The partial allosteric modulators (PAMs) of γ-aminobutyric acid-gated Cl− current intensities at γ-aminobutyric acid type A receptors have high affinity but low intrinsic efficacy on benzodiazepine recognition sites. Unlike the full allosteric modulators (FAM), like alprazolam, triazolam, and diazepam, PAMs are virtually devoid of unwanted side effects, including tolerance. Imidazenil (IMD) is a PAM that elicits potent anxiolytic and anticonvulsant actions in rodents and nonhuman primates and retains its anticonvulsant and anxiolytic effects, even in rodents that are tolerant to FAMs. IMD antagonizes the side effects of FAMs in rodents and nonhuman primates. Using patas monkeys and a multiple schedule with repeated acquisition and performance of chain responses, we report that IMD administration for 17 days antagonized without showing tolerance ALP-induced disruption of acquisition. PMID:10696114

An improved recommendation algorithm via weakening indirect linkage effect

NASA Astrophysics Data System (ADS)

Chen, Guang; Qiu, Tian; Shen, Xiao-Quan

2015-07-01

We propose an indirect-link-weakened mass diffusion method (IMD), by considering the indirect linkage and the source object heterogeneity effect in the mass diffusion (MD) recommendation method. Experimental results on the MovieLens, Netflix, and RYM datasets show that, the IMD method greatly improves both the recommendation accuracy and diversity, compared with a heterogeneity-weakened MD method (HMD), which only considers the source object heterogeneity. Moreover, the recommendation accuracy of the cold objects is also better elevated in the IMD than the HMD method. It suggests that eliminating the redundancy induced by the indirect linkages could have a prominent effect on the recommendation efficiency in the MD method. Project supported by the National Natural Science Foundation of China (Grant No. 11175079) and the Young Scientist Training Project of Jiangxi Province, China (Grant No. 20133BCB23017).

Lymphatic microvessel density as a predictive marker for the recurrence time of pterygium: A three-year follow-up study

PubMed Central

Lin, Haotian; Luo, Lixia; Ling, Shiqi; Chen, Wan; Liu, Zhaochuan; Zhong, Xiaojian; Wu, Changrui; Liu, Yizhi

2013-01-01

Purpose To investigate whether lymphatic microvessel density (LMVD) could be used as a predictive marker for the recurrence time of pterygia. Methods This was a prospective case series study. Ninety-six patients with unilateral eye primary nasal pterygia were included. The patients were clinically evaluated to grade the severity of their pterygia (32 were Grade 1, 29 were Grade 2, and 35 were Grade 3) before they underwent bare sclera resection with the use of mitomycin C. Excised tissues from the 96 patients and the ten normal nasal conjunctiva obtained from age-matched donor eyeballs (controls) were immunostained with LYVE-1 and CD31 monoclonal antibodies to evaluate LMVD and blood microvessel density (BMVD). The patients were followed up for three years or until pterygium recurrence was identified, which was defined as fibrovascular regrowth past the limbus in a previously compromised area. The recurrence time (RT) for a pterygium was calculated, and its relationship with LMVD and/or BMVD was statistically analyzed. Results In total, there were 24 cases of pterygium recurrence. The recurrence rate of Grade 1 was 28.1% (9/32), Grade 2 was 24.1% (7/29), and Grade 3 was 22.9% (8/35), as classified in the primary pterygium (p>0.05); the overall recurrence rate was 25% (24/96) for all patients during the three-year follow-up. In the tissue analysis, there were a small number of CD31 (+), LYVE-1(-) BMVD and only a few CD31 (weak), LYVE-1(+) LMVD in the ten normal nasal conjunctiva tissues. BMVD and LMVD increased significantly in the pterygium tissue compared to the control tissue and were significantly correlated with the width and area of pterygium in Grades 1–3 (all p values <0.05). RT was not correlated with BMVD or pterygium grade, but LMVD was significantly and negatively correlated with RT within each group and in the total patient cohort. Furthermore, we determined that an LMVD greater than 20 in the surgical specimens predicted pterygium recurrence. Conclusions The LMVD of surgical specimens is an independent risk factor and a valuable predictive factor for the recurrence time of pterygia. PMID:23378730

Silencing of Apis mellifera dorsal genes reveals their role in expression of the antimicrobial peptide defensin-1.

PubMed

Lourenço, Anete Pedro; Florecki, Mônica Mazzei; Simões, Zilá Luz Paulino; Evans, Jay Daniel

2018-04-17

Like all other insects, two key signaling pathways (Toll and Imd) regulate the induction of honey bee immune effectors that target microbial pathogens. Among these effectors are antimicrobial peptides (AMPs) that are presumed to be produced by the NF-κB factors Dorsal and Relish from the Toll and Imd pathways, respectively. Using in silico analysis, we previously proposed that the honey bee AMP defensin-1 was regulated by the Toll pathway, while hymenoptaecin was regulated by Imd and abaecin by both the Toll and Imd pathways. Here we use an RNA interference (RNAi) assay to determine the role of Dorsal in regulating abaecin and defensin-1. Honey bees have two dorsal genes (dorsal-1 and dorsal-2) and two splicing isoforms of dorsal-1 (dorsal-1A and dorsal-1B). Accordingly, we used both single and multiple (double or triple) isoform knockdown strategies to clarify the roles of dorsal proteins and their isoforms. Down-regulation of defensin-1 was observed for dorsal-1A and dorsal-2 knockdowns, but abaecin expression was not affected by dorsal RNAi. We conclude that defensin-1 is regulated by Dorsal (Toll pathway). This article is protected by copyright. All rights reserved. © 2018 The Royal Entomological Society.

[Pathologic change of elastic fibers with difference of microvessel density and expression of angiogenesis-related proteins in internal hemorrhoid tissues].

PubMed

Han, Wei; Wang, Zhen-jun; Zhao, Bo; Yang, Xin-qing; Wang, Dong; Wang, Jian-pin; Tang, Xiu-ying; Zhao, Fa; Hung, Yan-ting

2005-01-01

To investigate the pathological variations in internal hemorrhoid and evaluate the expression of nitric- oxide synthase(NOS),vascular endothelial growth factor(VEGF),matrix metalloproteinase- 2(MMP2) and MMP9. Normal anal cushion and internal hemorrhoids tissue samples were obtained from 24 patients with iii degree hemorrhoids after procedure for prolapse and hemorrhoids(PPH) procedure. The expression of NOS, VEGF, MMP2, MMP9 and CD34 were detected by immunohistochemical staining; the microvessel density (MVD) was counted by anti- CD34 antibody; the elastic fibers were detected by orcein staining. There were statistically significant differences in the expression of MVD, VEGF, MMP9 between internal hemorrhoid tissue and normal anal cushions(P< 0.05). iNOS was significantly increased in hemorrhoid tissue, but no significant difference between normal anal cushions and hemorrhoid tissue. Morphological abnormalities such as breaking, distortion, mortality, hyaline degeneration were found in elastic fibers of internal hemorrhoid tissue, but not in normal anal cushions. Angiogenesis is evident in hemorrhoid tissue, suggesting the possible mechanism in the pathogenesis of hemorrhoids. The direct degeneration effect of MMP9 on supporting structure elastic fibers in anal cushion is another important mechanism. The high expression of iNOS suggests the inflammatory factors involve in the pathogenesis of hemorrhoids, and NO may be involve in pathological effect on hemorrhoids.

Investigating the effect of tumor vascularization on magnetic targeting in vivo using retrospective design of experiment.

PubMed

Mei, Kuo-Ching; Bai, Jie; Lorrio, Silvia; Wang, Julie Tzu-Wen; Al-Jamal, Khuloud T

2016-11-01

Nanocarriers take advantages of the enhanced permeability and retention (EPR) to accumulate passively in solid tumors. Magnetic targeting has shown to further enhance tumor accumulation in response to a magnetic field gradient. It is widely known that passive accumulation of nanocarriers varies hugely in tumor tissues of different tumor vascularization. It is hypothesized that magnetic targeting is likely to be influenced by such factors. In this work, magnetic targeting is assessed in a range of subcutaneously implanted murine tumors, namely, colon (CT26), breast (4T1), lung (Lewis lung carcinoma) cancer and melanoma (B16F10). Passively- and magnetically-driven tumor accumulation of the radiolabeled polymeric magnetic nanocapsules are assessed with gamma counting. The influence of tumor vasculature, namely, the tumor microvessel density, permeability and diameter on passive and magnetic tumor targeting is assessed with the aid of the retrospective design of experiment (DoE) approach. It is clear that the three tumor vascular parameters contribute greatly to both passive and magnetically targeted tumor accumulation but play different roles when nanocarriers are targeted to the tumor with different strategies. It is concluded that tumor permeability is a rate-limiting factor in both targeting modes. Diameter and microvessel density influence passive and magnetic tumor targeting, respectively. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

A phosphodiesterase 4B-dependent interplay between tumor cells and the microenvironment regulates angiogenesis in B-cell lymphoma

PubMed Central

Suhasini, Avvaru N.; Lin, An-Ping; Bhatnagar, Harshita; Kim, Sang-Woo; Moritz, August W.; Aguiar, Ricardo C. T.

2015-01-01

Angiogenesis associates with poor outcome in diffuse large B-cell lymphoma (DLBCL), but the contribution of the lymphoma cells to this process remains unclear. Addressing this knowledge gap may uncover unsuspecting proangiogenic signaling nodes and highlight alternative antiangiogenic therapies. Here we identify the second messenger cyclic-AMP (cAMP) and the enzyme that terminates its activity, phosphodiesterase 4B (PDE4B), as regulators of B-cell lymphoma angiogenesis. We first show that cAMP, in a PDE4B-dependent manner, suppresses PI3K/AKT signals to down-modulate VEGF secretion and vessel formation in vitro. Next, we create a novel mouse model that combines the lymphomagenic Myc transgene with germline deletion of Pde4b. We show that lymphomas developing in a Pde4b-null background display significantly lower microvessel density in association with lower VEGF levels and PI3K/AKT activity. We recapitulate these observations by treating lymphoma-bearing mice with the FDA-approved PDE4 inhibitor Roflumilast. Lastly, we show that primary human DLBCLs with high PDE4B expression display significantly higher microvessel density. Here, we defined an unsuspected signaling circuitry in which the cAMP generated in lymphoma cells downmodulates PI3K/AKT and VEGF secretion to negatively influence vessel development in the microenvironment. These data identify PDE4 as an actionable antiangiogenic target in DLBCL. PMID:26503641

Flow of a circulating tumor cell and red blood cells in microvessels

NASA Astrophysics Data System (ADS)

Takeishi, Naoki; Imai, Yohsuke; Yamaguchi, Takami; Ishikawa, Takuji

2015-12-01

Quantifying the behavior of circulating tumor cells (CTCs) in the blood stream is of fundamental importance for understanding metastasis. Here, we investigate the flow mode and velocity of CTCs interacting with red blood cells (RBCs) in various sized microvessels. The flow of leukocytes in microvessels has been described previously; a leukocyte forms a train with RBCs in small microvessels and exhibits margination in large microvessels. Important differences in the physical properties of leukocytes and CTCs result from size. The dimensions of leukocytes are similar to those of RBCs, but CTCs are significantly larger. We investigate numerically the size effects on the flow mode and the cell velocity, and we identify similarities and differences between leukocytes and CTCs. We find that a transition from train formation to margination occurs when (R -a ) /tR≈1 , where R is the vessel radius, a is the cell radius, and tR is the thickness of RBCs, but that the motion of RBCs differs from the case of leukocytes. Our results also show that the velocities of CTCs and leukocytes are larger than the average blood velocity, but only CTCs move faster than RBCs for microvessels of R /a ≈1.5 -2.0 . These findings are expected to be useful not only for understanding metastasis, but also for developing microfluidic devices.

Small RNA-Seq analysis reveals microRNA-regulation of the Imd pathway during Escherichia coli infection in Drosophila.

PubMed

Li, Shengjie; Shen, Li; Sun, Lianjie; Xu, Jiao; Jin, Ping; Chen, Liming; Ma, Fei

2017-05-01

Drosophila have served as a model for research on innate immunity for decades. However, knowledge of the post-transcriptional regulation of immune gene expression by microRNAs (miRNAs) remains rudimentary. In the present study, using small RNA-seq and bioinformatics analysis, we identified 67 differentially expressed miRNAs in Drosophila infected with Escherichia coli compared to injured flies at three time-points. Furthermore, we found that 21 of these miRNAs were potentially involved in the regulation of Imd pathway-related genes. Strikingly, based on UAS-miRNAs line screening and Dual-luciferase assay, we identified that miR-9a and miR-981 could both negatively regulate Drosophila antibacterial defenses and decrease the level of the antibacterial peptide, Diptericin. Taken together, these data support the involvement of miRNAs in the regulation of the Drosophila Imd pathway. Copyright © 2017 Elsevier Ltd. All rights reserved.

Angiogenesis and expression of vascular endothelial growth factor, tumour necrosis factor-α and hypoxia inducible factor-1α in canine renal cell carcinoma.

PubMed

Yhee, J Y; Yu, C H; Kim, J H; Im, K S; Kim, N H; Brodersen, B W; Doster, A R; Sur, J-H

2012-01-01

The aim of the present study was to determine the distribution and characteristics of microvessels in various histological types of canine renal cell carcinoma (RCC). The study compared microvessel density (MVD) and distribution of blood vessels according to histological type and evaluated the presence of angiogenesis-related proteins. Nine archival samples of canine RCC were studied. MVD was calculated as the mean number of blood vessels per mm(2). The diameter of blood vessels was calculated by determining either the length of the long axis of blood vessels (diameter(max)) or the mean distance from the centre of each blood vessel to the tunica adventia (diameter(mean)). A significant difference in MVD was evident between RCCs and normal kidneys (46.6 ± 28.0 versus 8.4 ± 2.2 microvessels/mm(2)). Diameter(max) in canine RCCs (34.1 ± 14.7 μm) was also significantly different from normal canine kidney (23.2 ± 3.4 μm). Vascular endothelial growth factor (VEGF) was expressed by tumour cells and vascular endothelial cells and tumour necrosis factor (TNF)-α expression was observed in vascular endothelial cells in both neoplastic and normal kidney. Although VEGF is involved in angiogenesis and correlates with tumour stage of development, no correlation was found between VEGF expression and MVD. Tumour-associated macrophages expressing TNF-α and hypoxia inducible factor 1α were identified in peritumoural tissue and may play an important role in angiogenesis. Copyright © 2011 Elsevier Ltd. All rights reserved.

The use of 5-fluorouracil-loaded nanobubbles combined with low-frequency ultrasound to treat hepatocellular carcinoma in nude mice.

PubMed

Li, Qiaoya; Li, Hongyang; He, Chengjun; Jing, Zhouhong; Liu, Changan; Xie, Juan; Ma, Wenwen; Deng, Huisheng

2017-11-21

This study aimed to investigate the therapeutic effects of 5-fluorouracil (5-FU)-loaded nanobubbles irradiated with low-intensity, low-frequency ultrasound in nude mice with hepatocellular carcinoma (HCC). A transplanted tumor model of HCC in nude mice was established in 40 mice, which were then randomly divided equally into four groups: group A (saline), group B (5-FU-loaded nanobubbles), group C (5-FU-loaded nanobubbles with non-low-frequency ultrasound), and group D (5-FU-loaded nanobubbles with low-frequency ultrasound). The tumor size in each mouse was observed via ultrasound before and after the treatments. Inhibition of the tumor growth in each group was compared, and survival curves were generated. Tumor tissues were removed to determine the apoptotic index using the TUNEL method and quantitative analysis. Tumor tissues with CD34-positive microvessels were observed by immunohistochemistry, and the tumor microvessel densities were calculated. The growth rate of the tumor volumes in group D was significantly slower than that in the other groups, while the tumor inhibition rates and apoptotic index in group D were significantly higher than those of the other groups. The number of microvessels staining positive for CD34 was decreased in group D. Therefore, group D presented the most significant inhibitory effects. Therefore, 5-FU-loaded nanobubbles subjected to irradiation with low-frequency ultrasound could further improve drug targeting and effectively inhibit the growth of transplanted tumors, which is expected to become an ideal drug carrier and targeted drug delivery system for the treatment of HCC in the future.

Is social deprivation an independent predictor of outcomes following cardiac surgery? An analysis of 240,221 patients from a national registry.

PubMed

Barnard, James; Grant, Stuart W; Hickey, Graeme L; Bridgewater, Ben

2015-06-29

Social deprivation impacts on healthcare outcomes but is not included in the majority of cardiac surgery risk prediction models. The objective was to investigate geographical variations in social deprivation of patients undergoing cardiac surgery and identify whether social deprivation is an independent predictor of outcomes. National Adult Cardiac Surgery Audit data for coronary artery bypass graft (CABG), or valve surgery performed in England between April 2003 and March 2013, were analysed. Base hospitals in England were divided into geographical regions. Social deprivation was measured by quintile groups of the index of multiple deprivation (IMD) score with the first quintile group (Q1) being the least, and the last quintile group (Q5) the most deprived group. In-hospital mortality and midterm survival were analysed using mixed effects logistic, and stratified Cox proportional hazards regression models respectively. 240,221 operations were analysed. There was substantial regional variation in social deprivation with the proportion of patients in IMD Q5 ranging from 34.5% in the North East to 6.5% in the East of England. Following adjustment for preoperative risk factors, patients undergoing all cardiac surgery in IMD Q5 were found to have an increased risk of in-hospital mortality relative to IMD Q1 (OR=1.13; 95%CI 1.03 to 1.24), as were patients undergoing isolated CABG (OR=1.19; 95%CI 1.03 to 1.37). For midterm survival, patients in IMD Q5 had an increased hazard in all groups (HRs ranged between 1.10 (valve+CABG) and 1.26 (isolated CABG)). For isolated CABG, the median postoperative length of stay was 6 and 7 days, respectively, for IMD Q1-Q4 and Q5. Significant regional variation exists in the social deprivation of patients undergoing cardiac surgery in England. Social deprivation is associated with an increased risk of in-hospital mortality and reduced midterm survival. These findings have implications for health service provision, risk prediction models and analyses of surgical outcomes. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Application of Neural Networks to Predict UH-60L Electrical Generator Condition using (IMD-HUMS) Data

DTIC Science & Technology

2006-12-01

Data transfer unit ( DTU ) • Remote data concentrator (RDC) • Main processor unit (MPU) • 2 junction boxes (JB1/JB2) • 20 drive train and...NETWORKS TO PREDICT UH-60L ELECTRICAL GENERATOR CONDITION USING (IMD-HUMS) DATA by Evangelos Tourvalis December 2006 Thesis Advisor...including the time for reviewing instruction, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the

A RHIM with a View: FLYing with Functional Amyloids.

PubMed

Shin, Sunny; Cherry, Sara

2017-10-17

Recognition of bacterial peptidoglycan by the Drosophila IMD pathway triggers NF-κB activation and an associated immune response. In this issue of Immunity, Kleino et al. (2017) show that proteins in the IMD pathway form functional amyloids via a cryptic motif resembling the RHIM motif found in mammalian RIPK proteins. Amyloid formation can be negatively regulated, suggesting that it presents a regulatory point in multiple biological processes. Copyright © 2017 Elsevier Inc. All rights reserved.

An entomopathogenic bacterium, Xenorhabdus nematophila, suppresses expression of antimicrobial peptides controlled by Toll and Imd pathways by blocking eicosanoid biosynthesis.

PubMed

Hwang, Jihyun; Park, Youngjin; Kim, Yonggyun; Hwang, Jihyun; Lee, Daeweon

2013-07-01

Immune-associated genes of the beet armyworm, Spodoptera exigua, were predicted from 454 pyrosequencing transcripts of hemocytes collected from fifth instar larvae challenged with bacteria. Out of 22,551 contigs and singletons, 36% of the transcripts had at least one significant hit (E-value cutoff of 1e-20) and used to predict immune-associated genes implicated in pattern recognition, prophenoloxidase activation, intracellular signaling, and antimicrobial peptides (AMPs). Immune signaling and AMP genes were further confirmed in their expression patterns in response to different types of microbial challenge. To discriminate the AMP expression signaling between Toll and Imd pathways, RNA interference was applied to specifically knockdown each signal pathway; the separate silencing treatments resulted in differential suppression of AMP genes. An entomopathogenic bacterium, Xenorhabdus nematophila, suppressed expression of most AMP genes controlled by Toll and Imd pathways, while challenge with heat-killed X. nematophila induced expression of all AMPs in experimental larvae. Benzylideneacetone (BZA), a metabolite of X. nematophila, suppressed the AMP gene inductions when it was co-injected with the heat-killed X. nematophila. However, arachidonic acid, a catalytic product of PLA2 , significantly reversed the inhibitory effect of BZA on the AMP gene expression. This study suggests that X. nematophila suppresses AMP production controlled by Toll and Imd pathways by inhibiting eicosanoid biosynthesis in S. exigua. © 2013 Wiley Periodicals, Inc.

[Inherited metabolic disorders in pediatric emergency services].

PubMed

Molina Gutiérrez, M A; López López, R; Morais López, A; Bueno Barriocanal, M; Martínez Ojinaga Nodal, E; Alcolea Sánchez, A M; García García, S

2015-06-01

Advances in the early diagnosis and treatment have led to improved survival, and a better quality of life for patients with inherited metabolic disorders (IMD). They can go to the Pediatric Emergency Services (PES) for reasons unrelated to their disease. The purpose of this study was to review the characteristics of visitors to the PES of these patients in a tertiary hospital. A retrospective observational study was conducted on all visits from patients with IMD to the PES of Hospital Infantil La Paz over the years 2011 and 2012. IMD type, complaint, duration of symptoms, need for hospitalization, and presence of metabolic decompensation was recorded. A total of 107 visits were analyzed, with the most frequent reason being for consultation of respiratory processes (30.8%). When the consultation was for vomiting, patients with protein-related disorders were those who delayed less in going to PES. One third of visitors were admitted, half of them due to metabolic decompensation of the underlying pathology. Patients with IMD came to PES for many different reasons, which in some cases were the cause or consequence of an acute metabolic decompensation that led to hospitalization. Being diseases with low prevalence, it would be useful to have diagnostic and therapeutic protocols in order to provide optimal care. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

High levels of socioeconomic deprivation do not inhibit patients' communication of concerns in head and neck cancer review clinics.

PubMed

Allen, S; Harris, R; Brown, S L; Humphris, G; Zhou, Y; Rogers, S N

2018-06-13

To examine associations between socioeconomic status and the extent to which patients with cancer of the head and neck expressed concerns to surgeons during routine follow-up clinics, we analysed audio recordings of 110 consultations with one consultant. We used the Verona Coding Definitions of Emotional Sequences (VRCoDES) to measure communication between the doctor and the patient, and grouped the English indices of multiple deprivation (IMD) 2015 scores into deciles to compare the VRCoDES with socioeconomic status. There were no significant correlations between IMD decile and the number and type of cues and concerns, or the type of response by the consultant, but there was a positive correlation between IMD decile and duration of appointment (r=0.288, p<0.01). When the duration of appointment was controlled for, there was a negative correlation between IMD decile and number of cues and concerns (r=-0.221, p<0.05). These findings question the assumption that socioeconomic status is associated with a patient's willingness to express concerns. Shorter consultations suggest that less time is spent responding to their concerns or building a rapport. Clinicians might find it advantageous to adopt strategies that will improve their understanding of these patients and help them to communicate more effectively. Copyright © 2018 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

IMPACT OF CHRONIC ANTI-CHOLESTEROL THERAPY ON DEVELOPMENT OF MICROVASCULAR RAREFACTION IN THE METABOLIC SYNDROME

PubMed Central

Goodwill, Adam G.; Frisbee, Stephanie J.; Stapleton, Phoebe A.; James, Milinda E.; Frisbee, Jefferson C.

2011-01-01

Object The obese Zucker rat (OZR) model of the metabolic syndrome is partly characterized by moderate hypercholesterolemia in addition to other contributing co-morbidities. Previous results suggest that vascular dysfunction in OZR is associated with chronic reduction in vascular nitric oxide (NO) bioavailability and chronic inflammation, both frequently associated with hypercholesterolemia. As such, we evaluated the impact of chronic cholesterol reducing therapy on the development of impaired skeletal muscle arteriolar reactivity and microvessel density in OZR and its impact on chronic inflammation and NO bioavailability. Materials and Methods Beginning at 7 weeks of age, male OZR were treated with gemfibrozil, probucol, atorvastatin or simvastatin (in chow) for 10 weeks. Subsequently, plasma and vascular samples were collected for biochemical/molecular analyses, while arteriolar reactivity and microvessel network structure were assessed using established methodologies after 3, 6 and 10 weeks of drug therapy Results All interventions were equally effective at reducing total cholesterol, although only the statins also blunted the progressive reductions to vascular NO bioavailability, evidenced by greater maintenance of acetylcholine-induced dilator responses, an attenuation of adrenergic constrictor reactivity, and an improvement in agonist-induced NO production. Comparably, while minimal improvements to arteriolar wall mechanics were identified with any of the interventions, chronic statin treatment reduced the rate of microvessel rarefaction in OZR. Associated with these improvements was a striking statin-induced reduction in inflammation in OZR, such that numerous markers of inflammation were correlated with improved microvascular reactivity and density. However, using multivariate discriminant analyses, plasma RANTES, IL-10, MCP-1 and TNF-α were determined to be the strongest contributors to differences between groups, although their relative importance varied with time. Conclusions While the positive impact of chronic statin treatment on vascular outcomes in the metabolic syndrome are independent of changes to total cholesterol, and are more strongly associated with improvements to vascular NO bioavailability and attenuated inflammation, these results provide both a spatial and temporal framework for targeted investigation into mechanistic determinants of vasculopathy in the metabolic syndrome. PMID:19905967

Correlation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Neurotoxicity with Blood-Brain Barrier Monoamine Oxidase Activity

NASA Astrophysics Data System (ADS)

Kalaria, Rajesh N.; Mitchell, Mary Jo; Harik, Sami I.

1987-05-01

Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism in humans and subhuman primates, but not in rats and many other laboratory animals; mice are intermediate in their susceptibility. Since MPTP causes selective dopaminergic neurotoxicity when infused directly into rat substantia nigra, we hypothesized that systemic MPTP may be metabolized by monoamine oxidase and/or other enzymes in rat brain capillaries and possibly other peripheral organs and thus prevented from reaching its neuronal sites of toxicity. We tested this hypothesis by assessing monoamine oxidase in isolated cerebral microvessels of humans, rats, and mice by measuring the specific binding of [3H]pargyline, an irreversible monoamine oxidase inhibitor, and by estimating the rates of MPTP and benzylamine oxidation. [3H]Pargyline binding to rat cerebral microvessels was about 10-fold higher than to human or mouse microvessels. Also, MPTP oxidation by rat brain microvessels was about 30-fold greater than by human microvessels; mouse microvessels yielded intermediate values. These results may explain, at least in part, the marked species differences in susceptibility to systemic MPTP. They also suggest the potential importance of ``enzyme barriers'' at the blood-brain interface that can metabolize toxins not excluded by structural barriers, and may provide biological bases for developing therapeutic strategies for the prevention of MPTP-induced neurotoxicity and other neurotoxic conditions including, possibly, Parkinson disease.

Expression of pERK and pAKT in human astrocytomas: correlation with IDH1-R132H presence, vascular endothelial growth factor, microvascular characteristics and clinical outcome.

PubMed

Saetta, Angelica A; Levidou, Georgia; El-Habr, Elias A; Panayotidis, Ioannis; Samaras, Vassilis; Thymara, Irene; Sakellariou, Stratigoula; Boviatsis, Efstathios; Patsouris, Efstratios; Korkolopoulou, Penelope

2011-06-01

Although pERK and pAKT are reportedly activated in various neoplasms, little information is available about their significance in astrocytomas. Paraffin-embedded tissue from 82 patients with diffuse infiltrating astrocytomas (grades II to IV) was investigated for the association of pERK and pAKT activation with clinicopathological features, vascular endothelial growth factor (VEGF), isocitrate dehydrogenase 1 and microvascular parameters. Nuclear pERK labelling index (LI) increased with increasing cytoplasmic pERK LI and nuclear and cytoplasmic pAKT LI (p = 0.0019, p = 0.0260 and p = 0.0012, respectively). Accordingly, cytoplasmic pERK increased with increasing levels of nuclear (p = 0.0001) and marginally with cytoplasmic pAKT LI (p = 0.0526). Nuclear and cytoplasmic pERK LI and nuclear pAKT LI were positively correlated with tumour histological grade (p = 0.0040, p = 0.0238 for pERK and p = 0.0004 for pAKT, respectively). VEGF expression was correlated with nuclear pERK (p = 0.0099) and nuclear pAKT LI (p = 0.0002). Interestingly, pERK cytoplasmic LI increased with microvessel calibre (p = 0.0287), whereas pAKT nuclear LI was marginally related to microvessel density (p = 0.0685). The presence of IDH1-R132H was related only to histological grade and lower microvessel calibre. Multivariate survival analysis in the entire cohort selected cytoplasmic pAKT LI (p = 0.045), histological grade, microvessel calibre (p = 0.028), patients' age, gender and surgical excision as independent predictors of survival. Moreover, in glioblastomas, pERK nuclear LI emerged as a favourable prognosticator in the presence of IDH1-R132H. pERK and pAKT in astrocytomas are interrelated and associated with tumour grade and angiogenesis. Moreover, the importance of cytoplasmic pAKT immunoexpression in patients' prognosis and nuclear pERK immunoexpression in glioblastomas is confirmed.

Retinal microvascular network alterations: potential biomarkers of cerebrovascular and neural diseases.

PubMed

Cabrera DeBuc, Delia; Somfai, Gabor Mark; Koller, Akos

2017-02-01

Increasing evidence suggests that the conditions of retinal microvessels are indicators to a variety of cerebrovascular, neurodegenerative, psychiatric, and developmental diseases. Thus noninvasive visualization of the human retinal microcirculation offers an exceptional opportunity for the investigation of not only the retinal but also cerebral microvasculature. In this review, we show how the conditions of the retinal microvessels could be used to assess the conditions of brain microvessels because the microvascular network of the retina and brain share, in many aspects, standard features in development, morphology, function, and pathophysiology. Recent techniques and imaging modalities, such as optical coherence tomography (OCT), allow more precise visualization of various layers of the retina and its microcirculation, providing a "microscope" to brain microvessels. We also review the potential role of retinal microvessels in the risk identification of cerebrovascular and neurodegenerative diseases. The association between vision problems and cerebrovascular and neurodegenerative diseases, as well as the possible role of retinal microvascular imaging biomarkers in cerebrovascular and neurodegenerative screening, their potentials, and limitations, are also discussed. Copyright © 2017 the American Physiological Society.

Estimating the potential impact on dental caries in children of fluoridating a UK city.

PubMed

Downer, M C; Drugan, C S; Foster, G R K; Tickle, M

2011-03-01

To estimate the potential reduction in dental caries among 5-6-year-old children in a city in the South West of England after six years of water fluoridation. Thirteen out of 35 inner city wards and seven out of 43 outer city wards (sharing the same water supply) having the highest mean dmft of 5-6-year-olds (recorded in a census survey in 2005/6) and/or highest indexes of multiple deprivation (IMD) were the principal focal point. Population demographic data and 5-6-year-old caries prevalence and experience were examined. Mean IMD scores and aggregated, weighted mean values for dmft and caries prevalence were referred to previously published regression analyses of caries levels plotted against IMD for 34 fluoridated (F) and 233 non-fluoridated (NF) health districts in England in order to estimate potential caries reductions. Mean dmft of 5-6-year-olds in the 20 wards with the highest caries levels and/or social deprivation was 2.10 (95% CI 1.87, 2.33) and caries prevalence 49% (95% CI 47%, 52%). In three wards, mean dmft exceeded 2.60. Population of the selected wards was approximately 210,800 with a mean IMD score of 33.70 As a conservative estimate, after six years of fluoridation a caries reduction of > 40% could be expected in 5-6-year-olds for the conurbation overall and for the 20 high caries/high IMD wards, with a gain of 12 percentage points in the absolute proportion caries-free. The overall population of the 78 wards served by the three relevant water treatment works identified was approximately 700,000. On the basis of current caries levels and population demographics, it appears that a comprehensive fluoridation scheme covering the inner and outer city districts would substantially improve the dental health of the city's children.

An outbreak of serogroup C (ST-11) meningococcal disease in Tijuana, Mexico.

PubMed

Chacon-Cruz, Enrique; Espinosa-De Los Monteros, Luz Elena; Navarro-Alvarez, Samuel; Aranda-Lozano, Jose Luis; Volker-Soberanes, Maria Luisa; Rivas-Landeros, Rosa Maria; Alvelais-Arzamendi, Ariadna Annete; Vazquez, Julio Alberto

2014-05-01

Invasive meningococcal disease (IMD) has been reported to be endemic in children from Tijuana, Mexico and the risk of an outbreak was always a threat. To describe all clinical, epidemiological and microbiological features of a meningococcal outbreak that occurred in Tijuana, Mexico. All cases with IMD were admitted at different emergency departments within the city and diagnosed by culture and agglutination tests. Further restriction fragment length polymorphism pulse field gel electrophoresis (RFLP-PFGE) and multi locus sequence typing (MLST) were performed. All clinical and epidemiological characteristics and interventions were evaluated, as well as risk factors associated with mortality. From 30 January 2013 to 30 March 2013 there were 19 cases of IMD all caused by Neisseria meningitidis serogroup C. The median age was 16 years (2-47), with higher frequency among individuals at least 13 years old (73.7%). At admission, meningitis was the main clinical presentation (94.7%), followed by purpura (78.9%), septic shock (42.1%) and disseminated intravascular coagulation (DIC, 36.8%). Overall mortality was seven (36.8%). Variables associated with higher mortality were, at admission, presence of septic shock, DIC and thrombocytopenia less than 70,000. All 19 cases had no identifiable site or cluster as the source of the outbreak. RFLP-PFGE showed a discriminatory power for only one profile on all N. meningitidis strains analyzed and a clone ST-11 was identified in all strains. Public health interventions were continuous case reporting of all suspected cases of IMD, an increase in active surveillance in all hospitals, training of medical and laboratory personnel, massive and rapid chemoprophylaxis to all close contacts as indicated, and promotion of good health habits. An outbreak with high mortality of IMD occurred in Tijuana, Mexico. This event and evidence of endemicity should encourage health authorities to evaluate meningococcal vaccination in the region.

Moving Beyond Average Values: Assessing the Night-To-Night Instability of Sleep and Arousal in DSM-IV-TR Insomnia Subtypes

PubMed Central

Sánchez-Ortuño, M. Montserrat; Carney, Colleen E.; Edinger, Jack D.; Wyatt, James K.; Harris, Andrea

2011-01-01

Study Objectives: We explored differences between individuals with DSM-IV-TR diagnoses of primary insomnia (PI) and insomnia related to a mental disorder (IMD) by using serial measurements of self-reported sleep variables (sleep onset latency, SOL; wake after sleep onset, WASO; total sleep time, TST; sleep efficiency, SE), and visual analogue scale ratings of 2 forms of bedtime arousal (cognitive and emotional). Furthermore, we sought to examine the relationship between sleep and arousal within each diagnostic subgroup. Design: Between-group and within-group comparisons. Setting: Duke and Rush University Medical Centers, USA. Participants: One hundred eighty-seven insomnia sufferers (126 women, average age 47.15 years) diagnosed by sleep specialists at 2 sleep centers as PI patients (n = 126) and IMD patients (n = 61). Interventions: N/A Measurements and Results: Multilevel models for sleep measures indicated that IMD displayed significantly more instability across nights in their TST (i.e., larger changes) than did PI patients. With respect to pre-sleep arousal, IMD patients exhibited higher mean levels of emotional arousal, as well as more instability on the nightly ratings of this measure. Within the PI group, correlational analyses revealed a moderate relationship between the 2 arousal variables and SOL (r values 0.29 and 0.26), whereas the corresponding correlations were negligible and statistically nonsignificant in the IMD group. Conclusions: We found a number of differences on nighttime variables between those diagnosed with primary insomnia and those diagnosed with insomnia related to a mental disorder. These differences imply different perpetuating mechanisms involved in their ongoing sleep difficulties. Additionally, they support the categorical distinctiveness and the concurrent validity of these insomnia subtypes. Citation: Sánchez-Ortuño MM; Carney CE; Edinger JD; Wyatt JK; Harris A. Moving beyond average values: assessing the night-to-night instability of sleep and arousal in DSM-IV-TR insomnia subtypes. SLEEP 2011;34(4):531-539 PMID:21461332

Deregulation of DNA-dependent protein kinase catalytic subunit contributes to human hepatocarcinogenesis development and has a putative prognostic value.

PubMed

Evert, M; Frau, M; Tomasi, M L; Latte, G; Simile, M M; Seddaiu, M A; Zimmermann, A; Ladu, S; Staniscia, T; Brozzetti, S; Solinas, G; Dombrowski, F; Feo, F; Pascale, R M; Calvisi, D F

2013-11-12

The DNA-repair gene DNA-dependent kinase catalytic subunit (DNA-PKcs) favours or inhibits carcinogenesis, depending on the cancer type. Its role in human hepatocellular carcinoma (HCC) is unknown. DNA-dependent protein kinase catalytic subunit, H2A histone family member X (H2AFX) and heat shock transcription factor-1 (HSF1) levels were assessed by immunohistochemistry and/or immunoblotting and qRT-PCR in a collection of human HCC. Rates of proliferation, apoptosis, microvessel density and genomic instability were also determined. Heat shock factor-1 cDNA or DNA-PKcs-specific siRNA were used to explore the role of both genes in HCC. Activator protein 1 (AP-1) binding to DNA-PKcs promoter was evaluated by chromatin immunoprecipitation. Kaplan-Meier curves and multivariate Cox model were used to study the impact on clinical outcome. Total and phosphorylated DNA-PKcs and H2AFX were upregulated in HCC. Activated DNA-PKcs positively correlated with HCC proliferation, genomic instability and microvessel density, and negatively with apoptosis and patient's survival. Proliferation decline and massive apoptosis followed DNA-PKcs silencing in HCC cell lines. Total and phosphorylated HSF1 protein, mRNA and activity were upregulated in HCC. Mechanistically, we demonstrated that HSF1 induces DNA-PKcs upregulation through the activation of the MAPK/JNK/AP-1 axis. DNA-dependent protein kinase catalytic subunit transduces HSF1 effects in HCC cells, and might represent a novel target and prognostic factor in human HCC.

Evaluation of mast cell counts and microvessel density in reactive lesions of the oral cavity.

PubMed

Kouhsoltani, Maryam; Moradzadeh Khiavi, Monir; Tahamtan, Shabnam

2016-01-01

Background. Reliable immunohistochemical assays to assess the definitive role of mast cells (MCs) and angiogenesis in the pathogenesis of oral reactive lesions are generally not available. The aim of the present study was to evaluate mast cell counts (MCC) and microvessel density (MVD) in oral reactive lesions and determine the correlation between MCC and MVD. Methods. Seventy-five cases of reactive lesions of the oral cavity, including pyogenic granuloma, fibroma, peripheral giant cell granuloma, inflammatory fibrous hyperplasia, peripheral ossifying fibroma (15 for each category) were immunohisto-chemically stained with MC tryptase and CD31. Fifteen cases of normal gingival tissue were considered as the control group. The mean MCC and MVD in superficial and deep connective tissues were assessed and total MCC and MVD was computed for each lesion. Results . Statistically significant differences were observed in MCC and MVD between the study groups (P < 0.001). MC tryptase and CD31 expression increased in the superficial connective tissue of each lesion in comparison to the deep con-nective tissue. A significant negative correlation was not found between MCC and MVD in oral reactive lesions (P < 0.001, r = -0.458). Conclusion. Although MCs were present in the reactive lesions of the oral cavity, a direct correlation between MCC and MVD was not found in these lesions. Therefore, a significant interaction between MCs and endothelial cells and an active role for MCs in the growth of oral reactive lesions was not found in this study.

ALK1 expression in oral lichen planus: a possible relation to microvessel density.

PubMed

Hazzaa, Hala H A; El-Wakeel, Naglaa M; Attia, Enas A S; Abo Hager, Eman A

2016-05-01

To assess the expression of activin receptor-like kinase 1 (ALK1) and investigate its possible relationship with microvessel density (MVD) in different forms of oral lichen planus (OLP) compared to controls' biopsies. Biopsies from 20 reticular/papular OLP (R/PLP), 20 atrophic/erosive OLP (A/ELP) patients, and 20 healthy subjects were immunohistochemically analyzed and statistically compared and correlated for ALK1 expression and MVD as assessed by CD34 expression. All OLP specimens revealed the presence of positive cytoplasmic CD34 immunostaining in endothelial cells, with statistically high significant MVD in each of R/PLP (Median; M = 4.40) and A/ELP (M = 7.69) compared to controls (M = 1.16) (P < 0.001). Statistically significant MVD was found in A/ELP compared to R/PLP (P < 0.001). All control specimens revealed negative ALK1 immunostaining of the few inflammatory cells found, while 85% of A/ELP cases and 70% of R/PLP cases showed positively immunostained sections for ALK-1, with statistically significant higher ALK1 expression In A/ELP (M = 1.95) compared to R/PLP (M = 0.86) (P = 0.005). No significant correlation between CD34 and ALK1 was detected in R/PLP (r = 0.081), while a barely moderate positive correlation was found in A/ELP (r = 0.396). ALK1 expression and MVD are increased in OLP, particularly in A/ELP type. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Sublingual microcirculatory alterations in cirrhotic patients.

PubMed

Gonzalez Ballerga, Esteban; Pozo, Mario O; Rubatto Birri, Paolo N; Kanoore Edul, Vanina Siham; Sorda, Juan A; Daruich, Jorge; Dubin, Arnaldo

2018-05-01

To assess sublingual microcirculation in cirrhotic patients and its relationship to spider angiomas, complications, and outcome. Thirty-one cirrhotic patients were prospectively compared to 31 matched controls. Sublingual microcirculation was evaluated by videomicroscopy. We specifically looked for capillaries with increased RBCV, which was defined as a velocity higher than the percentile 100th of controls. Compared to controls, cirrhotic patients showed decreased total and PVD (14.4 ± 2.2 vs 16.0 ± 1.3 and 14.1 ± 2.3 vs 15.9 ± 1.6 mm/mm 2 , respectively, P < .001 for both) and increased HFI (0.64 ± 0.39 vs 0.36 ± 0.21, P = .001). They also exhibited high RBCV in 2% of the microvessels (P < .0001). Patients with MELD score ≥10 had higher RBCV than patients with score <10 (1414 ± 290 vs 1206 ± 239 μm/s, P < .05). Patients with spider angiomas showed lower vascular densities. Microcirculation did not differ between survivors and nonsurvivors. Cirrhosis is associated with microcirculatory alterations that can be easily monitored in the sublingual mucosa. Alterations included decreased density and PPV and hyperdynamic microvessels. The most striking finding, however, was the microvascular heterogeneity. Patients with spider angiomas had more severe alterations. Larger studies should clarify the relationship between microcirculatory abnormalities and outcome. © 2018 John Wiley & Sons Ltd.

The gain-of-function GLI1 transcription factor TGLI1 enhances expression of VEGF-C and TEM7 to promote glioblastoma angiogenesis.

PubMed

Carpenter, Richard L; Paw, Ivy; Zhu, Hu; Sirkisoon, Sherona; Xing, Fei; Watabe, Kounosuke; Debinski, Waldemar; Lo, Hui-Wen

2015-09-08

We recently discovered that truncated glioma-associated oncogene homolog 1 (TGLI1) is highly expressed in glioblastoma (GBM) and linked to increased GBM vascularity. The mechanisms underlying TGLI1-mediated angiogenesis are unclear. In this study, we compared TGLI1- with GLI1-expressing GBM xenografts for the expression profile of 84 angiogenesis-associated genes. The results showed that expression of six genes were upregulated and five were down-regulated in TGLI1-carrying tumors compared to those with GLI1. Vascular endothelial growth factor-C (VEGF-C) and tumor endothelial marker 7 (TEM7) were selected for further investigations because of their significant correlations with high vascularity in 135 patient GBMs. TGLI1 bound to both VEGF-C and TEM7 gene promoters. Conditioned medium from TGLI1-expressing GBM cells strongly induced tubule formation of brain microvascular endothelial cells, and the induction was prevented by VEGF-C/TEM7 knockdown. Immunohistochemical analysis of 122 gliomas showed that TGLI1 expression was positively correlated with VEGF-C, TEM7 and microvessel density. Analysis of NCBI Gene Expression Omnibus datasets with 161 malignant gliomas showed an inverse relationship between tumoral VEGF-C, TEM7 or microvessel density and patient survival. Together, our findings support an important role that TGLI1 plays in GBM angiogenesis and identify VEGF-C and TEM7 as novel TGLI1 target genes of importance to GBM vascularity.

The 15-LO-1/15-HETE system promotes angiogenesis by upregulating VEGF in ischemic brains.

PubMed

Chen, Li; Zhu, Yan-Mei; Li, Yu-Nong; Li, Peng-Yan; Wang, Di; Liu, Yu; Qu, You-Yang; Zhu, Da-Ling; Zhu, Yu-Lan

2017-09-01

Angiogenesis promotes neurobehavioral recovery after cerebral ischemic stroke. 15(S)-hydroxyeicosatetraenoic acid (15-HETE) is one of the major metabolites of arachidonic acid by 15-lipoxygenase (15-LO) and stimulates the production of vascular endothelial growth factor (VEGF), thus, inducing autocrine-mediated angiogenesis. The present study aimed to investigate the role of 15-LO/15-HETE system on VEGF expression and angiogenesis in brain ischemia. Rat cerebral arterial vascular endothelial cells were used to set up a cell injury model of oxygen-glucose deprivation and reoxygenation (OGD/R), mimicking a condition of brain ischemia. A mouse model of middle cerebral artery occlusion (MCAO) was established. Oxygen-glucose deprivation increased cellular expression of 15-LO-1 and VEGF. Transfection of 15-LO-1 siRNA depleted cells of 15-LO-1, and sequentially induced downregulation of VEGF expression; while, incubation of 15-HETE increased the expression of VEGF. Incubation of 15-HETE attenuated the reduction in cell viability induced by oxygen-glucose deprivation, and promoted cell migration, while transfection of 15-LO-1 siRNA showed an opposite effect. In animal experiments, the density of microvessels in hypoxic regions of brains was significantly increased after MCAO, while intracerebroventricular delivery of 15-LO-1 siRNA significantly reduced the density of microvessels, and downregulates VEGF expression. The results indicate that the 15-LO-1/15-HETE system promotes angiogenesis in ischemic brains by upregulation of VEGF, representing a potential target for improving neurobehavioral recovery after cerebral ischemic stroke.

Clinicopathologic and prognostic implications of progranulin in breast carcinoma.

PubMed

Li, Li-qin; Huang, Hui-lian; Ping, Jin-liang; Wang, Xiao-hong; Zhong, Jing; Dai, Li-cheng

2011-07-05

Progranulin is a newly discovered 88-kDa glycoprotein originally purified from the highly tumorigenic mouse teratoma-derived cell line PC. Its expression is closely correlated with the development and metastasis of several cancers. However, no immunohistochemical evidence currently exists to correlate progranulin expression with clinicopathologic features in breast carcinoma biopsies, and the role of progranulin as a new marker of metastatic risk and prognosis in breast cancer has not yet been studied. The aim of this study was to investigate the clinicopathologic and prognostic implications of progranulin expression in breast carcinoma and its correlation with tumor angiogenesis. Progranulin expression was determined immunohistochemically in 183 surgical specimens from patients with breast cancer and 20 tissue samples from breast fibroadenomas. The tumor angiogenesis-related biomarker, vascular endothelial growth factor was assayed and microvessel density was assessed by counting vascular endothelial cells in tumor tissues labeled with endoglin antibody. The relationship between progranulin expression and the clinicopathologic data were analyzed. Progranulin proteins were overexpressed in breast cancer. The level of progranulin expression was significantly correlated with tumor size (P = 0.004), lymph node metastasis (P < 0.001) and TNM staging (P < 0.001). High progranulin expression was associated with higher tumor angiogenesis, reflected by increased vascular endothelial growth factor expression (P < 0.001) and higher microvessel density (P = 0.002). Progranulin may be a valuable marker for assessing the metastasis and prognosis of breast cancer, and could provide the basis for new combination regimens with antiangiogenic activity.

Cyclooxygenase-2 expression in human gastric tubular adenomas and carcinomas; correlation with intratumoral microvessel density and apoptotic index.

PubMed

Honjo, Soichiro; Kase, Satoru; Osaki, Mitsuhiko; Ardyanto, Tonang Dwi; Kaibara, Nobuaki; Ito, Hisao

2004-01-01

Cyclooxygenase (COX)-2 plays an important role in carcinogenesis in various human malignancies. This study examined the relationship among COX-2 expression, angiogenesis and apoptosis in human gastric adenoma and carcinoma. We examined the expression of COX-2 in 30 tubular adenomas and 11 carcinomas, comparing it with intratumoral microvessel density (IMVD) and apoptotic index (AI) by immunohistochemistry and the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-digoxygenin nick-end labeling (TUNEL) procedure. Immunohistochemistry demonstrated positive expression of COX-2 in 15 (50.0%) adenomas and in 50 (53.1%) carcinomas, respectively. The frequency of COX-2 expression was significantly higher in intestinal-type carcinomas than in diffuse-type, regardless of the tumor stage. The IMVD was significantly higher in the early and advanced carcinomas than in the adenomas and also higher in the COX-2-positive adenomas and carcinomas than in the negative ones. The AI was significantly higher in the adenomas than in the carcinomas and also in the COX-2-negative adenomas and intestinal-type early carcinomas than in their positive counterparts, respectively (p < 0.05). The IMVD and AI showed significant inverse correlation in both the adenomas (p=0.02, r=-0.64) and carcinomas (p=0.04, r=-0.18). COX-2 expression might be an early event in gastric tumorigenesis and provide a preferential advantage for tumor cell proliferation because of its vascular-rich microenvironment and escape from tumor cell apoptosis, especially in intestinal-type gastric carcinomas.

Angiogenesis and lymphangiogenesis as prognostic factors after therapy in patients with cervical cancer

PubMed Central

Makarewicz, Roman; Kopczyńska, Ewa; Marszałek, Andrzej; Goralewska, Alina; Kardymowicz, Hanna

2012-01-01

Aim of the study This retrospective study attempts to evaluate the influence of serum vascular endothelial growth factor C (VEGF-C), microvessel density (MVD) and lymphatic vessel density (LMVD) on the result of tumour treatment in women with cervical cancer. Material and methods The research was carried out in a group of 58 patients scheduled for brachytherapy for cervical cancer. All women were patients of the Department and University Hospital of Oncology and Brachytherapy, Collegium Medicum in Bydgoszcz of Nicolaus Copernicus University in Toruń. VEGF-C was determined by means of a quantitative sandwich enzyme immunoassay using a human antibody VEGF-C ELISA produced by Bender MedSystem, enzyme-linked immunosorbent detecting the activity of human VEGF-C in body fluids. The measure for the intensity of angiogenesis and lymphangiogenesis in immunohistochemical reactions is the number of blood vessels within the tumour. Statistical analysis was done using Statistica 6.0 software (StatSoft, Inc. 2001). The Cox proportional hazards model was used for univariate and multivariate analyses. Univariate analysis of overall survival was performed as outlined by Kaplan and Meier. In all statistical analyses p < 0.05 (marked red) was taken as significant. Results In 51 patients who showed up for follow-up examination, the influence of the factors of angiogenesis, lymphangiogenesis, patients’ age and the level of haemoglobin at the end of treatment were assessed. Selected variables, such as patients’ age, lymph vessel density (LMVD), microvessel density (MVD) and the level of haemoglobin (Hb) before treatment were analysed by means of Cox logical regression as potential prognostic factors for lymph node invasion. The observed differences were statistically significant for haemoglobin level before treatment and the platelet number after treatment. The study revealed the following prognostic factors: lymph node status, FIGO stage, and kind of treatment. No statistically significant influence of angiogenic and lymphangiogenic factors on the prognosis was found. Conclusion Angiogenic and lymphangiogenic factors have no value in predicting response to radiotherapy in cervical cancer patients. PMID:23788848

Atmospheric Chemistry of Neonicotinoids Used in Urban Areas

NASA Astrophysics Data System (ADS)

Finlayson-Pitts, B. J.; Aregahegn, K.; Shemesh, D.; Gerber, R. B.

2016-12-01

Neonicotinoid (NN) pesticides are used extensively in both urban and agricultural settings to control sucking pests such as aphids, as well as for flea control for domestic pets. As a result, they are commonly found on surfaces that are exposed to the atmosphere. Imidacloprid (IMD) is one of the major NNs in pest control formulations. While there have been a number of studies of IMD reactions in solution, there are relatively few surface reactions that are relevant to atmospheric exposures. We report here laboratory studies of the photochemistry of IMD on surfaces in which quantum yields are measured and combined with absorption cross sections to estimate tropospheric lifetimes with respect to photolysis. Products identified using a combination of ATR-FTIR, DART-MS and ESI-MS include the desnitro and urea derivatives in the solid, and N2O in the gas phase. Quantum chemical calculations suggest a mechanism for the photolysis and production of these products. The implications for altering toxicity through atmospheric reactions will be discussed.

Security and privacy issues in implantable medical devices: A comprehensive survey.

PubMed

Camara, Carmen; Peris-Lopez, Pedro; Tapiador, Juan E

2015-06-01

Bioengineering is a field in expansion. New technologies are appearing to provide a more efficient treatment of diseases or human deficiencies. Implantable Medical Devices (IMDs) constitute one example, these being devices with more computing, decision making and communication capabilities. Several research works in the computer security field have identified serious security and privacy risks in IMDs that could compromise the implant and even the health of the patient who carries it. This article surveys the main security goals for the next generation of IMDs and analyzes the most relevant protection mechanisms proposed so far. On the one hand, the security proposals must have into consideration the inherent constraints of these small and implanted devices: energy, storage and computing power. On the other hand, proposed solutions must achieve an adequate balance between the safety of the patient and the security level offered, with the battery lifetime being another critical parameter in the design phase. Copyright © 2015 Elsevier Inc. All rights reserved.

Should Metabolic Diseases Be Systematically Screened in Nonsyndromic Autism Spectrum Disorders?

PubMed Central

Schiff, Manuel; Benoist, Jean-François; Aïssaoui, Sofiane; Boepsflug-Tanguy, Odile; Mouren, Marie-Christine; de Baulny, Hélène Ogier; Delorme, Richard

2011-01-01

Background In the investigation of autism spectrum disorders (ASD), a genetic cause is found in approximately 10–20%. Among these cases, the prevalence of the rare inherited metabolic disorders (IMD) is unknown and poorly evaluated. An IMD responsible for ASD is usually identified by the associated clinical phenotype such as dysmorphic features, ataxia, microcephaly, epilepsy, and severe intellectual disability (ID). In rare cases, however, ASD may be considered as nonsyndromic at the onset of a related IMD. Objectives To evaluate the utility of routine metabolic investigations in nonsyndromic ASD. Patients and Methods We retrospectively analyzed the results of a metabolic workup (urinary mucopolysaccharides, urinary purines and pyrimidines, urinary creatine and guanidinoacetate, urinary organic acids, plasma and urinary amino acids) routinely performed in 274 nonsyndromic ASD children. Results The metabolic parameters were in the normal range for all but 2 patients: one with unspecific creatine urinary excretion and the other with persistent 3-methylglutaconic aciduria. Conclusions These data provide the largest ever reported cohort of ASD patients for whom a systematic metabolic workup has been performed; they suggest that such a routine metabolic screening does not contribute to the causative diagnosis of nonsyndromic ASD. They also emphasize that the prevalence of screened IMD in nonsyndromic ASD is probably not higher than in the general population (<0.5%). A careful clinical evaluation is probably more reasonable and of better medical practice than a costly systematic workup. PMID:21760924

Functional Analysis of the Twin-Arginine Translocation Pathway in Corynebacterium glutamicum ATCC 13869▿

PubMed Central

Kikuchi, Yoshimi; Date, Masayo; Itaya, Hiroshi; Matsui, Kazuhiko; Wu, Long-Fei

2006-01-01

Compared to those of other gram-positive bacteria, the genetic structure of the Corynebacterium glutamicum Tat system is unique in that it contains the tatE gene in addition to tatA, tatB, and tatC. The tatE homologue has been detected only in the genomes of gram-negative enterobacteria. To assess the function of the C. glutamicum Tat pathway, we cloned the tatA, tatB, tatC, and tatE genes from C. glutamicum ATCC 13869 and constructed mutants carrying deletions of each tat gene or of both the tatA and tatE genes. Using green fluorescent protein (GFP) fused with the twin-arginine signal peptide of the Escherichia coli TorA protein, we demonstrated that the minimal functional Tat system required TatA and TatC. TatA and TatE provide overlapping function. Unlike the TatB proteins from gram-negative bacteria, C. glutamicum TatB was dispensable for Tat function, although it was required for maximal efficiency of secretion. The signal peptide sequence of the isomaltodextranase (IMD) of Arthrobacter globiformis contains a twin-arginine motif. We showed that both IMD and GFP fused with the signal peptide of IMD were secreted via the C. glutamicum Tat pathway. These observations indicate that IMD is a bona fide Tat substrate and imply great potential of the C. glutamicum Tat system for industrial production of heterologous folded proteins. PMID:16997984

Dissemination of the ST-103 clonal complex serogroup C meningococci in Salvador, Brazil.

PubMed

Cordeiro, Soraia Machado; Cardoso, Cristiane Wanderley; de Araújo, Lorena Galvão; Ribeiro, Luis Eduardo; Azevedo, Jailton; Silva, Rita de Cassia Vilasboas; Dos Reis, Mitermayer Galvão; Ko, Albert Icksang; Reis, Joice Neves

2018-01-01

Invasive meningococcal disease (IMD) is a major public health problem worldwide. An epidemic of serogroup C (NmC) IMD occurred in 2010 in the city of Salvador. In this study, we describe the antigenic and genetic characterization of meningococcal isolates collected from meningitis cases in Salvador from 2001 to 2012. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) were performed for the analysis of IMD isolates. A total of 733 cases were identified, and the serogroup was determined for 391 (53.0%) of these. Most cases were caused by NmC (53%) or B (47%). The most prevalent strains were B:4,7:P1.19,15 (32.9%; 129/391) and C:23:P1.14-6 (28.6%; 112/391). Based on PFGE/MLST analysis, 71.3% (77/108 PFGE-tested isolates) clustered as two clones of sequence type ST-3779 and ST-3780, both belonging to the ST-103 clonal complex. ST-3779 has been detected in Salvador since 1996 and together with ST-3780 became predominant after 2005. There was a predominance of C:23:P1.14-6, ST-3779/3780 in Salvador during the period of 2007-2012, establishing a major clonal lineage, which remained in the community for a long time; this has serious implications for public health, particularly in terms of prevention and control strategies of IMD. Copyright © 2017 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

High-performance MgB2 superconducting wires for use under liquid-helium-free conditions fabricated using an internal Mg diffusion process

NASA Astrophysics Data System (ADS)

Ye, ShuJun; Song, Minghui; Matsumoto, Akiyoshi; Togano, Kazumasa; Takeguchi, Masaki; Ohmura, Takahito; Kumakura, Hiroaki

2013-12-01

MgB2 has a superconducting transition temperature (Tc) of 39 K, which is much higher than that for practical metallic superconductors. Thus, it is hoped that MgB2 can not only replace metallic superconductors, but can be used under liquid-helium-free conditions, for example, at temperatures of 10-20 K that can easily be achieved using cryocooling systems. However, to date, the reported critical current density (Jc) for MgB2 wires is not high enough for large-scale applications in liquid-helium-free conditions. In the present study, successful fabrication of high-performance MgB2 superconducting wires was carried out using an internal Mg diffusion (IMD) process, involving a p-dimethylbenzene (C8H10) pre-treatment of carbon-coated B powder with nanometer-sized particles. The resulting wires exhibited the highest ever Jc of 1.2 × 105 A cm-2 at 4.2 K and 10 T, and an engineering critical current density (Je) of about 1 × 104 A cm-2. Not only in 4.2 K, but also in 10 K, the Jc values for the wires fabricated in the present study are in fact higher than that for Nb-Ti wires at 4.2 K for the magnetic fields at which the measurements were carried out. At 20 K and 5 T, the Jc and Je were about 7.6 × 105 A cm-2 and 5.3 × 103 A cm-2, respectively, which are the highest values reported for MgB2 wires to date. The results of a detailed microstructural analysis suggested that the main reason for the superior electrical performance was the high density of the MgB2 layer rather than just the small grain size, and that the critical current could be further increased by suitable control of the microstructure. These high-performance IMD-processed MgB2 wires are thus promising superconductors for applications such as magnetic resonance imaging and maglev trains that can operate under liquid-helium-free conditions.

Biological basis and pathological relevance of microvascular thrombosis.

PubMed

Pfeiler, Susanne; Massberg, Steffen; Engelmann, Bernd

2014-05-01

Microvascular thrombosis indicates a pathological occlusion of microvessels by fibrin- and/or platelet-rich thrombi. It is observed during systemic infections, cancer, myocardial infarction, stroke, neurodegenerative diseases and in thrombotic microangiopathies. Microvessel thrombosis can cause greatly differing symptoms that range from limited changes in plasma coagulation markers to severe multi-organ failure. Because microvessel thrombi are difficult to detect and often occur only transiently, their importance for disease development and host biology is likely markedly under-appreciated. Recently, clear indications for a biological basis of microvascular thrombosis have been obtained. During systemic infections microvessel thrombosis can mediate an intravascular innate immune response (immunothrombosis). This biological form of thrombosis is based on the generation of fibrin inside blood vessels and is critically triggered by neutrophils and their interactions with platelets which result in the release of neutrophil extracellular traps (extracellular nucleosomes). Immunothrombosis is critically supported by neutrophil elastase and the activator molecules of blood coagulation tissue factor and factor XII. Identification of the biological driving forces of microvascular thrombosis should help to elucidate the mechanisms promoting pathological vessel occlusions in both microvessels and large vessels. Copyright © 2014 Elsevier Ltd. All rights reserved.

Nonendothelial source of nitric oxide in arterioles but not in venules: alternative source revealed in vivo by diaminofluorescein microfluorography.

PubMed

Kashiwagi, Satoshi; Kajimura, Mayumi; Yoshimura, Yasunori; Suematsu, Makoto

2002-12-13

This study aimed to examine topographic distribution of microvascular NO generation in vivo. To this end, nitrosonium ion (NO+)-sensitive diaminofluorescein diacetate was superfused continuously on the rat mesentery and the fluorescence was visualized in the microvessels through laser confocal microfluorography. Two major sites exhibited a time-dependent elevation of the fluorescence: microvascular endothelia and mast cells. As judged by the fluorescence sensitivity to local application of different inhibitors of NO synthase (NOS), NO availability in arteriolar endothelium and mast cells appeared to be maintained mainly by NOS1, whereas that in venular endothelium greatly depends on NOS3. In venules, the magnitude of inhibitory responses elicited by the inhibitors was positively correlated with the density of leukocyte adhesion. NOS inhibitors significantly reduced, but did not eliminate, the NO+-associated fluorescence in arterioles, capillaries, and venules, suggesting alternative sources of NO in circulation for these microvessels. Immunohistochemistry for NOS isozymes revealed that NOS1 occurred not only in nerve fibers innervated to arterioles but also abundantly in mast cells. Laser flow cytometry of peritoneal cells in vitro revealed abundant expression of NOS1 in mast cells. Interestingly, NOS3 occurred in endothelia of capillaries and venules but not in those of distal arterioles with comparable diameters. These results suggest that the arterioles receive NO from nonendothelial origins involving NOS1 present in nerve terminals and mast cells, whereas venules depend on the endothelial NOS as a major source. Furthermore, nonenzymatic sources of NO from circulating reservoirs constitute a notable fraction throughout different classes of microvessels. The full text of this article is available at http://www.circresaha.org.

Multimodal optical imaging of microvessel network convective oxygen transport dynamics.

PubMed

Dedeugd, Casey; Wankhede, Mamta; Sorg, Brian S

2009-04-01

Convective oxygen transport by microvessels depends on several parameters, including red blood cell flux and oxygen saturation. We demonstrate the use of intravital microscopy techniques to measure hemoglobin saturations, red blood cell fluxes and velocities, and microvessel cross-sectional areas in regions of microvascular networks containing multiple vessels. With these methods, data can be obtained at high spatial and temporal resolution and correlations between oxygen transport and hemodynamic parameters can be assessed. In vivo data are presented for a mouse mammary adenocarcinoma grown in a dorsal skinfold window chamber model.

NADPH Oxidase-Mediated ROS Production Determines Insulin's Action on the Retinal Microvasculature.

PubMed

Kida, Teruyo; Oku, Hidehiro; Horie, Taeko; Matsuo, Junko; Kobayashi, Takatoshi; Fukumoto, Masanori; Ikeda, Tsunehiko

2015-10-01

To determine whether insulin induces nitric oxide (NO) formation in retinal microvessels and to examine the effects of high glucose on the formation of NO. Freshly isolated rat retinal microvessels were incubated in normal (5.5 mM) or high (20 mM) glucose with or without insulin (100 nM). The levels of insulin-induced NO and reactive oxygen species (ROS) in the retinal microvessels were determined semiquantitatively using fluorescent probes, 4,5-diaminofluorescein diacetate, and hydroethidine, respectively, and a laser scanning confocal microscope. The insulin-induced changes of NO in rat retinal endothelial cells and pericytes cultured at different glucose concentrations (5.5 and 25 mM) were determined using flow cytometry. Nitric oxide synthase (NOS) protein levels were determined by Western blot analysis; intracellular levels of ROS were determined using fluorescence-activated cell sorting (FACS) analysis of ethidium fluorescence; and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase RNA expression was quantified using real-time PCR. Exposure of microvessels to insulin under normal glucose conditions led to a significant increase in NO levels; however, this increase was significantly suppressed when the microvessels were incubated under high glucose conditions. Intracellular levels of ROS were significantly increased in both retinal microvessels and cultured microvascular cells under high glucose conditions. The expression of NOS and NADPH oxidase were significantly increased in endothelial cells and pericytes under high glucose conditions. The increased formation of NO by insulin and its suppression by high glucose conditions suggests that ROS production mediated by NADPH oxidase is important by insulin's effect on the retinal microvasculature.

A comparative study of the spatial distribution of mast cells and microvessels in the foetal, adult human thymus and thymoma.

PubMed

Raica, Marius; Cimpean, Anca Maria; Nico, Beatrice; Guidolin, Diego; Ribatti, Domenico

2010-02-01

Mast cells (MCs) are widely distributed in human and animal tissues and have been shown to play an important role in angiogenesis in normal and pathological conditions. Few data are available about the relationship between MCs and blood vessels in the normal human thymus, and there are virtually no data about their distribution and significance in thymoma. The aim of this study was to analyse the spatial distribution of MCs and microvessels in the normal foetal and adult thymus and thymoma. Twenty biopsy specimens of human thymus, including foetal and adult normal thymus and thymoma were analysed. Double staining with CD34 and mast cell tryptase was used to count both mast cells and microvessels in the same fields. Computer-assisted image analysis was performed to characterize the spatial distribution of MCs and blood vessels in selected specimens. Results demonstrated that MCs were localized exclusively to the medulla. Their number was significantly higher in thymoma specimens as compared with adult and foetal normal specimens respectively. In contrast the microvessel area was unchanged. The analysis of the spatial distribution and relationship between MCs and microvessels revealed that only in the thymoma specimens was there a significant spatial association between MCs and microvessels. Overall, these data suggest that MCs do not contribute significantly to the development of the vascular network in foetal and adult thymus, whereas in thymoma they show a close relationship to blood vessels. This could be an expression of their involvement not only in endothelial cells but also in tumour cell proliferation.

Thrombin Induces Inositol Trisphosphate-Mediated Spatially Extensive Responses in Lung Microvessels.

PubMed

Escue, Rachel; Kandasamy, Kathirvel; Parthasarathi, Kaushik

2017-04-01

Activation of plasma membrane receptors initiates compartmentalized second messenger signaling. Whether this compartmentalization facilitates the preferential intercellular diffusion of specific second messengers is unclear. Toward this, the receptor-mediated agonist, thrombin, was instilled into microvessels in a restricted region of isolated blood-perfused mouse lungs. Subsequently, the thrombin-induced increase in endothelial F-actin was determined using confocal fluorescence microscopy. Increased F-actin was evident in microvessels directly treated with thrombin and in those located in adjoining thrombin-free regions. This increase was abrogated by inhibiting inositol trisphosphate-mediated calcium release with Xestospongin C (XeC). XeC also inhibited the thrombin-induced increase in the amplitude of endothelial cytosolic Ca 2+ oscillations. Instillation of thrombin and XeC into adjacent restricted regions increased F-actin in microvessels in the thrombin-treated and adjacent regions but not in those in the XeC-treated region. Thus, inositol trisphosphate, and not calcium, diffused interendothelially to the spatially remote thrombin-free microvessels. Thus, activation of plasma membrane receptors increased the ambit of inflammatory responses via a second messenger different from that used by stimuli that induce cell-wide increases in second messengers. Thrombin however failed to induce the spatially extensive response in microvessels of mice lacking endothelial connexin43, suggesting a role for connexin43 gap junctions. Compartmental second messenger signaling and interendothelial communication define the specific second messenger involved in exacerbating proinflammatory responses to receptor-mediated agonists. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

A computational model of in vitro angiogenesis based on extracellular matrix fibre orientation.

PubMed

Edgar, Lowell T; Sibole, Scott C; Underwood, Clayton J; Guilkey, James E; Weiss, Jeffrey A

2013-01-01

Recent interest in the process of vascularisation within the biomedical community has motivated numerous new research efforts focusing on the process of angiogenesis. Although the role of chemical factors during angiogenesis has been well documented, the role of mechanical factors, such as the interaction between angiogenic vessels and the extracellular matrix, remains poorly understood. In vitro methods for studying angiogenesis exist; however, measurements available using such techniques often suffer from limited spatial and temporal resolutions. For this reason, computational models have been extensively employed to investigate various aspects of angiogenesis. This paper outlines the formulation and validation of a simple and robust computational model developed to accurately simulate angiogenesis based on length, branching and orientation morphometrics collected from vascularised tissue constructs. Microvessels were represented as a series of connected line segments. The morphology of the vessels was determined by a linear combination of the collagen fibre orientation, the vessel density gradient and a random walk component. Excellent agreement was observed between computational and experimental morphometric data over time. Computational predictions of microvessel orientation within an anisotropic matrix correlated well with experimental data. The accuracy of this modelling approach makes it a valuable platform for investigating the role of mechanical interactions during angiogenesis.

Inability of immunomorphometric assessment of angiogenesis to distinguish primary versus secondary myelofibrosis.

PubMed

Sharma, Prashant; Pati, Hara Prasad; Mishra, Pravas Chandra; Dinda, Amit Kumar; Gupta, Ruchika; Sharma, Alok; Jacob, Tony George

2011-08-01

To explore the utility of bone marrow (BM) angiogenesis in differentiating primary myelofibrosis (PMF) from secondary myelofibrosis (MF). CD34 immunostaining was performed on BM biopsies from 21 PMFs, 23 non-PMF myeloproliferative neoplasms (MPN) with associated MF, 20 secondary MF samples, and 10 nonfibrotic controls. Microvessel density (MVD) and microvessel surface area (MSA), along with blood and BM findings were compared between the groups. The post-MPN MF cases included chronic myeloid leukemia-MF and polycythemia vera-MF. Etiologies of secondary MF were metastatic carcinomas, non-MPN hematologic malignancies, tuberculosis, autoimmune MF, and osteopetrosis. Megakaryocytic clustering was the most frequent and intrasinusoidal hematopoiesis the most specific feature of PMF. Higher reticulin grade, collagenization, and osteomyelosclerosis were commoner in PMF. MVD and MSA were significantly increased in fibrotic marrows regardless of etiology. Although mean MVD as well as MSA were highest in PMF, extensive overlaps among groups and marked heterogeneity in the secondary MF group rendered them of limited utility in the differential diagnosis. Enhanced angiogenesis is not entirely specific for PMF. Overlaps with secondary MF limits its differential diagnostic utility. Pathogenetically, our findings suggest that enhanced angiogenesis is a secondary paraneoplastic stromal response shared by various unrelated conditions.

Mathematical beta function formulation for maxillary arch form prediction in normal occlusion population.

PubMed

Mina, Morteza; Borzabadi-Farahani, Ali; Tehranchi, Azita; Nouri, Mahtab; Younessian, Farnaz

2017-04-01

The aim of this study was to assess the dental arch curvature in subjects with normal occlusion in an Iranian population and propose a beta function formula to predict maxillary arch form using the mandibular intermolar widths (IMW) and intermolar depths (IMD). The materials used were study casts of 54 adolescents with normal occlusion and mean age of 14.1 years (25 males, 29 females, age range 12-16 years). Curve-fitting analyses were carried out and the curves passing through the facial-axis point of the canines, premolars, first molars, and the incisal edges of the anterior teeth were studied using a 3D laser scanner. Using the measured IMW and IMD of the dental arches at the maxillary and mandibular first molar region, a beta function formula proposed for predicting maxillary arch form. The accuracy of the proposed formula was assessed on 10 randomly selected dental casts. The mean (SD) of the maxillary and mandibular IMW and IMD were 57.92 (4.75), 54.19 (5.31), and 31.59 (2.90) and 28.10 (2.59) mm, respectively. There was no gender dimorphism (P > 0.05) for both variables (IMW, IMD). There was a strong positive association (n = 10, Pearson r = 0.98, P < 0.05) between the measured (actual) maxillary arch length and proposed arch length derived from generated formula. The goodness of fit (whole arch) for the proposed beta function formula, using adjusted r square measure and root mean square in 10 patients averaged 0.97 and 1.49 mm, respectively. The corresponding figures for the maxillary anterior arch (canine to canine) were 0.90 and 0.92 mm, respectively. The proposed beta function formula used for predicting maxillary arch form based on two mandibular measures (IMW, IMD) was found to have a high accuracy for maxillary arch prediction in the Iranian population and may be used as a guide to fabricate customized arch wires or as an aid in maxillary reconstructive surgery.

Comparison of Precipitation from Gauge and Tropical Rainfall Measurement Mission (TRMM) for River Basins of India

NASA Astrophysics Data System (ADS)

Mondal, A.; Chandniha, S. K.; Lakshmi, V.; Kundu, S.; Hashemi, H.

2017-12-01

This study compares the monthly precipitation from the gridded rain gauge data collected by India Meteorological Department (IMD) and the retrievals from the Tropical Rainfall Measurement Mission (TRMM) for the river basins of India using the TRMM Multisatellite Precipitation Analysis (TMPA) version 7 (V7). The IMD and TMPA datasets have the same spatial resolution (0.25°×0.25°) and extend from 1998 to 2013. The TRMM data accuracy for the river basins is assessed by comparison with IMD using root mean square error (RMSE), normalized mean square error (NMSE), Nash-Sutcliffe coefficient (NASH) and correlation coefficient (CC) methods. The Mann-Kendall (MK) and modified Mann-Kendall (MMK) tests have been applied for analyzing the data trend, and the change has been detected by Sen's Slope using both data sets for annual and seasonal time periods. The change in intensity of precipitation is estimated by percentage for comparing actual differences in various river basins. Variation in precipitation is high (>100 mm represents >15% of average annual precipitation) in Brahmaputra, rivers draining into Myanmar (RDM), rivers draining into Bangladesh (RDB), east flowing rivers between Mahanadi and Godavari (EMG), east flowing rivers between Pennar and Cauvery (EPC), Cauvery and Tapi. The NASH and CC values vary between 0.80 to 0.98 and 0.87 to 0.99 in all river basins except area of north Ladakh not draining into Indus (NLI) and east flowing rivers south of Cauvery (ESC), while RMSE and NMSE vary from 15.95 to 101.68 mm and 2.66 to 58.38 mm, respectively. The trends for TMPA and IMD datasets from 1998 to 2013 are quite similar in MK (except 4 river basins) and MMK (except 3 river basins). The estimated results imply that the TMPA precipitation show good agreement and can be used in climate studies and hydrological simulations in locations/river basins where the number of rain gauge stations is not adequate to quantify the spatial variability of precipitation. Keywords: Precipitation data comparison, IMD, TRMM, river basins, Mann-Kendall test

Distortion cancellation performance of miniature delay filters for feed-forward linear power amplifiers.

PubMed

Roy, Manas K

2002-11-01

The technique of feed-forward amplitude control has been widely used in the linearization of power amplifiers for wireless communication systems. In this technique, an error signal due to third order intermodulation distortion (IMD) is extracted, amplified, and used to correct the delayed main line distorted signal. For example, a miniature prototype base station for the Global System for Mobile Communications/Code Division Multiple Access (GSM/CDMA) cellular system uses feed-forward amplifiers with bulky and expensive coaxial cables, about 20 feet in length, to provide about 25 ns of delay. This paper shows alternate space-saving approaches of achieving these delays using three different types of delay filters: electromagnetic interdigital/lumped (<2.5"), ceramic (<1.8"), and ladder-type surface acoustic wave (SAW) (0.15"). The delay lines introduce phase and amplitude imbalance and delay mismatch in the linearization loop due to fabrication tolerances. These adversely affect the IMD cancellation. Using an RF system simulation tool, this paper critically compares the IMD cancellation performance achieved using the three technologies. Simulation results show that the optimization of delay mismatch can achieve the desired cancellation more easily than other parameters. It is shown that, if the critical system parameter (phase deviation from linearity), is maintained at <2.5 degrees peak-to-peak over a 20 MHz bandwidth in the frequency range 855 MHz to 875 MHz, one can achieve 25 dB of IMD cancellation performance. This paper concludes with the suggestion of a set of realistic specifications for a miniature delay filter for the low power loop of the feed-forward amplifier.

Comparison of regional and seasonal changes and trends in daily surface temperature extremes over India and its subregions

NASA Astrophysics Data System (ADS)

Dimri, A. P.

2018-04-01

Regional changes in surface meteorological variables are one of the key issues affecting the Indian subcontinent especially in recent decades. These changes impact agriculture, health, water, etc., hence important to assess and investigate these changes. The Indian subcontinent is characterized by heterogeneous temperature regimes at regional and seasonal scales. The India Meteorological Department (IMD) observations are limited to recent decades as far as its spatial distribution is concerned. In particular, over Hilly region, these observations are sporadic. Due to variable topography and heterogeneous land use/land cover, it is complex to substantiate impacts. The European Centre for Medium-Range Weather Forecasts (ECMWF) ERA-Interim (ERA-I) reanalysis not only covers a larger spatial domain but also provides a greater number of inputs than IMD. This study used ERA-I in conjunction with IMD gridded data to provide a comparative assessment of changing temperature patterns over India and its subregions at both regional and seasonal scales. Warming patterns are observed in both ERA-I and IMD data sets. Cold nights decrease during winter; warm days increase and warm spell duration increased during winter could become a cause of concern for society, agriculture, socio-economic reasons, and health. Increasing warm days over the hilly regions may affect the corresponding snow cover and thus river hydrology and glaciological dynamics. Such changes during monsoon are slower, which could be attributed to moisture availability to dampen the temperature changes. On investigation and comparison thereon, the present study provisions usages of ERA-I-based indices for various impact and adaptation studies.

Whey-hydrolyzed peptide-enriched immunomodulating diet prevents progression of liver cirrhosis in rats.

PubMed

Jobara, Kanta; Kaido, Toshimi; Hori, Tomohide; Iwaisako, Keiko; Endo, Kosuke; Uchida, Yoichiro; Uemoto, Shinji

2014-10-01

Liver fibrosis and subsequent cirrhosis is a major cause of death worldwide, but few effective antifibrotic therapies are reported. Whey-hydrolyzed peptide (WHP), a major peptide component of bovine milk, exerts anti-inflammatory effects in experimental models. A WHP-enriched diet is widely used for immunomodulating diets (IMD) in clinical fields. However, the effects of WHP on liver fibrosis remain unknown. The aim of this study was to investigate the antifibrotic effects of WHP in a rat cirrhosis model. Progressive liver fibrosis was induced by repeated intraperitoneal administration of dimethylnitrosamine (DMN) for 3 wk. Rats were fed either a WHP-enriched IMD (WHP group) or a control enteral diet (control group). The degree of liver fibrosis was compared between groups. Hepatocyte-protective effects were examined using hepatocytes isolated from rats fed a WHP diet. Reactive oxygen species and glutathione in liver tissue were investigated in the DMN cirrhosis model. Macroscopic and microscopic progression of liver fibrosis was remarkably suppressed in the WHP group. Elevated serum levels of liver enzymes and hyaluronic acid, and liver tissue hydroxyproline content were significantly attenuated in the WHP group. Necrotic hepatocyte rates with DMN challenge, isolated from rats fed a WHP-enriched IMD, were significantly lower. In the DMN cirrhosis model, reactive oxygen species were significantly lower, and glutathione was significantly higher in the WHP group's whole liver tissue. A WHP-enriched IMD effectively prevented progression of DMN-induced liver fibrosis in rats via a direct hepatocyte-protective effect and an antioxidant effect through glutathione synthesis. Copyright © 2014 Elsevier Inc. All rights reserved.

Beneficial effects of gluten free diet in potential coeliac disease in adult population.

PubMed

Imperatore, Nicola; Tortora, Raffaella; De Palma, Giovanni Domenico; Capone, Pietro; Gerbino, Nicolò; Donetto, Sara; Testa, Anna; Caporaso, Nicola; Rispo, Antonio

2017-08-01

To date, potential coeliac disease (PCD) occurring in adults remains an almost unexplored condition. To explore the prognostic role of Marsh grade in adult PCD patients, and to evaluate the effects of gluten-containing diet (GCD) in asymptomatic PCD patients. We retrospectively evaluated all consecutive adult PCD patients followed-up for at least 6 years. Patients were divided into: Group A (patients with Marsh 0 histology) and Group B (Marsh 1 patients). Symptomatic patients were started gluten-free diet (GFD), while asymptomatic subjects were kept on GCD and were followed-up. 56 PCD patients were enrolled (21 in Group A and 35 in Group B). Forty-three patients were symptomatic and started GFD. Of these, none of 15 patients in Group A and 8 of 28 patients in Group B developed immune-mediated disorders (IMD) during follow-up (P=0.03; OR=4.2). The 13 asymptomatic PCD patients were kept on GCD. During the follow-up, 9 patients developed CD-related symptoms, 6 villous atrophy and 8 IMD. At the end, patients kept on GCD were at higher risk of developing IMD than those following a GFD (61% vs 18%, P=0.03, OR=3.3). Although PCD with normal mucosa seems to be a milder disease, the continuation of GCD places patients at a high risk of developing villous atrophy and IMD compared to commencement of GFD. Adult PCD patients should start GFD even if not symptomatic. Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Drosophila immunity: analysis of PGRP-SB1 expression, enzymatic activity and function.

PubMed

Zaidman-Rémy, Anna; Poidevin, Mickael; Hervé, Mireille; Welchman, David P; Paredes, Juan C; Fahlander, Carina; Steiner, Hakan; Mengin-Lecreulx, Dominique; Lemaitre, Bruno

2011-02-18

Peptidoglycan is an essential and specific component of the bacterial cell wall and therefore is an ideal recognition signature for the immune system. Peptidoglycan recognition proteins (PGRPs) are conserved from insects to mammals and able to bind PGN (non-catalytic PGRPs) and, in some cases, to efficiently degrade it (catalytic PGRPs). In Drosophila, several non-catalytic PGRPs function as selective peptidoglycan receptors upstream of the Toll and Imd pathways, the two major signalling cascades regulating the systemic production of antimicrobial peptides. Recognition PGRPs specifically activate the Toll pathway in response to Lys-type peptidoglycan found in most Gram-positive bacteria and the Imd pathway in response to DAP-type peptidoglycan encountered in Gram-positive bacilli-type bacteria and in Gram-negative bacteria. Catalytic PGRPs on the other hand can potentially reduce the level of immune activation by scavenging peptidoglycan. In accordance with this, PGRP-LB and PGRP-SC1A/B/2 have been shown to act as negative regulators of the Imd pathway. In this study, we report a biochemical and genetic analysis of PGRP-SB1, a catalytic PGRP. Our data show that PGRP-SB1 is abundantly secreted into the hemolymph following Imd pathway activation in the fat body, and exhibits an enzymatic activity towards DAP-type polymeric peptidoglycan. We have generated a PGRP-SB1/2 null mutant by homologous recombination, but its thorough phenotypic analysis did not reveal any immune function, suggesting a subtle role or redundancy of PGRP-SB1/2 with other molecules. Possible immune functions of PGRP-SB1 are discussed.

Unexpected role of the IMD pathway in Drosophila gut defense against Staphylococcus aureus.

PubMed

Hori, Aki; Kurata, Shoichiro; Kuraishi, Takayuki

2018-01-01

In this study, fruit fly of the genus Drosophila is utilized as a suitable model animal to investigate the molecular mechanisms of innate immunity. To combat orally transmitted pathogenic Gram-negative bacteria, the Drosophila gut is armed with the peritrophic matrix, which is a physical barrier composed of chitin and glycoproteins: the Duox system that produces reactive oxygen species (ROS), which in turn sterilize infected microbes, and the IMD pathway that regulates the expression of antimicrobial peptides (AMPs), which in turn control ROS-resistant pathogens. However, little is known about the defense mechanisms against Gram-positive bacteria in the fly gut. Here, we show that the peritrophic matrix protects Drosophila against Gram-positive bacteria S. aureus. We also define the few roles of ROS in response to the infection and show that the IMD pathway is required for the clearance of ingested microbes, possibly independently from AMP expression. These findings provide a new aspect of the gut defense system of Drosophila, and helps to elucidate the processes of gut-microbe symbiosis and pathogenesis. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

PGRP-SD, an Extracellular Pattern-Recognition Receptor, Enhances Peptidoglycan-Mediated Activation of the Drosophila Imd Pathway.

PubMed

Iatsenko, Igor; Kondo, Shu; Mengin-Lecreulx, Dominique; Lemaitre, Bruno

2016-11-15

Activation of the innate immune response in Metazoans is initiated through the recognition of microbes by host pattern-recognition receptors. In Drosophila, diaminopimelic acid (DAP)-containing peptidoglycan from Gram-negative bacteria is detected by the transmembrane receptor PGRP-LC and by the intracellular receptor PGRP-LE. Here, we show that PGRP-SD acted upstream of PGRP-LC as an extracellular receptor to enhance peptidoglycan-mediated activation of Imd signaling. Consistent with this, PGRP-SD mutants exhibited impaired activation of the Imd pathway and increased susceptibility to DAP-type bacteria. PGRP-SD enhanced the localization of peptidoglycans to the cell surface and hence promoted signaling. Moreover, PGRP-SD antagonized the action of PGRP-LB, an extracellular negative regulator, to fine-tune the intensity of the immune response. These data reveal that Drosophila PGRP-SD functions as an extracellular receptor similar to mammalian CD14 and demonstrate that, comparable to lipopolysaccharide sensing in mammals, Drosophila relies on both intra- and extracellular receptors for the detection of bacteria. Copyright © 2016 Elsevier Inc. All rights reserved.

Combination with third-generation bisphosphonate (YM529) and interferon-alpha can inhibit the progression of established bone renal cell carcinoma.

PubMed

Kurabayashi, Atsushi; Inoue, Keiji; Fukuhara, Hideo; Karashima, Takashi; Fukata, Satoshi; Kawada, Chiaki; Shuin, Taro; Furihata, Mutsuo

2015-08-01

The aim of this study was to investigate whether the third-generation nitrogen-containing bisphosphonate (YM529) can inhibit the progression of established bone renal cell carcinoma (RCC) and to elucidate its mechanism. Antiproliferative effect and apoptosis induction of RCC cells and mouse osteoclasts by YM529 and/or interferon-alpha (IFN-α) were evaluated in vitro using cell counting and in vivo using soft X-ray, the TUNEL method and tartrate-resistant acid phosphatase stain. For the in vivo study, male athymic BALB/cA Jc1-nu nude mice bearing human RCC cell line RBM1-IT4 cells were treated with YM529 and/or IFN-α. The biological activity of osteoclasts was evaluated using the pit formation assay. The antiangiogenetic effect by YM529 and/or IFN-α was analyzed using micro-vessel density and in situ mRNA hybridization. Osteoclast number in bone tumors was decreased in YM529-treated mouse. YM529 also inhibited osteoclast activity and proliferation in vitro, whereas basic fibroblast growth factor expressions and micro-vessel density within tumors were inhibited by IFN-α. Neither YM529 nor IFN-α alone significantly inhibited the growth of established bone metastatic tumors. Combined treatment with YM529 and IFN-α may be beneficial in patients with human RCC bone metastasis. Their effects are mediated by osteoclast recruitment inhibition and inactivation by YM529 and antiangiogenesis by IFN-α. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Influence of shape and dispersion media of titanium dioxide nanostructures on microvessel network and ossification.

PubMed

Freyre-Fonseca, Verónica; Medina-Reyes, Estefany I; Téllez-Medina, Darío I; Paniagua-Contreras, Gloria L; Monroy-Pérez, Eric; Vaca-Paniagua, Felipe; Delgado-Buenrostro, Norma L; Flores-Flores, José O; López-Villegas, Edgar O; Gutiérrez-López, Gustavo F; Chirino, Yolanda I

2018-02-01

Titanium dioxide nanoparticles (TiO 2 NPs) production has been used for pigment, food and cosmetic industry and more recently, shaped as belts for treatment of contaminated water, self-cleaning windows and biomedical applications. However, the toxicological data have demonstrated that TiO 2 NPs inhalation induce inflammation in in vivo models and in vitro exposure leads to cytotoxicity and DNA damage. Dermal exposure has limited adverse effects and the possible risks for implants used for tissue regeneration is still under research. Then, it has been difficult to establish a straight statement about TiO 2 NPs toxicity since route of exposure and shapes of nanoparticles play an important role in the effects. In this study we aimed to investigate the effect of three different types of TiO 2 NPs (industrial, food-grade and belts) dispersed in fetal bovine serum (FBS) and saline solution (SS) on microvessel network, angiogenesis gene expression and femur ossification using a chick embryo model after an acute exposure of NPs on the day 7 after eggs fertilization. Microvascular density of chorioallantoic membrane (CAM) was analyzed after 7days of NPs injection and vehicles induced biological effects per se. NPs dispersed in FBS or SS have slight differences in microvascular density, mainly opposite effect on angiogenesis gene expression and no effects on femur ossification for NPs dispersed in SS. Interestingly, NPs shaped as belts dramatically prevented the alterations in ossification induced by FBS used as vehicle. Copyright © 2017 Elsevier B.V. All rights reserved.

Role of endothelial-to-mesenchymal transition in the pathogenesis of central nervous system hemangioblastomas.

PubMed

Takada, Shigeki; Hojo, Masato; Takebe, Noriyoshi; Tanigaki, Kenji; Miyamoto, Susumu

2018-06-07

Hemangioblastomas (HBs) are benign vascular tumors of the central nervous system and histologically contain abundant microvessels. Therefore, they clinically exhibit vascular malformation-like characteristics. It has been described that endothelial-to-mesenchymal transition (EndMT) contributes to the pathogenesis of cerebral cavernous malformations. However, it remains unknown whether EndMT contributes to the pathogenesis of central nervous system HBs. The aim of our study was to investigate whether EndMT occurs in central nervous system HBs. Ten central nervous system HBs were immunohistochemically investigated. CD31 (an endothelial marker) and EndMT markers, such as α-smooth muscle actin (a mesenchymal marker) and CD44 (a mesenchymal stem cell marker), were expressed in the endothelial layer of microvessels in all cases. These findings suggest that endothelial cells (ECs) of microvessels in central nervous system HBs have acquired mesenchymal and stem-cell-like characteristics and undergone EndMT. In all cases, both ephrin-B2 and EphB4, which are not detected in adult normal brain vessels, were expressed in the endothelial layer of microvessels. These data suggest that ECs of microvessels in central nervous system HBs are immature or malformed cells and have both arterial and venous characteristics. This is the first report showing the possibility that EndMT contributes to the pathogenesis of central nervous system HBs. It is likely that ECs of microvessels in central nervous system HBs are immature or malformed cells and have both arterial and venous characteristics. EndMT is expected to be a new therapeutic target in central nervous system HBs. Copyright © 2018 Elsevier Inc. All rights reserved.

Effects of immersion depth on super-resolution properties of index-different microsphere-assisted nanoimaging

NASA Astrophysics Data System (ADS)

Zhou, Yi; Tang, Yan; He, Yu; Liu, Xi; Hu, Song

2018-03-01

In related applications of microsphere-assisted super-resolution imaging in biomedical visualization and microfluidic detection, liquids are widely used as background media. For the first time, we quantitatively demonstrate that the maximum irradiances, focal lengths, and waists of photonic nanojets (PNJs) will logically vary with different immersion depths (IMDs). The experimental observations also numerically illustrate the trends of the lateral magnification and field of view (FOV) with the gradual evaporation of ethyl alcohol. This work can provide exact quantitative information for the proper selection of microspheres and IMD for the high-quality discernment of nanostructures.

Gaussian beam in two-photon fluorescence imaging of rat brain microvessel

NASA Astrophysics Data System (ADS)

Shi, Lingyan; Rodríguez-Contreras, Adrián; Alfano, Robert R.

2014-12-01

The critical optical properties of a Gaussian laser beam in two-photon or multiphoton fluorescence imaging, including the beam spot size, depth of focus, and intensity profile, are investigated for spatially locating nanoscale solutes in and surrounding the microvessels of rat brain.

Mechanisms for microvascular damage induced by ultrasound-activated microbubbles

NASA Astrophysics Data System (ADS)

Chen, Hong; Brayman, Andrew A.; Evan, Andrew P.; Matula, Thomas J.

2012-10-01

To provide insight into the mechanisms of microvascular damage induced by ultrasound-activated microbubbles, experimental studies were performed to correlate microvascular damage to the dynamics of bubble-vessel interactions. High-speed photomicrography was used to record single microbubbles interacting with microvessels in ex vivo tissue, under the exposure of short ultrasound pulses with a center frequency of 1 MHz and peak negative pressures (PNP) ranging from 0.8-4 MPa. Vascular damage associated with observed bubble-vessel interactions was either indicated directly by microbubble extravasation or examined by transmission electron microscopy (TEM) analyses. As observed previously, the high-speed images revealed that ultrasound-activated microbubbles could cause distention and invagination of adjacent vessel walls, and could form liquid jets in microvessels. Vessel distention, invagination, and liquid jets were associated with the damage of microvessels whose diameters were smaller than those of maximally expanded microbubbles. However, vessel invagination appeared to be the dominant mechanism for the damage of relative large microvessels.

Mechanisms for microvascular damage induced by ultrasound-activated microbubbles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen Hong; Brayman, Andrew A.; Evan, Andrew P.

To provide insight into the mechanisms of microvascular damage induced by ultrasound-activated microbubbles, experimental studies were performed to correlate microvascular damage to the dynamics of bubble-vessel interactions. High-speed photomicrography was used to record single microbubbles interacting with microvessels in ex vivo tissue, under the exposure of short ultrasound pulses with a center frequency of 1 MHz and peak negative pressures (PNP) ranging from 0.8-4 MPa. Vascular damage associated with observed bubble-vessel interactions was either indicated directly by microbubble extravasation or examined by transmission electron microscopy (TEM) analyses. As observed previously, the high-speed images revealed that ultrasound-activated microbubbles could cause distentionmore » and invagination of adjacent vessel walls, and could form liquid jets in microvessels. Vessel distention, invagination, and liquid jets were associated with the damage of microvessels whose diameters were smaller than those of maximally expanded microbubbles. However, vessel invagination appeared to be the dominant mechanism for the damage of relative large microvessels.« less

An enhanced narrow-band imaging method for the microvessel detection

NASA Astrophysics Data System (ADS)

Yu, Feng; Song, Enmin; Liu, Hong; Wan, Youming; Zhu, Jun; Hung, Chih-Cheng

2018-02-01

A medical endoscope system combined with the narrow-band imaging (NBI), has been shown to be a superior diagnostic tool for early cancer detection. The NBI can reveal the morphologic changes of microvessels in the superficial cancer. In order to improve the conspicuousness of microvessel texture, we propose an enhanced NBI method to improve the conspicuousness of endoscopic images. To obtain the more conspicuous narrow-band images, we use the edge operator to extract the edge information of the narrow-band blue and green images, and give a weight to the extracted edges. Then, the weighted edges are fused with the narrow-band blue and green images. Finally, the displayed endoscopic images are reconstructed with the enhanced narrow-band images. In addition, we evaluate the performance of enhanced narrow-band images with different edge operators. Experimental results indicate that the Sobel and Canny operators achieve the best performance of all. Compared with traditional NBI method of Olympus company, our proposed method has more conspicuous texture of microvessel.

Ultra-high Speed Optical Imaging of Ultrasound-activated Microbubbles in Mesenteric Microvessels

NASA Astrophysics Data System (ADS)

Chen, Hong

Ultrasound contrast agent microbubbles have gained widespread applications in diagnostic and therapeutic ultrasound. Animal studies of bioeffects induced by ultrasound-activated microbubbles have demonstrated that microbubbles can cause microvessel damage. Much scientific attention has been attracted to such microvascular bioeffects, not only because of the related safety concerns, but also because of the potential useful applications of microbubbles in the intravascular delivery of drugs and genetic materials into target tissues. A significant challenge in using microbubbles in medical ultrasound is the lack of knowledge about how the microbubbles behave in blood vessels when exposed to ultrasound and how their interactions with ultrasound cause vascular damage. Although extensive studies were performed in the past to study the dynamics of microbubbles, most of those studies were performed in vitro and did not directly address the clinical environment in which microbubbles are injected into blood vessels. In this thesis work, a synchronized optical-acoustic system was set up for ultrahigh speed imaging of insonated microbubbles in microvessels. The recorded images revealed the formation of microjets penetrating the microbubbles, as well as vessel distention (motion outward against the surrounding tissue) and vessel invagination (motion inward toward the lumen) caused by the expansion and collapse of the microbubbles, respectively. Contrary to current paradigms which propose that microbubbles damage vessels either by distending them or by forming liquid jets impinging on them, microbubbles translation and jetting were in the direction away from the nearest vessel wall; furthermore, invagination typically exceeded distention in arterioles and venules. Vessel invagination was found to be associated with vascular damage. These studies suggest that vessel invagination may be a newly discovered potential mechanism for vascular damage by ultrasound-activated microbubbles. The dynamics of bubble-vessel interactions are coupled intimately with the viscoelastic properties of the microvessels. To probe these properties, a method based on the relaxation times of the invaginated microvessels was used to estimate the relaxation time constants of the microvessels. It was found that the time constants were on microsecond time scales, which provided insight into the unique and unknown viscoelastic properties of the microvessels.

[Relationship between the changes in ischemia/reperfusion cerebro-microvessel basement membrane injury and gelatinase system in senile rat].

PubMed

Li, Jian-sheng; Liu, Ke; Liu, Jing-xia; Wang, Ming-hang; Zhao, Yue-wu; Liu, Zheng-guo

2008-11-01

To study the relationship of cerebro-microvessel basement membrane injury and gelatinase system after cerebral ischemia/reperfusion (I/R) in aged rats. Cerebral I/R injury model was reproduced by intraluminal silk ligature thrombosis of the middle cerebral artery occlusion (MCAO). Rats were divided randomly into sham control and I/R groups in young rats [ischemia 3 hours (I 3 h) and reperfusion 6 hours (I/R 6 h), 12 hours (I/R 12 h), 24 hours (I/R 24 h), 3 days (I/R 3 d), 6 days (I/R 6 d)], and sham control group and I/R group in aged rats (I 3 h and I/R 6 h, I/R 12 h, I/R 24 h , I/R 3 d, I/R 6 d). The change in cerebro-cortex microvessel basement membrane structure, basement membrane type IV collagen (Col IV) and laminin (LN) contents, matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) expression in every group were determined with immunohistochemical method and zymogram analysis. With the increase in age, Col IV and LN contents of the microvessel basement membrane were increased, and MMP-2 and MMP-9 expressions were stronger. With prolongation of I/R, the degradation of microvessel basement membrane components (Col IV and LN) was positively correlated with the duration of cerebral I/R. MMP-2 expression was increased gradually, and MMP-9 and TIMP-1 expression increased at the beginning and decreased subsequently. Col IV(I 3 h, I/R 6 h , I/R 12 h), LN (I 3 h, I/R 6-24 h), MMP-2 (I 3 h, I/R 6 h-6 d) and MMP-9 (I 3 h, I/R 6-24 h) expression level in aged rats with I/R injury were higher, and TIMP-1 (I/R 24 h) expression was lower than those in young rats (P<0.05 or P<0.01). In addition, changes in MMP-2 and MMP-9 contents as determined by zymogram analysis method coincided with their immunoexpression. With the increase of age, alteration in membrane components of cerebro-microvessel basement membrane in rats is related with MMPs and TIMP. Cerebro-microvessel basement membrane injury is more serious in aged rats than that of young rats. Changes in cerebro-microvessel basement membrane injury in aged rats is related with gelatinase system change.

Three-dimensional motion and deformation of a red blood cell in bifurcated microvessels

NASA Astrophysics Data System (ADS)

Ye, Ting; Peng, Lina; Li, Yu

2018-02-01

Microvessels are generally not simple straight tubes, but rather they continually bifurcate (namely, diverging bifurcation) and merge with other microvessels (namely, converging bifurcation). This paper presents a simulation study on the three-dimensional motion and deformation of a red blood cell (RBC) in a bifurcated microvessel with both diverging and converging bifurcations. The motion of the fluids inside and outside of the RBC is modeled by smooth dissipative particle dynamics. The RBC membrane is modeled as a triangular network, having the ability to not only resist the stretching and bending deformations, but also to conserve the RBC volume and surface area. The bifurcation configurations have been studied, including the bifurcated angle and the branch diameter, as well as the RBC properties, including the initial shape, shear modulus, and bending modulus. The simulation results show that the RBC deformation can be divided into five stages, when the RBC flows through a diverging-converging bifurcated microvessel. In these five stages, the RBCs have similar deformation trends but different deformation indices, subject to different bifurcation configurations or different RBC properties. If the shear modulus is large enough, the RBC membrane presents several folds; if the bending modulus is large enough, the RBC loses the symmetry completely with the long shape. These results are helpful in understanding the motion and deformation of healthy or unhealthy cells in blood microcirculation.

A Decade of Invasive Meningococcal Disease Surveillance in Poland

PubMed Central

Skoczyńska, Anna; Waśko, Izabela; Kuch, Alicja; Kadłubowski, Marcin; Gołębiewska, Agnieszka; Foryś, Małgorzata; Markowska, Marlena; Ronkiewicz, Patrycja; Wasiak, Katarzyna; Kozińska, Aleksandra; Matynia, Bożena; Hryniewicz, Waleria

2013-01-01

Background Neisseria meningitidis is a leading etiologic agent of severe invasive disease. The objective of the study was to characterise invasive meningococcal disease (IMD) epidemiology in Poland during the last decade, based on laboratory confirmed cases. Methods The study encompassed all invasive meningococci collected between 2002 and 2011 in the National Reference Centre for Bacterial Meningitis. The isolates were re-identified and characterised by susceptibility testing, MLST analysis, porA and fetA sequencing. A PCR technique was used for meningococcal identification directly from clinical materials. Results In the period studied, 1936 cases of IMD were confirmed, including 75.6% identified by culture. Seven IMD outbreaks, affecting mostly adolescents, were reported; all were caused by serogroup C meningococci of ST-11. The highest incidence was observed among children under one year of age (15.71/100,000 in 2011). The general case fatality rate in the years 2010–2011 was 10.0%. Meningococci of serogroup B, C, Y and W-135 were responsible for 48.8%, 36.6%, 1.2% and 1.2% of cases, respectively. All isolates were susceptible to third generation cephalosporins, chloramphenicol, ciprofloxacin, and 84.2% were susceptible to penicillin. MLST analysis (2009–2011) revealed that among serogroup B isolates the most represented were clonal complexes (CC) ST-32CC, ST-18CC, ST-41/44CC, ST-213CC and ST-269CC, and among serogroup C: ST-103CC, ST-41/44CC and ST-11CC. Conclusions The detection of IMD in Poland has changed over time, but observed increase in the incidence of the disease was mostly attributed to changes in the surveillance system including an expanded case definition and inclusion of data from non-culture diagnostics. PMID:23977184

Inherited metabolic disorders presenting as acute liver failure in newborns and young children: King's College Hospital experience.

PubMed

Hegarty, Robert; Hadzic, Nedim; Gissen, Paul; Dhawan, Anil

2015-10-01

Acute liver failure (ALF) in children is a rare condition that is often fatal without liver transplantation. The diagnostic work-up is complex, and the etiology is unidentified in up to half of patients, making decisions like therapeutic transplantation extremely difficult. We collected clinical, laboratory, and outcome data on all patients under 5 years of age who were admitted between January 2001 and December 2011 to King's College Hospital with ALF secondary to an inherited metabolic disease (IMD), a common cause of pediatric acute liver failure. Thirty-six of 127 children with ALF had a metabolic etiology: galactosemia (17); mitochondrial respiratory chain disorder (MRCD, 7); ornithine transcarbamylase (OTC) deficiency (4); tyrosinemia type 1 (4); Niemann-Pick disease type C (NPC, 3); and congenital disorder of glycosylation type 1b (1). Seven children died: MRCD (4) and NPC (3). Four children were transplanted: OTC deficiency (1) and MRCD (3). Fifteen of 25 children followed up showed evidence of developmental delay. IMD is the most common group of disorders in this age group; indeterminate cases may yet include undiagnosed metabolic disorders; the overall survival rate is good but largely depends on diagnosis, while developmental outcome of the surviving patients is less favorable. • Up to half of children with ALF may be undiagnosed. • IMD is a common cause of pediatric acute liver failure. What is New: • Initial diagnostic clues may be gathered from the child's age and laboratory parameters. • Survival of children with IMD-related ALF is good, but developmental outcome is less favorable. • In the future, novel sequencing methods will aid in the diagnosis of disorders in which therapeutic decisions depend upon.

Statistical and Hydrological evaluation of precipitation forecasts from IMD MME and ECMWF numerical weather forecasts for Indian River basins

NASA Astrophysics Data System (ADS)

Mohite, A. R.; Beria, H.; Behera, A. K.; Chatterjee, C.; Singh, R.

2016-12-01

Flood forecasting using hydrological models is an important and cost-effective non-structural flood management measure. For forecasting at short lead times, empirical models using real-time precipitation estimates have proven to be reliable. However, their skill depreciates with increasing lead time. Coupling a hydrologic model with real-time rainfall forecasts issued from numerical weather prediction (NWP) systems could increase the lead time substantially. In this study, we compared 1-5 days precipitation forecasts from India Meteorological Department (IMD) Multi-Model Ensemble (MME) with European Center for Medium Weather forecast (ECMWF) NWP forecasts for over 86 major river basins in India. We then evaluated the hydrologic utility of these forecasts over Basantpur catchment (approx. 59,000 km2) of the Mahanadi River basin. Coupled MIKE 11 RR (NAM) and MIKE 11 hydrodynamic (HD) models were used for the development of flood forecast system (FFS). RR model was calibrated using IMD station rainfall data. Cross-sections extracted from SRTM 30 were used as input to the MIKE 11 HD model. IMD started issuing operational MME forecasts from the year 2008, and hence, both the statistical and hydrologic evaluation were carried out from 2008-2014. The performance of FFS was evaluated using both the NWP datasets separately for the year 2011, which was a large flood year in Mahanadi River basin. We will present figures and metrics for statistical (threshold based statistics, skill in terms of correlation and bias) and hydrologic (Nash Sutcliffe efficiency, mean and peak error statistics) evaluation. The statistical evaluation will be at pan-India scale for all the major river basins and the hydrologic evaluation will be for the Basantpur catchment of the Mahanadi River basin.

The impact of visual media to encourage low protein cooking in inherited metabolic disorders.

PubMed

Evans, S; Daly, A; Hopkins, V; Davies, P; MacDonald, A

2009-10-01

The use of educational visual aids is one way to help children with inherited metabolic disorders (IMD) understand and develop a positive attitude towards their low protein diet. However, it is difficult to establish their effectiveness in the clinical setting. The present study aimed to evaluate the impact of a low protein recipe book and accompanying DVD for children with IMD. One hundred and five children (53% female; median age = 6-8 years) with IMD on low protein diets were each given a low protein recipe book and DVD. After 6 months, children and carers were posted a questionnaire asking whether they used these resources; identifying any change in frequency of low protein cooking; and the outcome when preparing recipes. One hundred and two questionnaires were returned, representing 105 patients. Seventy percent (n = 71) of questionnaires were from carers. Ninety-three percent (n = 66) of carers acknowledged receipt of the resource; one-third (n = 22) had not watched the DVD and 23% (n = 15) had not opened the recipe book; 55% (n = 36) had tried the recipes; and 71% (n = 47) said the recipe book and/or DVD motivated them to try new recipes. Children were more likely to have watched the DVD (75%; n = 21/28) and read the recipe book (86%; n = 24/28) than carers. Although a helpful educational tool, just over one-half of respondents had used the resource. Identifying visual media that, by itself, will motivate most families of children with IMD to prepare low protein recipes may be unrealistic. The combined approach of visual aids and 'hands-on' practical experience, such as low protein cooking workshops and individual counselling, may be more beneficial.

Collagenase Treatment for Dupuytren Disease of the Thumb and First Web.

PubMed

Dreise, Marieke M; Stenekes, Martin W; Werker, Paul M N

2016-03-01

To evaluate the short-term effectiveness of collagenase Clostridium histolyticum to treat thumb and first web contractures in Dupuytren disease. We prospectively included 14 thumbs in 12 patients with a contracture at the metacarpophalangeal or interphalangeal joint of at least 20° with a palpable cord in the thumb (n = 8) or an adduction contracture of the thumb with palpable cords in the first web (n = 6). They received an injection containing 0.58 mg of collagenase Clostridium histolyticum in the fibrous cord divided over 3 spots. The contracture was released by carefully manipulating the thumb under local anesthesia 1 day later. The extension and abduction deficits were measured before and after the intervention (follow-up at 7 and 30 days and 6 months). Wilcoxon signed rank test was used to analyze the data. In the total sample, postintervention extension deficits were statistically significantly lower than preintervention deficits except in one patient who had a recurrence at 6 months compared with the 30-day posttreatment result. Intermetacarpophalangeal head distance (IMD) also improved significantly. In an analysis of subgroups, we compared the separate contributions of treatment of a pretendinous cord and a first web cord on both extension deficit and IMD. Treatment of pretendinous cords significantly affected both extension deficit and IMD. However, treatment of first web contractures did not significantly improve extension or IMD. Collagenase Clostridium histolyticum is a good treatment option for pretendinous cords in thumbs affected with Dupuytren disease because it provides good results, is minimally invasive, and has minor adverse events. Therapeutic IV. Copyright © 2016 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

Development and Properties of Advanced Internal Magnesium Infiltration (AIMI) Processed MgB2 Wires

DOE Office of Scientific and Technical Information (OSTI.GOV)

Collings, Prof Edward William; Sumption, Prof Michael D; Li, Guangze

The development, processing, properties, and formation mechanisms of Advanced Internal Magnesium Infiltration (AIMI) MgB2 wires are discussed against a background of the related and original processes, Internal-Magnesium-Diffusion (IMD) and Magnesium-Reactive-Liquid-Infiltration (Mg-RLI). First reviewed are the formation, properties and applications of Mg-RLI bulks as basis for discussions of Mg-RLI-processed and IMD-processed wires. The transition from Mg-RLI- and IMD- to AIMI wires is explained, and the relative performances of powder-in-tube (PIT), IMD and AIMI wires are summarized in the form of an iso-Je diagram of Jc,nb versus Anb/ATOT in which ATOT, Anb, Jc,nb, and Je are, respectively, the wire s cross-sectional area,more » the area inside the chemical barrier, the critical current (Ic) normalized to Anb, and Ic normalized to ATOT. After the details of AIMI wire fabrication selection of starting powders, dopants, and reaction heat treatments are introduced the report goes on to describe in detail the development of high performance AIMI wires: layer Jcs, fill factors, Jes, and the effects of wire size, multifilamentarization, doping with C, and co-doping with C and Dy2O3. The two-stage mechanism of layer formation in AIMI wires is discussed: first the reactive infiltration of liquid Mg into a porous B pack, a process that terminates with the formation of a dense MgB2 layer; second the slow diffusion of Mg into any remaining B through that MgB2 layer. The report concludes with a brief general discussion of anisotropy, current percolation, and the Jc field dependence of MgB2 wires.« less

Could Sodium Chloride be an Environmental Trigger for Immune-Mediated Diseases? An Overview of the Experimental and Clinical Evidence

PubMed Central

Toussirot, Eric; Béreau, Matthieu; Vauchy, Charline; Saas, Philippe

2018-01-01

Immune mediated diseases (IMDs) are complex chronic inflammatory diseases involving genetic and environmental factors. Salt intake has been proposed as a diet factor that can influence the immune response. Indeed, experimental data report the influence of sodium chloride on the differentiation of naive CD4+ T cells into IL-17 secreting T helper (Th) cells (Th17 cells), by a mechanism involving the serum glucocorticoid kinase-1 (SGK1) that promotes the expression of the IL-23 receptor (IL-23R). The IL-23/IL-23R is critical for pathogenic inflammatory Th17 cell differentiation. Experimental data in murine models of arthritis, colitis and encephalomyelitis corroborate these findings. This manuscript reviews the current knowledge on the effects of sodium chloride on innate and adaptive immunity. We also performed a systematic literature review for clinical studies examining the relationships between salt consumption and the development or the activity/severity of the most common IMDs mediated by the IL-23/Th17 pathway, i.e., rheumatoid arthritis (RA), multiple sclerosis (MS), and Crohn's disease (CD). Nine studies were found, 4 in RA, 4 in MS and 1 in CD. An association was found between developments of anti-citrullinated protein antibody (ACPA) positive RA in smokers and salt intake, but these results were not confirmed in another study. For MS, no association was observed in pediatric subjects while in adult patients, a link was found between salt intake and disease activity. However, this result was not confirmed in another study. These conflicting results highlight the fact that further evaluation in human IMDs is required. Moreover, physicians need to develop clinical trials with diet interventions to evaluate the impact of low salt intake on disease activity/severity of IMDs. PMID:29740348

Could Sodium Chloride be an Environmental Trigger for Immune-Mediated Diseases? An Overview of the Experimental and Clinical Evidence.

PubMed

Toussirot, Eric; Béreau, Matthieu; Vauchy, Charline; Saas, Philippe

2018-01-01

Immune mediated diseases (IMDs) are complex chronic inflammatory diseases involving genetic and environmental factors. Salt intake has been proposed as a diet factor that can influence the immune response. Indeed, experimental data report the influence of sodium chloride on the differentiation of naive CD4 + T cells into IL-17 secreting T helper (Th) cells (Th17 cells), by a mechanism involving the serum glucocorticoid kinase-1 (SGK1) that promotes the expression of the IL-23 receptor (IL-23R). The IL-23/IL-23R is critical for pathogenic inflammatory Th17 cell differentiation. Experimental data in murine models of arthritis, colitis and encephalomyelitis corroborate these findings. This manuscript reviews the current knowledge on the effects of sodium chloride on innate and adaptive immunity. We also performed a systematic literature review for clinical studies examining the relationships between salt consumption and the development or the activity/severity of the most common IMDs mediated by the IL-23/Th17 pathway, i.e., rheumatoid arthritis (RA), multiple sclerosis (MS), and Crohn's disease (CD). Nine studies were found, 4 in RA, 4 in MS and 1 in CD. An association was found between developments of anti-citrullinated protein antibody (ACPA) positive RA in smokers and salt intake, but these results were not confirmed in another study. For MS, no association was observed in pediatric subjects while in adult patients, a link was found between salt intake and disease activity. However, this result was not confirmed in another study. These conflicting results highlight the fact that further evaluation in human IMDs is required. Moreover, physicians need to develop clinical trials with diet interventions to evaluate the impact of low salt intake on disease activity/severity of IMDs.

On the Creation, Utility and Sustaining of Rare Diseases Research Networks: Lessons learned from the Urea Cycle Disorders Consortium, the Japanese Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases.

PubMed

Summar, Marshall L; Endo, Fumio; Kölker, Stefan

2014-01-01

The past two decades has seen a rapid expansion in the scientific and public interest in rare diseases and their treatment. One consequence of this has been the formation of registries/longitudinal natural history studies for these disorders. Given the expense and effort needed to develop and maintain such programs, we describe our experience with three linked registries on the same disease group, urea cycle disorders. The Urea Cycle Disorders Consortium (UCDC) was formed in the U.S. in 2003 in response to a request for application from the National Institutes of Health (NIH); the European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD) was formed in 2011 in response to a request for applications from the Directorate-General for Health and Consumers (DG SANCO) of the EU; and the Japanese Urea Cycle Disorders Consortium (JUCDC) was founded in 2012 as a sister organization to the UCDC and E-IMD. The functions of these groups are to collect natural history data, educate the professional and lay population, develop and test new treatments, and establish networks of excellence for the care for these disorders. The UCDC and JUCDC focus exclusively on urea cycle disorders while the E-IMD includes patients with urea cycle disorders and organic acidurias. More than 1400 patients have been enrolled in the three consortia, and numerous projects have been developed and joint meetings held including an international UCDC/E-IMD/JUCDC Urea Cycle meeting in Barcelona in 2013. This article summarizes some of the experiences from the three groups regarding formation, funding, and models for sustainability. Copyright © 2014 Elsevier Inc. All rights reserved.

On the Creation, Utility and Sustaining of Rare Diseases Research Networks: Lessons learned from the Urea Cycle Disorders Consortium, the Japanese Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases

PubMed Central

Summar, Marshall L.; Endo, Fumio; Kölker, Stefan

2016-01-01

The past two decades has seen a rapid expansion in the scientific and public interest in rare diseases and their treatment. One consequence of this has been the formation of registries/longitudinal natural history studies for these disorders. Given the expense and effort needed to develop and maintain such programs, we describe our experience with three linked registries on the same disease group, urea cycle disorders. The Urea Cycle Disorders Consortium (UCDC) was formed in the U.S. in 2003 in response to a request for application from the National Institutes of Health (NIH); the European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD) was formed in 2011 in response to a request for applications from the Directorate-General for Health and Consumers (DG SANCO) of the EU; and the Japanese Urea Cycle Disorders Consortium (JUCDC) was founded in 2012 as a sister organization to the UCDC and E-IMD. The functions of these groups are to collect natural history data, educate the professional and lay population, develop and test new treatments, and establish networks of excellence for the care for these disorders. The UCDC and JUCDC focus exclusively on urea cycle disorders while the E-IMD includes patients with urea cycle disorders and organic acidurias. More than 1400 patients have been enrolled in the three consortia, and numerous projects have been developed and joint meetings held including an international UCDC/E-IMD/JUCDC Urea Cycle meeting in Barcelona in 2013. This article summarizes some of the experiences from the three groups regarding formation, funding, and models for sustainability. PMID:25261246

Precipitation climatology over India: validation with observations and reanalysis datasets and spatial trends

NASA Astrophysics Data System (ADS)

Kishore, P.; Jyothi, S.; Basha, Ghouse; Rao, S. V. B.; Rajeevan, M.; Velicogna, Isabella; Sutterley, Tyler C.

2016-01-01

Changing rainfall patterns have significant effect on water resources, agriculture output in many countries, especially the country like India where the economy depends on rain-fed agriculture. Rainfall over India has large spatial as well as temporal variability. To understand the variability in rainfall, spatial-temporal analyses of rainfall have been studied by using 107 (1901-2007) years of daily gridded India Meteorological Department (IMD) rainfall datasets. Further, the validation of IMD precipitation data is carried out with different observational and different reanalysis datasets during the period from 1989 to 2007. The Global Precipitation Climatology Project data shows similar features as that of IMD with high degree of comparison, whereas Asian Precipitation-Highly-Resolved Observational Data Integration Towards Evaluation data show similar features but with large differences, especially over northwest, west coast and western Himalayas. Spatially, large deviation is observed in the interior peninsula during the monsoon season with National Aeronautics Space Administration-Modern Era Retrospective-analysis for Research and Applications (NASA-MERRA), pre-monsoon with Japanese 25 years Re Analysis (JRA-25), and post-monsoon with climate forecast system reanalysis (CFSR) reanalysis datasets. Among the reanalysis datasets, European Centre for Medium-Range Weather Forecasts Interim Re-Analysis (ERA-Interim) shows good comparison followed by CFSR, NASA-MERRA, and JRA-25. Further, for the first time, with high resolution and long-term IMD data, the spatial distribution of trends is estimated using robust regression analysis technique on the annual and seasonal rainfall data with respect to different regions of India. Significant positive and negative trends are noticed in the whole time series of data during the monsoon season. The northeast and west coast of the Indian region shows significant positive trends and negative trends over western Himalayas and north central Indian region.

[Mesh structure of two-dimensional tumor microvascular architecture phenotype heterogeneity in non-small cell lung cancer].

PubMed

Xiong, Zeng; Zhou, Hui; Liu, Jin-Kang; Hu, Cheng-Ping; Zhou, Mo-Ling; Xia, Yu; Zhou, Jian-Hua

2009-11-01

To investigate the structural characteristics and clinical significance of two-dimensional tumor microvascular architecture phenotype (2D-TMAP) in non-small cell lung cancer (NSCLC). Thirty surgical specimens of NSCLC were collected. The sections of the tumor tissues corresponding to the slice of CT perfusion imaging were selected to construct the 2D-TMAP expression. Spearman correlation analysis was used to examine the relation between the 2D-TMAP expression and the clinicopathological features of NSCLC. A heterogeneity was noted in the 2D-TMAP expression of NSCLC. The microvascular density (MVD) in the area surrounding the tumor was higher than that in the central area, but the difference was not statistically significant. The density of the microvessels without intact lumen was significantly greater in the surrounding area than in the central area (P=0.030). The total MVD was not correlated to tumor differentiation (r=0.042, P=0.831). The density of the microvessels without intact lumen in the surrounding area was positively correlated to degree of tumor differentiation and lymph node metastasis (r=0.528 and 0.533, P=0.041 and 0.028, respectively), and also to the expressions of vascular endothelial growth factor (VEGF), ephrinB2, EphB4, and proliferating cell nuclear antigen (PCNA) (r=0.504, 0.549, 0.549, and 0.370; P=0.005, 0.002, 0.002, and 0.048, respectively). The degree of tumor differentiation was positively correlated to PCNA and VEGF expression (r=0.604 and 0.370, P=0.001 and 0.048, respectively), but inversely to the integrity of microvascular basement membrane (r=-0.531, P=0.033). The 2D-TMAP suggests the overall state of the micro-environment for tumor growth. The 2D-TMAP of NSCLC regulates angiogenesis and tumor cell proliferation through a mesh-like structure, and better understanding of the characteristics and possible mechanism of 2D-TMAP expression can be of great clinical importance.

Naringin inhibits vascular endothelial cell apoptosis via endoplasmic reticulum stress- and mitochondrial-mediated pathways and promotes intraosseous angiogenesis in ovariectomized rats

PubMed Central

Li, Zhan-Chun; Tang, Lu-Min; Shao, Jiang; Li, He

2017-01-01

In this study, to investigate the effects of naringin on vascular endothelial cell (VEC) function, proliferation, apoptosis, and angiogenesis, rat VECs were cultured in vitro and randomly divided into four groups: control, serum-starved, low-concentration naringin treatment, and high-concentration naringin treatment. MTT assay was used to detect cell proliferation while Hoechst 33258 staining and flow cytometry were used to detect apoptosis. Changes in the expression of apoptosis-associated proteins [GRP78, CHOP, caspase-12, and cytochrome c (Cyt.c)] were detected using western blotting. JC-1 staining was employed to detect changes in mitochondrial membrane potential. Intracellular caspase-3, -8, and -9 activity was determined by spectrophotometry. ELISA was used to detect endothelin (ET), and a Griess assay was used to detect changes in the expression of nitric oxide (NO) in culture medium. The study further divided an ovariectomized (OVX) rat model of osteoporosis randomly into four groups: OVX, sham-operated, low-concentration naringin treatment (100 mg/kg), and high-concentration naringin treatment (200 mg/kg). After 3 months of treatment, changes in serum ET and NO expression, bone mineral density (BMD), and microvessel density of the distal femur (using CD34 labeling of VECs) were determined. At each concentration, naringin promoted VEC proliferation in a time- and dose-dependent manner. Naringin also significantly reduced serum starvation-induced apoptosis in endothelial cells, inhibited the expression of GRP78, CHOP, caspase-12, and Cyt.c proteins, and reduced mitochondrial membrane potential as well as reduced the activities of caspase-3 and -9. Furthermore, naringin suppressed ET in vitro and in vivo while enhancing NO synthesis. Distal femoral microvascular density assessment showed that the naringin treatment groups had a significantly higher number of microvessels than the OVX group, and that microvascular density was positively correlated with BMD. In summary, naringin inhibits apoptosis in VECs by blocking the endoplasmic reticulum (ER) stress- and mitochondrial-mediated pathways. Naringin also regulates endothelial cell function and promotes angiogenesis to exert its anti-osteoporotic effect. PMID:29039439

Naringin inhibits vascular endothelial cell apoptosis via endoplasmic reticulum stress‑ and mitochondrial‑mediated pathways and promotes intraosseous angiogenesis in ovariectomized rats.

PubMed

Shangguan, Wen-Ji; Zhang, Yue-Hui; Li, Zhan-Chun; Tang, Lu-Min; Shao, Jiang; Li, He

2017-12-01

In this study, to investigate the effects of naringin on vascular endothelial cell (VEC) function, proliferation, apoptosis, and angiogenesis, rat VECs were cultured in vitro and randomly divided into four groups: control, serum‑starved, low‑concentration naringin treatment, and high‑concentration naringin treatment. MTT assay was used to detect cell proliferation while Hoechst 33258 staining and flow cytometry were used to detect apoptosis. Changes in the expression of apoptosis‑associated proteins [GRP78, CHOP, caspase‑12, and cytochrome c (Cyt.c)] were detected using western blotting. JC‑1 staining was employed to detect changes in mitochondrial membrane potential. Intracellular caspase‑3, ‑8, and ‑9 activity was determined by spectrophotometry. ELISA was used to detect endothelin (ET), and a Griess assay was used to detect changes in the expression of nitric oxide (NO) in culture medium. The study further divided an ovariectomized (OVX) rat model of osteoporosis randomly into four groups: OVX, sham‑operated, low‑concentration naringin treatment (100 mg/kg), and high‑concentration naringin treatment (200 mg/kg). After 3 months of treatment, changes in serum ET and NO expression, bone mineral density (BMD), and microvessel density of the distal femur (using CD34 labeling of VECs) were determined. At each concentration, naringin promoted VEC proliferation in a time‑ and dose‑dependent manner. Naringin also significantly reduced serum starvation‑induced apoptosis in endothelial cells, inhibited the expression of GRP78, CHOP, caspase‑12, and Cyt.c proteins, and reduced mitochondrial membrane potential as well as reduced the activities of caspase‑3 and ‑9. Furthermore, naringin suppressed ET in vitro and in vivo while enhancing NO synthesis. Distal femoral microvascular density assessment showed that the naringin treatment groups had a significantly higher number of microvessels than the OVX group, and that microvascular density was positively correlated with BMD. In summary, naringin inhibits apoptosis in VECs by blocking the endoplasmic reticulum (ER) stress‑ and mitochondrial‑mediated pathways. Naringin also regulates endothelial cell function and promotes angiogenesis to exert its anti‑osteoporotic effect.

Existing reporting guidelines for clinical trials are not completely relevant for implantable medical devices: a systematic review.

PubMed

Motte, Anne-France; Diallo, Stéphanie; van den Brink, Hélène; Châteauvieux, Constance; Serrano, Carole; Naud, Carole; Steelandt, Julie; Alsac, Jean-Marc; Aubry, Pierre; Cour, Florence; Pellerin, Olivier; Pineau, Judith; Prognon, Patrice; Borget, Isabelle; Bonan, Brigitte; Martelli, Nicolas

2017-11-01

The aim of this study was to determine relevant items for reporting clinical trials on implantable medical devices (IMDs) and to identify reporting guidelines which include these items. A panel of experts identified the most relevant items for evaluating IMDs from an initial list based on reference papers. We then conducted a systematic review of articles indexed in MEDLINE. We retrieved reporting guidelines from the EQUATOR network's library for health research reporting. Finally, we screened these reporting guidelines to find those using our set of reporting items. Seven relevant reporting items were selected that related to four topics: randomization, learning curve, surgical setting, and device information. A total of 348 reporting guidelines were identified, among which 26 met our inclusion criteria. However, none of the 26 reporting guidelines presented all seven items together. The most frequently reported item was timing of randomization (65%). On the contrary, device information and learning curve effects were poorly specified. To our knowledge, this study is the first to identify specific items related to IMDs in reporting guidelines for clinical trials. We have shown that no existing reporting guideline is totally suitable for these devices. Copyright © 2017 Elsevier Inc. All rights reserved.

Cytokine Diedel and a viral homologue suppress the IMD pathway in Drosophila.

PubMed

Lamiable, Olivier; Kellenberger, Christine; Kemp, Cordula; Troxler, Laurent; Pelte, Nadège; Boutros, Michael; Marques, Joao Trindade; Daeffler, Laurent; Hoffmann, Jules A; Roussel, Alain; Imler, Jean-Luc

2016-01-19

Viruses are obligatory intracellular parasites that suffer strong evolutionary pressure from the host immune system. Rapidly evolving viral genomes can adapt to this pressure by acquiring genes that counteract host defense mechanisms. For example, many vertebrate DNA viruses have hijacked cellular genes encoding cytokines or cytokine receptors to disrupt host cell communication. Insect viruses express suppressors of RNA interference or apoptosis, highlighting the importance of these cell intrinsic antiviral mechanisms in invertebrates. Here, we report the identification and characterization of a family of proteins encoded by insect DNA viruses that are homologous to a 12-kDa circulating protein encoded by the virus-induced Drosophila gene diedel (die). We show that die mutant flies have shortened lifespan and succumb more rapidly than controls when infected with Sindbis virus. This reduced viability is associated with deregulated activation of the immune deficiency (IMD) pathway of host defense and can be rescued by mutations in the genes encoding the homolog of IKKγ or IMD itself. Our results reveal an endogenous pathway that is exploited by insect viruses to modulate NF-κB signaling and promote fly survival during the antiviral response.

Stereology techniques in radiation biology

NASA Technical Reports Server (NTRS)

Kubinova, Lucie; Mao, XiaoWen; Janacek, Jiri; Archambeau, John O.; Nelson, G. A. (Principal Investigator)

2003-01-01

Clinicians involved in conventional radiation therapy are very concerned about the dose-response relationships of normal tissues. Before proceeding to new clinical protocols, radiation biologists involved with conformal proton therapy believe it is necessary to quantify the dose response and tolerance of the organs and tissues that will be irradiated. An important focus is on the vasculature. This presentation reviews the methodology and format of using confocal microscopy and stereological methods to quantify tissue parameters, cell number, tissue volume and surface area, and vessel length using the microvasculature as a model tissue. Stereological methods and their concepts are illustrated using an ongoing study of the dose response of the microvessels in proton-irradiated hemibrain. Methods for estimating the volume of the brain and the brain cortex, the total number of endothelial cells in cortical microvessels, the length of cortical microvessels, and the total surface area of cortical microvessel walls are presented step by step in a way understandable for readers with little mathematical background. It is shown that stereological techniques, based on a sound theoretical basis, are powerful and reliable and have been used successfully.

Tc17 cells in patients with uterine cervical cancer.

PubMed

Zhang, Yan; Hou, Fei; Liu, Xin; Ma, Daoxin; Zhang, Youzhong; Kong, Beihua; Cui, Baoxia

2014-01-01

The existence of Tc17 cells was recently shown in several types of infectious and autoimmune diseases, but their distribution and functions in uterine cervical cancer (UCC) have not been fully elucidated. The frequency of Tc17 cells in peripheral blood samples obtained from UCC patients, cervical intraepithelial neoplasia (CIN) patients and healthy controls was determined by flow cytometry. Besides, the prevalence of Tc17 cells and their relationships to Th17 cells and Foxp3-expressing T cells as well as microvessels in tissue samples of the patients were assessed by immunohistochemistry staining. Compared to controls, patients with UCC or CIN had a higher proportion of Tc17 cells in both peripheral blood and cervical tissues, but the level of Tc17 cells in UCC tissues was significantly higher than that in CIN tissues. Besides, the increased level of Tc17 in UCC patients was associated with the status of pelvic lymph node metastases and increased microvessel density. Finally, significant correlations of infiltration between Tc17 cells and Th17 cells or Foxp3-expressing T cells were observed in UCC and CIN tissues. This study indicates that Tc17 cell infiltration in cervical cancers is associated with cancer progression accompanied by increased infiltrations of Th17 cells and regulatory T cells as well as promoted tumor vasculogenesis.

Parecoxib: an enhancer of radiation therapy for colorectal cancer.

PubMed

Xiong, Wei; Li, Wen-Hui; Jiang, Yong-Xin; Liu, Shan; Ai, Yi-Qin; Liu, Rong; Chang, Li; Zhang, Ming; Wang, Xiao-Li; Bai, Han; Wang, Hong; Zheng, Rui; Tan, Jing

2015-01-01

To study the effect of parecoxib, a novel cyclooxygenase-2 selective inhibitor, on the radiation response of colorectal cancer (CRC) cells and its underlying mechanisms. Both in vitro colony formation and apoptosis assays as well as in vivo mouse xenograft experiments were used to explore the radiosensitizing effects of parecoxib in human HCT116 and HT29 CRC cells. Parecoxib sensitized CRC cells to radiation in vitro with a sensitivity enhancement ratio of 1.32 for HCT116 cells and 1.15 for HT29 cells at a surviving fraction of 0.37. This effect was partially attributable to enhanced apoptosis induction by parecoxib combined with radiation, as illustrated using an in vitro apoptosis assays. Parecoxib augmented the tumor response of HCT116 xenografts to radiation, achieving growth delay more than 20 days and an enhancement factor of 1.53. In accordance with the in vitro results, parecoxib combined with radiation resulted in less proliferation and more apoptosis in tumors than radiation alone. Radiation monotherapy decreased microvessel density (MVD) and microvessel intensity (MVI), but increased the hypoxia level in xenografts. Parecoxib did not affect MVD, but it increased MVI and attenuated hypoxia. Parecoxib can effectively enhance radiation sensitivity in CRC cells through direct effects on tumor cells and indirect effects on tumor vasculature.

Smooth muscle‐generated methylglyoxal impairs endothelial cell‐mediated vasodilatation of cerebral microvessels in type 1 diabetic rats

PubMed Central

Alomar, Fadhel; Singh, Jaipaul; Jang, Hee‐Seong; Rozanzki, George J; Shao, Chun Hong; Padanilam, Babu J; Mayhan, William G

2016-01-01

Background and Purpose Endothelial cell‐mediated vasodilatation of cerebral arterioles is impaired in individuals with Type 1 diabetes (T1D). This defect compromises haemodynamics and can lead to hypoxia, microbleeds, inflammation and exaggerated ischaemia‐reperfusion injuries. The molecular causes for dysregulation of cerebral microvascular endothelial cells (cECs) in T1D remains poorly defined. This study tests the hypothesis that cECs dysregulation in T1D is triggered by increased generation of the mitochondrial toxin, methylglyoxal, by smooth muscle cells in cerebral arterioles (cSMCs). Experimental Approach Endothelial cell‐mediated vasodilatation, vascular transcytosis inflammation, hypoxia and ischaemia‐reperfusion injury were assessed in brains of male Sprague‐Dawley rats with streptozotocin‐induced diabetes and compared with those in diabetic rats with increased expression of methylglyoxal‐degrading enzyme glyoxalase‐I (Glo‐I) in cSMCs. Key Results After 7–8 weeks of T1D, endothelial cell‐mediated vasodilatation of cerebral arterioles was impaired. Microvascular leakage, gliosis, macrophage/neutrophil infiltration, NF‐κB activity and TNF‐α levels were increased, and density of perfused microvessels was reduced. Transient occlusion of a mid‐cerebral artery exacerbated ischaemia‐reperfusion injury. In cSMCs, Glo‐I protein was decreased, and the methylglyoxal‐synthesizing enzyme, vascular adhesion protein 1 (VAP‐1) and methylglyoxal were increased. Restoring Glo‐I protein in cSMCs of diabetic rats to control levels via gene transfer, blunted VAP‐1 and methylglyoxal increases, cECs dysfunction, microvascular leakage, inflammation, ischaemia‐reperfusion injury and increased microvessel perfusion. Conclusions and Implications Methylglyoxal generated by cSMCs induced cECs dysfunction, inflammation, hypoxia and exaggerated ischaemia‐reperfusion injury in diabetic rats. Lowering methylglyoxal produced by cSMCs may be a viable therapeutic strategy to preserve cECs function and blunt deleterious downstream consequences in T1D. PMID:27611446

Study on the Characteristics of Contrast-Enhanced Ultrasound and Its Utility in Assessing the Microvessel Density in Ovarian Tumors or Tumor-Like Lesions

PubMed Central

Wang, Junyan; Lv, Faqin; Fei, Xiang; Cui, Qiuli; Wang, Longxia; Gao, Xuewen; Yuan, Zhixian; Lin, Qian; Lv, Yali; Liu, Aijun

2011-01-01

Angiogenesis is a critical factor in tumor growth and metastasis, and microvessel density (MVD) was an important parameter for assessing vessels in tumors. However, radiologic assessment of tumor vascularity is not yet well established. In our study, we aimed at investigating the efficacy of contrast-enhanced ultrasonography (CEUS) in exploring the vascularity of the ovarian tumors or tumor-like lesions to assess the relationship between the parameters of the peak intensity (PI) and area under curve (AUC) on CEUS and MVD in ovarian masses. Compared to the contrast-enhanced ultrasound technique, conventional ultrasound shows limitation in differentiating benign and malignant ovarian tumors. The former is promising in improving the sensitivity of detecting small vessels and blood flow in ovarian tumors. Our results showed clear differences in enhancement patterns between benign and malignant ovary tumors or tumor-like lesions. The PI and AUC in the malignant tumors were significantly higher than those in the benign tumors or tumor-like lesions (p=0.001 and =0.01, respectively). The MVD was 43.1 ± 20.4 in the benign tumors or tumor-like lesions and was 65.3 ± 22.3 in the malignant ones (p= 0.01). In both the benign and malignant groups, the PI and AUC were correlated significantly with the MVD (r=0.595, p = 0.001; r =0.533, p = 0.003, respectively). The PI and AUC in CEUS can reflect the MVD in ovarin tumors. The PI and AUC of the ovarian masses in the contrast transvaginal sonography show significant correlation with the angiogenesis and may help in assessing tumor vascularity in ovarian masses. PMID:21614152

Prognostic significance of epithelial/stromal caveolin-1 expression in prostatic hyperplasia, high grade prostatic intraepithelial hyperplasia and prostatic carcinoma and its correlation with microvessel density.

PubMed

Mohammed, Dareen A; Helal, Duaa S

2017-03-01

Caveolin-1 may play a role in cancer development and progression. The aim was to record the expression and localization of caveolin-1 in benign prostatic hyperplasia (BPH), high grade prostatic intraepithelial neoplasia (HGPIN) and prostatic carcinoma (PCa). Microvessel density was evaluated with CD34 immunostain. Correlations with known prognostic factors of PCa were recorded. Immunohistochemical expression of caveolin-1 and the MVD was evaluated in 65 cases; BPH (25), HGPIN (20) and PCa (20). Stromal caveolin-1expression was significantly higher in BPH than HGPIN and PCca. There was significant inverse relation between stromal caveolin-1 expression and extension to lymph node and seminal vesicle in carcinoma cases. Epithelial caveolin-1 was significantly higher in carcinomas than in BPH and HGPIN. Epithelial expression in carcinoma was significantly associated with preoperative PSA, Gleason score and lymph node extension. MVD was significantly higher in PCa than in BPH and HGPIN. There were significant relations between MVD and preoperative PSA, Gleason score, lymph node and seminal vesicle extension. Stromal caveolin-1 was associated with low MVD while epithelial caveolin-1 with high MVD. Caveolin-1 plays an important role in prostatic carcinogenesis and metastasis. Stromal expression of caveolin-1 in PCa is lowered in relation to BPH and HGPIN. In PCa; stromal caveolin-1 was associated with good prognostic parameters. Epithelial caveolin-1 is significantly increased in PCa than BPH and HGPIN. It is associated with clinically aggressive disease. Caveolin-1 may play a role in angiogenesis. Copyright © 2017 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V. All rights reserved.

Novel MET/TIE2/VEGFR2 inhibitor altiratinib inhibits tumor growth and invasiveness in bevacizumab-resistant glioblastoma mouse models

PubMed Central

Piao, Yuji; Park, Soon Young; Henry, Verlene; Smith, Bryan D.; Tiao, Ningyi; Flynn, Daniel L.

2016-01-01

Background Glioblastoma highly expresses the proto-oncogene MET in the setting of resistance to bevacizumab. MET engagement by hepatocyte growth factor (HGF) results in receptor dimerization and autophosphorylation mediating tumor growth, invasion, and metastasis. Evasive revascularization and the recruitment of TIE2-expressing macrophages (TEMs) are also triggered by anti-VEGF therapy. Methods We investigated the activity of altiratinib (a novel balanced inhibitor of MET/TIE2/VEGFR2) against human glioblastoma stem cell lines in vitro and in vivo using xenograft mouse models. The biological activity of altiratinib was assessed in vitro by testing the expression of HGF-stimulated MET phosphorylation as well as cell viability after altiratinib treatment. Tumor volume, stem cell and mesenchymal marker levels, microvessel density, and TIE2-expressing monocyte infiltration were evaluated in vivo following treatment with a control, bevacizumab alone, bevacizumab combined with altiratinib, or altiratinib alone. Results In vitro, HGF-stimulated MET phosphorylation was completely suppressed by altiratinib in GSC17 and GSC267, and altiratinib markedly inhibited cell viability in several glioblastoma stem cell lines. More importantly, in multiple xenograft mouse models, altiratinib combined with bevacizumab dramatically reduced tumor volume, invasiveness, mesenchymal marker expression, microvessel density, and TIE2-expressing monocyte infiltration compared with bevacizumab alone. Furthermore, in the GSC17 xenograft model, altiratinib combined with bevacizumab significantly prolonged survival compared with bevacizumab alone. Conclusions Together, these data suggest that altiratinib may suppress tumor growth, invasiveness, angiogenesis, and myeloid cell infiltration in glioblastoma. Thus, altiratinib administered alone or in combination with bevacizumab may overcome resistance to bevacizumab and prolong survival in patients with glioblastoma. PMID:26965451

Microvessel Density Evaluation of the Effect of Enamel Matrix Derivative on Soft Tissue After Implant Placement: A Preliminary Study.

PubMed

Guimarães, George Furtado; de Araújo, Vera Cavalcanti; Nery, James Carlos; Peruzzo, Daiane Cristina; Soares, Andresa Borges

2015-01-01

Enamel matrix derivative (EMD) is commonly used in periodontal therapy and has been used successfully for periodontal regeneration. In addition, this material has a possible angiogenic effect that has been associated with enhanced wound healing. The aim of this study was to evaluate the effect of EMD on microvessel density (angiogenesis) on the soft tissues surrounding newly placed implants after 14 days. Five patients were selected, each requiring at least one implant on each side of the maxilla, in a split-mouth experimental design. The implants were placed in a two-stage procedure. Each side was then randomized as test or control. On the test side, 0.1 mL of EMD was topically applied to the soft tissues surrounding the implants, while the control side did not receive any treatment. Second-stage surgery was performed after 14 days. A 6-mm punch biopsy was performed for each implant, with the samples subsequently prepared for histology and immunohistochemistry. Quantitative vascularization analysis was performed, which involved counting three areas or "hotspots" containing vessels strongly positive for CD34 and CD105, a pan-endothelial and new vessel marker, respectively. There was no significant difference between test and control groups when evaluating the formation of new blood vessels. The total number of blood vessels, however, was significantly higher in the group treated with EMD (test group). Within the limits of the present study, it can be concluded that topical application of EMD on the soft tissues surrounding newly placed implants resulted in an increased number of blood vessels at 14 days, suggesting that EMD may play a beneficial role in this aspect of wound healing.

Thromboxane synthase expression and correlation with VEGF and angiogenesis in non-small cell lung cancer.

PubMed

Cathcart, Mary Clare; Gately, Kathy; Cummins, Robert; Drakeford, Clive; Kay, Elaine W; O'Byrne, Kenneth J; Pidgeon, Graham P

2014-05-01

Thromboxane synthase (TXS) metabolizes prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with angiogenesis and poor outcome. TXS has been identified as a potential therapeutic target in NSCLC. This study examines a link between TXS expression, angiogenesis, and survival in NSCLC. TXS and VEGF metabolite levels were measured in NSCLC serum samples (n=46) by EIA. TXB2 levels were correlated with VEGF. A 204-patient TMA was stained for TXS, VEGF, and CD-31 expression. Expression was correlated with a range of clinical parameters, including overall survival. TXS expression was correlated with VEGF and CD-31. Stable TXS clones were generated and the effect of overexpression on tumor growth and angiogenesis markers was examined in-vitro and in-vivo (xenograft mouse model). Serum TXB2 levels were correlated with VEGF (p<0.05). TXS and VEGF were expressed to a varying degree in NSCLC tissue. TXS was associated with VEGF (p<0.0001) and microvessel density (CD-31; p<0.05). TXS and VEGF expression levels were higher in adenocarcinoma (p<0.0001) and female patients (p<0.05). Stable overexpression of TXS increased VEGF secretion in-vitro. While no significant association with patient survival was observed for either TXS or VEGF in our patient cohort, TXS overexpression significantly (p<0.05) increased tumor growth in-vivo. TXS overexpression was also associated with higher levels of VEGF, microvessel density, and reduced apoptosis in xenograft tumors. TXS promotes tumor growth in-vivo in NSCLC, an effect which is at least partly mediated through increased tumor angiogenesis. Copyright © 2014 Elsevier B.V. All rights reserved.

EMMPRIN as a novel target for pancreatic cancer therapy

PubMed Central

Kim, Hyunki; Zhai, Guihua; Liu, Zhiyong; Samuel, Sharon; Shah, Nemil; Helman, Emily E.; Knowles, Joseph A.; Stockard, Cecil R.; Fineberg, Naomi S.; Grizzle, William E.; Zhou, Tong; Zinn, Kurt R.; Rosenthal, Eben L.

2013-01-01

The objective of this study was to evaluate extracelluar matrix metalloproteinase (EMMPRIN) as a novel target in orthotopic pancreatic-cancer murine models. MIA PaCa-2 human pancreatic tumor cells were implanted in groups 1 and 3-7, while MIA PaCa-2 EMMPRIN knockdown cells were implanted in group 2. Dosing with anti-EMMPRIN antibody started immediately after implantation for groups 1-3 (residual tumor model) and at 21 days after cell implantation for groups 4-7 (established tumor model). Groups 3, 5, and 7 were treated with anti-EMMRPIN antibody (0.2-1.0 mg) twice weekly for 2-3 weeks, while the other groups served as the control. In residual tumor model, tumor growth of anti-EMMPRIN treated group was successfully arrested for 21 days (15±4 mm3), significantly lower than that of EMMPRIN knockdown group (80±15 mm3; p=0.001) or control group (240±41 mm3; p<0.001). In established tumor model, anti-EMMPRIN therapy lowered tumor-volume increase about 40% compared with control regardless of dose amount. Ki67-expressed cell densities of group 5 was 939±150 mm−2, significantly lower than that of group 4 (1709±145 mm−2; p=0.006). Microvessel density of group 5 (30±6 mm−2) was also significantly lower than that of group 4 (53±5 mm−2; p=0.014), while the microvessel size of group 5 (191±22 μm2) was significantly larger than that of group 4 (113±26 μm2; p=0.049). These data show the high potential of anti-EMMPRIN therapy for pancreatic cancer, and support its clinical translation. PMID:21730821

Comparative analysis of COX-2, vascular endothelial growth factor and microvessel density in human renal cell carcinomas.

PubMed

Hemmerlein, B; Galuschka, L; Putzer, N; Zischkau, S; Heuser, M

2004-12-01

Cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) are frequently up-regulated in malignant tumours and play a role in proliferation, apoptosis, angiogenesis and tumour invasion. In the present study, the expression of COX-2 and VEGF in renal cell carcinoma (RCC) was analysed and correlated with the microvessel density (MVD). COX-2 and VEGF were analysed by realtime reverse transcriptase-polymerase chain reaction and immunohistochemistry. The MVD was assessed by CD31 immunohistochemistry. The expression of COX-2 and VEGF was determined in the RCC cell lines A498 and Caki-1 under short-term hypoxia and in multicellular tumour cell aggregates. COX-2 was expressed in RCC by tumour epithelia, endothelia and macrophages in areas of cystic tumour regression and tumour necrosis. COX-2 protein in RCC was not altered in comparison with normal renal tissue. VEGF mRNA was up-regulated in RCC and positively correlated with MVD. RCC with high up-regulation of VEGF mRNA showed weak intracytoplasmic expression of VEGF in tumour cells. Intracytoplasmic VEGF protein expression was negatively correlated with MVD. In RCC with necrosis the MVD was reduced in comparison with RCC without necrosis. A498 RCC cells down-regulated COX-2 and up-regulated VEGF under conditions of hypoxia. In Caki-1 cells COX-2 expression remained stable, whereas VEGF was significantly up-regulated. In multicellular A498 cell aggregates COX-2 and VEGF were up-regulated centrally, whereas no gradient was found in Caki-1 cells. COX-2 and VEGF are potential therapeutic targets because COX-2 and VEGF are expressed in RCC and associated cell populations such as endothelia and monocytes/macrophages.

Number of circulating endothelial progenitor cells and intratumoral microvessel density in non-small cell lung cancer patients: differences in angiogenic status between adenocarcinoma histologic subtypes.

PubMed

Maeda, Ryo; Ishii, Genichiro; Ito, Masami; Hishida, Tomoyuki; Yoshida, Junji; Nishimura, Mitsuyo; Haga, Hironori; Nagai, Kanji; Ochiai, Atsushi

2012-03-01

Angiogenesis plays a significant role in tumor progression. This study examined the association between the number of circulating endothelial progenitor cells (EPCs), intratumoral microvessel density (MVD) (both of which may be markers for neovascularization), and lung cancer histological types, particularly adenocarcinoma histological subtypes. A total of 83 stage I non-small cell lung cancer (NSCLC) patients underwent complete tumor resection between November 2009 and July 2010. The number of EPCs from the pulmonary artery of the resected lungs was measured by assaying CD34/vascular endothelial growth factor receptor 2 positive cells, and the MVD was assessed immunohistochemically in tumor specimens by staining for CD34. A statistically significant correlation between the number of EPCs from pulmonary artery and intratumoral MVD was found (p < 0.001). No statistically significant differences in the number of EPCs and the MVD were observed between the adenocarcinomas and the squamous cell carcinomas. Among the adenocarcinoma histological subtypes, a higher number of EPCs and MVD were found significantly more frequently in solid adenocarcinomas than in nonsolid adenocarcinomas (p < 0.001 and p = 0.011, respectively). In addition, solid adenocarcinomas showed higher levels of vascular endothelial growth factor using quantitative real-time polymerase chain reaction in the tumor tissue samples than in the nonsolid adenocarcinomas (p = 0.005). The higher number of circulating EPCs and the MVD of solid adenocarcinoma may indicate the presence of differences in the tumor angiogenic status between early-stage adenocarcinoma histological subtypes. Among adenocarcinoma patients, patients with solid adenocarcinoma may be the best candidates for antiangiogenic therapies.

Effects of radiotherapy and chemotherapy on angiogenesis and leukocyte infiltration in rectal cancer.

PubMed

Baeten, Coen I M; Castermans, Karolien; Lammering, Guido; Hillen, Femke; Wouters, Bradly G; Hillen, Harry F P; Griffioen, Arjan W; Baeten, Cornelius G M I

2006-11-15

We and others have shown that angiogenesis and leukocyte infiltration are important prognostic factors in rectal cancer. However, little is known about its possible changes in response to radiotherapy (RTX), which is frequently given to rectal tumors as a neoadjuvant treatment to improve the prognosis. We therefore investigated the biologic effects of RTX on these parameters using fresh-frozen biopsy samples of tumor and normal mucosa tissue before and after RTX. Biopsy samples were taken from a total of 34 patients before and after either a short course or long course of RTX combined with chemotherapy. The following parameters were analyzed by immunohistochemistry, flow cytometry, or quantitative real-time polymerase chain reaction: Microvessel density, leukocyte infiltration, proliferating epithelial and tumor cells, proliferating endothelial cells, adhesion molecule expression on endothelial cells, and the angiogenic mRNA profile. The tumor biopsy samples taken after RTX treatment demonstrated a significant decrease in microvessel density and the number of proliferating tumor cells and proliferating endothelial cells (p < 0.001). In contrast, the leukocyte infiltration, the levels of basic fibroblast growth factor in carcinoma tissue, and the adhesion molecule expression on endothelial cells in normal as well as carcinoma tissue increased significantly (p < 0.05). Our data show that together with an overall decrease in tumor cell and endothelial cell proliferation, RTX results in an increase in the expression of adhesion molecules that stimulate leukocyte infiltration. This suggests the possibility that, in addition to its direct cytotoxic effect, radiation may also stimulate an immunologic tumor response that could contribute to the documented improvement in local tumor control and distal failure rate of rectal cancers.

Microvessel density in head and neck squamous cell carcinoma.

PubMed

Szafarowski, Tomasz; Sierdzinski, Janusz; Szczepanski, Miroslaw J; Whiteside, Theresa L; Ludwig, Nils; Krzeski, Antoni

2018-05-10

Microvessel density (MVD) corresponds to the intensity of neo-angiogenesis. MVD assessments are based on the expression levels of the vascular endothelium markers such as, e.g., CD34 or CD105. The goal of this study was to assess MVD among patients with head and neck squamous cell carcinoma (HNSCC), and to evaluate the predictive value of MVD in head and neck cancers. The study included 49 patients treated for HNSCC and 11 patients with dysplasia of the upper respiratory tract epithelium. Control tissues consisted of 12 normal mucous membranes of the throat. Expression levels of MVD markers were assessed by immunohistochemistry (IHC) using tissue microarrays (TMA). Clinicopathological factors and patients' survival over the 5-year follow-up period were analyzed. The MVD/CD34 values were found to be significantly elevated in the HNSCCs compared to the non-malignant control tissues (p = 0.001) and to dysplastic tissues. (p = 0.02). Significantly higher MVD/CD105 values were also seen in the tumor compared to the control tissues (p = 0.001) or the dysplastic tissues (p = 0.001). Unexpectedly, significantly lower MVD/CD34 values were seen in the tumor tissues of patients with the T3-T4 tumors compared to those with T1-T2 tumors (p = 0.01). HNSCCs have statistically higher MVD values compared to dysplasia of the upper respiratory tract epithelium. However, the MVD/CD34 values did not correlate with local invasiveness (the T feature) of HNSCCs. This counterintuitive observation suggests that assessments of MVD as performed on TMA by IHC using anti-CD34 or anti-CD105 antibodies considered to be specific for endothelial cell markers might underestimate the extent of the tumor vascularity in HNSCC.

Anti-tumor activity of high-dose EGFR tyrosine kinase inhibitor and sequential docetaxel in wild type EGFR non-small cell lung cancer cell nude mouse xenografts

PubMed Central

Tang, Ning; Zhang, Qianqian; Fang, Shu; Han, Xiao; Wang, Zhehai

2017-01-01

Treatment of non-small-cell lung cancer (NSCLC) with wild-type epidermal growth factor receptor (EGFR) is still a challenge. This study explored antitumor activity of high-dose icotinib (an EGFR tyrosine kinase inhibitor) plus sequential docetaxel against wild-type EGFR NSCLC cells-generated nude mouse xenografts. Nude mice were subcutaneously injected with wild-type EGFR NSCLC A549 cells and divided into different groups for 3-week treatment. Tumor xenograft volumes were monitored and recorded, and at the end of experiments, tumor xenografts were removed for Western blot and immunohistochemical analyses. Compared to control groups (negative control, regular-dose icotinib [IcoR], high-dose icotinib [IcoH], and docetaxel [DTX]) and regular icotinib dose (60 mg/kg) with docetaxel, treatment of mice with a high-dose (1200 mg/kg) of icotinib plus sequential docetaxel for 3 weeks (IcoH-DTX) had an additive effect on suppression of tumor xenograft size and volume (P < 0.05). Icotinib-containing treatments markedly reduced phosphorylation of EGFR, mitogen activated protein kinase (MAPK), and protein kinase B (Akt), but only the high-dose icotinib-containing treatments showed an additive effect on CD34 inhibition (P < 0.05), an indication of reduced microvessel density in tumor xenografts. Moreover, high-dose icotinib plus docetaxel had a similar effect on mouse weight loss (a common way to measure adverse reactions in mice), compared to the other treatment combinations. The study indicate that the high dose of icotinib plus sequential docetaxel (IcoH-DTX) have an additive effect on suppressing the growth of wild-type EGFR NSCLC cell nude mouse xenografts, possibly through microvessel density reduction. Future clinical trials are needed to confirm the findings of this study. PMID:27852073

Efficacy of Sunitinib and Radiotherapy in Genetically Engineered Mouse Model of Soft-Tissue Sarcoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yoon, Sam S.; Stangenberg, Lars; Lee, Yoon-Jin

Purpose: Sunitinib (SU) is a multitargeted receptor tyrosine kinase inhibitor of the vascular endothelial growth factor and platelet-derived growth factor receptors. The present study examined SU and radiotherapy (RT) in a genetically engineered mouse model of soft tissue sarcoma (STS). Methods and Materials: Primary extremity STSs were generated in genetically engineered mice. The mice were randomized to treatment with SU, RT (10 Gy x 2), or both (SU+RT). Changes in the tumor vasculature before and after treatment were assessed in vivo using fluorescence-mediated tomography. The control and treated tumors were harvested and extensively analyzed. Results: The mean fluorescence in themore » tumors was not decreased by RT but decreased 38-44% in tumors treated with SU or SU+RT. The control tumors grew to a mean of 1378 mm{sup 3} after 12 days. SU alone or RT alone delayed tumor growth by 56% and 41%, respectively, but maximal growth inhibition (71%) was observed with the combination therapy. SU target effects were confirmed by loss of target receptor phosphorylation and alterations in SU-related gene expression. Cancer cell proliferation was decreased and apoptosis increased in the SU and RT groups, with a synergistic effect on apoptosis observed in the SU+RT group. RT had a minimal effect on the tumor microvessel density and endothelial cell-specific apoptosis, but SU alone or SU+RT decreased the microvessel density by >66% and induced significant endothelial cell apoptosis. Conclusion: SU inhibited STS growth by effects on both cancer cells and tumor vasculature. SU also augmented the efficacy of RT, suggesting that this combination strategy could improve local control of STS.« less

Brain vascular image enhancement based on gradient adjust with split Bregman

NASA Astrophysics Data System (ADS)

Liang, Xiao; Dong, Di; Hui, Hui; Zhang, Liwen; Fang, Mengjie; Tian, Jie

2016-04-01

Light Sheet Microscopy is a high-resolution fluorescence microscopic technique which enables to observe the mouse brain vascular network clearly with immunostaining. However, micro-vessels are stained with few fluorescence antibodies and their signals are much weaker than large vessels, which make micro-vessels unclear in LSM images. In this work, we developed a vascular image enhancement method to enhance micro-vessel details which should be useful for vessel statistics analysis. Since gradient describes the edge information of the vessel, the main idea of our method is to increase the gradient values of the enhanced image to improve the micro-vessels contrast. Our method contained two steps: 1) calculate the gradient image of LSM image, and then amplify high gradient values of the original image to enhance the vessel edge and suppress low gradient values to remove noises. Then we formulated a new L1-norm regularization optimization problem to find an image with the expected gradient while keeping the main structure information of the original image. 2) The split Bregman iteration method was used to deal with the L1-norm regularization problem and generate the final enhanced image. The main advantage of the split Bregman method is that it has both fast convergence and low memory cost. In order to verify the effectiveness of our method, we applied our method to a series of mouse brain vascular images acquired from a commercial LSM system in our lab. The experimental results showed that our method could greatly enhance micro-vessel edges which were unclear in the original images.

The fabrication of PLGA microvessel scaffolds with nano-patterned inner walls.

PubMed

Wang, Gou-Jen; Lin, Yan-Cheng; Hsu, Shan-Hui

2010-10-01

Poly (lactic-co-glycolic acid) (PLGA) is one of the most commonly used biodegradable, biocompatible materials. Nanostructured PLGA has immense potential for application in tissue engineering. In this article we discuss a novel approach for the fabrication of PLGA microvessel scaffolds with nanostructured inner walls. In this novel nano-patterning approach, the thermal reflow technique is first adapted to fabricate a semi-cylindrical photoresist master mold. A thin film of titanium and a thin film of aluminum are sputtered in sequence on the semi-cylindrical microvessel network. Aluminum foil anodization is then executed to transform the aluminum thin film into a porous anodic aluminum oxide (AAO) film. During the casting process a PLGA solution is cast on the AAO film to build up semi-cylindrical PLGA microstructures with nanostructured inner walls after which inductive coupled plasma (ICP) is implemented to assist bonding of the two PLGA structures. The result is the building of a network of microchannels with nano-patterned inner walls. Bovine endothelial cells (BECs) are carefully cultured in the scaffold via semi-dynamic seeding for 7 days. Observations show that the BECs grew more separately in a nano-patterned microvessel scaffold than they did in a smooth surface scaffold.

Properties of an intergenic terminator and start site switch that regulate IMD2 transcription in yeast.

PubMed

Jenks, M Harley; O'Rourke, Thomas W; Reines, Daniel

2008-06-01

The IMD2 gene in Saccharomyces cerevisiae is regulated by intracellular guanine nucleotides. Regulation is exerted through the choice of alternative transcription start sites that results in synthesis of either an unstable short transcript terminating upstream of the start codon or a full-length productive IMD2 mRNA. Start site selection is dictated by the intracellular guanine nucleotide levels. Here we have mapped the polyadenylation sites of the upstream, unstable short transcripts that form a heterogeneous family of RNAs of approximately 200 nucleotides. The switch from the upstream to downstream start sites required the Rpb9 subunit of RNA polymerase II. The enzyme's ability to locate the downstream initiation site decreased exponentially as the start was moved downstream from the TATA box. This suggests that RNA polymerase II's pincer grip is important as it slides on DNA in search of a start site. Exosome degradation of the upstream transcripts was highly dependent upon the distance between the terminator and promoter. Similarly, termination was dependent upon the Sen1 helicase when close to the promoter. These findings extend the emerging concept that distinct modes of termination by RNA polymerase II exist and that the distance of the terminator from the promoter, as well as its sequence, is important for the pathway chosen.

Activation of PmRelish from Penaeus monodon by yellow head virus.

PubMed

Visetnan, Suwattana; Supungul, Premruethai; Hirono, Ikuo; Tassanakajon, Anchalee; Rimphanitchayakit, Vichien

2015-02-01

Humoral innate immune response against pathogenic infection is partly responsible by the Imd pathway in which a transcription factor Relish relays the infection signals to the nuclei for the expression of antimicrobial proteins. A PmRelish gene which encoded a protein of 1195 amino acids was cloned. The PmRelish was constitutively expressed in all tissues tested and mostly up-regulated upon YHV infection. In hemocytes, the PmRelish expression was up-regulated upon Vibrio harveyi, yellow head virus (YHV) and white spot syndrome virus (WSSV) challenges. Using dsRNA silencing of PmRelish gene, it was shown that the expression of penaeidin5 but not anti-lipopolysaccharide factor ALFPm3, crustinPm1 and penaeidin3 was under the regulation of Imd pathway. Under PmRelish silencing, the shrimp were more susceptible to infection by YHV with the 50% survival rate reduced from about 72 h to 42 h. The PmRelish was detected in the cytoplasm of all the hemocytes from both uninfected and YHV-infected shrimp. The accumulation of activated PmRelish in the nuclei was not clearly observed but the activated PmRelish was detected in the YHV-infected hemocytes by Western blot analysis. Thus, the PmRelish and, hence, the Imd pathway respond to the YHV infection. Copyright © 2014 Elsevier Ltd. All rights reserved.

Deriving high-resolution protein backbone structure propensities from all crystal data using the information maximization device.

PubMed

Solis, Armando D

2014-01-01

The most informative probability distribution functions (PDFs) describing the Ramachandran phi-psi dihedral angle pair, a fundamental descriptor of backbone conformation of protein molecules, are derived from high-resolution X-ray crystal structures using an information-theoretic approach. The Information Maximization Device (IMD) is established, based on fundamental information-theoretic concepts, and then applied specifically to derive highly resolved phi-psi maps for all 20 single amino acid and all 8000 triplet sequences at an optimal resolution determined by the volume of current data. The paper shows that utilizing the latent information contained in all viable high-resolution crystal structures found in the Protein Data Bank (PDB), totaling more than 77,000 chains, permits the derivation of a large number of optimized sequence-dependent PDFs. This work demonstrates the effectiveness of the IMD and the superiority of the resulting PDFs by extensive fold recognition experiments and rigorous comparisons with previously published triplet PDFs. Because it automatically optimizes PDFs, IMD results in improved performance of knowledge-based potentials, which rely on such PDFs. Furthermore, it provides an easy computational recipe for empirically deriving other kinds of sequence-dependent structural PDFs with greater detail and precision. The high-resolution phi-psi maps derived in this work are available for download.

Is There a Direct Correlation Between Microvascular Wall Structure and k-Trans Values Obtained From Perfusion CT Measurements in Lymphomas?

PubMed

Horger, Marius; Fallier-Becker, Petra; Thaiss, Wolfgang M; Sauter, Alexander; Bösmüller, Hans; Martella, Manuela; Preibsch, Heike; Fritz, Jan; Nikolaou, Konstantin; Kloth, Christopher

2018-05-03

This study aimed to test the hypothesis that ultrastructural wall abnormalities of lymphoma vessels correlate with perfusion computed tomography (PCT) kinetics. Our local institutional review board approved this prospective study. Between February 2013 and June 2016, we included 23 consecutive subjects with newly diagnosed lymphoma, who were referred for computed tomography-guided biopsy (6 women, 17 men; mean age, 60.61 ± 12.43 years; range, 28-74 years) and additionally agreed to undergo PCT of the target lymphoma tissues. PCT was obtained for 40 seconds using 80 kV, 120 mAs, 64 × 0.6-mm collimation, 6.9-cm z-axis coverage, and 26 volume measurements. Mean and maximum k-trans (mL/100 mL/min), blood flow (BF; mL/100 mL/min) and blood volume (BV) were quantified using the deconvolution and the maximum slope + Patlak calculation models. Immunohistochemical staining was performed for microvessel density quantification (vessels/m 2 ), and electron microscopy was used to determine the presence or absence of tight junctions, endothelial fenestration, basement membrane, and pericytes, and to measure extracellular matrix thickness. Extracellular matrix thickness as well as the presence or absence of tight junctions, basal lamina, and pericytes did not correlate with computed tomography perfusion parameters. Endothelial fenestrations correlated significantly with mean BF deconvolution (P = .047, r = 0.418) and additionally was significantly associated with higher mean BV deconvolution (P < .005). Mean k-trans Patlak correlated strongly with mean k-trans deconvolution (r = 0.939, P = .001), and both correlated with mean BF deconvolution (P = .001, r = 0.748), max BF deconvolution (P = .028, r = 0.564), mean BV deconvolution (P = .001, r = 0.752), and max BV deconvolution (P = .001, r = 0.771). Microvessel density correlated with max k-trans deconvolution (r = 0.564, P = .023). Vascular endothelial growth factor receptor-3 expression (receptor specific for lymphatics) correlated significantly with max k-trans Patlak (P = .041, r = 0.686) and mean BF deconvolution (P = .038, r = 0.695). k-Trans values of PCT do not correlate with ultrastructural microvessel features, whereas endothelial fenestrations correlate with increased intra-tumoral BVs. Copyright © 2018 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.

Dynamics of Immune System Gene Expression upon Bacterial Challenge and Wounding in a Social Insect (Bombus terrestris)

PubMed Central

Erler, Silvio; Popp, Mario; Lattorff, H. Michael G.

2011-01-01

The innate immune system which helps individuals to combat pathogens comprises a set of genes representing four immune system pathways (Toll, Imd, JNK and JAK/STAT). There is a lack of immune genes in social insects (e.g. honeybees) when compared to Diptera. Potentially, this might be compensated by an advanced system of social immunity (synergistic action of several individuals). The bumble bee, Bombus terrestris, is a primitively eusocial species with an annual life cycle and colonies headed by a single queen. We used this key pollinator to study the temporal dynamics of immune system gene expression in response to wounding and bacterial challenge. Antimicrobial peptides (AMP) (abaecin, defensin 1, hymenoptaecin) were strongly up-regulated by wounding and bacterial challenge, the latter showing a higher impact on the gene expression level. Sterile wounding down-regulated TEP A, an effector gene of the JAK/STAT pathway, and bacterial infection influenced genes of the Imd (relish) and JNK pathway (basket). Relish was up-regulated within the first hour after bacterial challenge, but decreased strongly afterwards. AMP expression following wounding and bacterial challenge correlates with the expression pattern of relish whereas correlated expression with dorsal was absent. Although expression of AMPs was high, continuous bacterial growth was observed throughout the experiment. Here we demonstrate for the first time the temporal dynamics of immune system gene expression in a social insect. Wounding and bacterial challenge affected the innate immune system significantly. Induction of AMP expression due to wounding might comprise a pre-adaptation to accompanying bacterial infections. Compared with solitary species this social insect exhibits reduced immune system efficiency, as bacterial growth could not be inhibited. A negative feedback loop regulating the Imd-pathway is suggested. AMPs, the end product of the Imd-pathway, inhibited the up-regulation of the transcription factor relish, which is necessary for effector gene expression. PMID:21479237

Evaluation of the BioVigilant IMD-A, a novel optical spectroscopy technology for the continuous and real-time environmental monitoring of viable and nonviable particles. Part II. Case studies in environmental monitoring during aseptic filling, intervention assessments, and glove integrity testing in manufacturing isolators.

PubMed

Miller, Michael J; Walsh, Michael R; Shrake, Jerry L; Dukes, Randall E; Hill, Daniel B

2009-01-01

This paper describes the use of the BioVigilant IMD-A, a real-time and continuous monitoring technology based on optical spectroscopy, to simultaneously and instantaneously detect, size, and enumerate both viable and nonviable particles in a variety of filling and transfer isolator environments during an aseptic fill, transfer of sterilized components, and filling interventions. Continuous monitoring of three separate isolators for more than 16 h and representing more than 28 m3 of air per isolator (under static conditions) yielded a mean viable particle count of zero (0) per cubic meter. Although the mean count per cubic meter was zero, the detection of very low levels of single viable particles was randomly observed in each of these sampling runs. No viable particles were detected during the manual transfer of sterilized components from transfer isolators into a filling isolator, and similar results were observed during an aseptic fill, a filling needle change-out procedure, and during disassembly, movement, and reassembly of a vibrating stopper bowl. During the continuous monitoring of a sample transfer port and a simulated mousehole, no viable particles were detected; however, when the sampling probe was inserted beyond the isolator-room interface, the IMD-A instantaneously detected and enumerated both viable and nonviable particles originating from the surrounding room. Data from glove pinhole studies showed no viable particles being observed, although significant viable particles were immediately detected when the gloves were removed and a bare hand was allowed to introduce microorganisms into the isolator. The IMD-A technology offers the industry an unprecedented advantage over growth-based bioaerosol samplers for monitoring the state of microbiological control in pharmaceutical manufacturing environments, and represents significant progress toward the acceptance of microbiology process analytical technology solutions for the industry.

Characteristics of Japanese Patients with Becker Muscular Dystrophy and Intermediate Muscular Dystrophy in a Japanese National Registry of Muscular Dystrophy (Remudy): Heterogeneity and Clinical Variation.

PubMed

Mori-Yoshimura, Madoka; Mitsuhashi, Satomi; Nakamura, Harumasa; Komaki, Hirofumi; Goto, Kanako; Yonemoto, Naohiro; Takeuchi, Fumi; Hayashi, Yukiko K; Murata, Miho; Takahashi, Yuji; Nishino, Ichizo; Takeda, Shin'ichi; Kimura, En

2018-01-01

Obtaining an adequate number of patients to conduct a natural history study for rare diseases such as Becker muscular dystrophy (BMD) is difficult. The present study used data from Remudy, a national registry for neuromuscular diseases in Japan, to conduct a phenotypic analysis of BMD. We analyzed Remudy data of participants with dystrophinopathy. All participants who were aged 17 and older and were ambulant at age 13 were included in this study. Participants were divided into two groups: those with BMD who were ambulant at age 17, and those with intermediate muscular dystrophy (IMD) who lost ambulation by age 17. Frequent mutations were analyzed by age at ambulation, cardiopulmonary function, and genotype. For clinical comparisons, participants who were administered steroids were excluded. From July 2009 through September 2015, 192 participants had registered with Remudy. Mean participant age was 34.80±13.3 (range, 17-78) years, and 52.1% of participants were ambulant. Of the entire study population, 50.5% had cardiomyopathy and 35.9% had respiratory failure. Three participants required invasive ventilation and 30 required non-invasive ventilation. Nineteen of the 30 non-invasive ventilator users were part-time users. In total, 138 (71.9%) had BMD and 54 (28.1%) had IMD. The most frequent mutation was ex45_ex47del (36 participants). Among participants with frequent in-frame mutations, those with the ex45-49del mutation lost their ambulation earlier than those with the ex45_ex47del mutation. A total of 67 different exon deletions and duplications were identified in the study population. We clarified the clinical phenotypes of Japanese patients with BMD/IMD using data from Remudy. Our results suggest that not only IMD but also BMD are associated with risk of respiratory dysfunction.

LASER BIOLOGY AND MEDICINE: Recording of lymph flow dynamics in microvessels using correlation properties of scattered coherent radiation

NASA Astrophysics Data System (ADS)

Fedosov, I. V.; Tuchin, Valerii V.; Galanzha, E. I.; Solov'eva, A. V.; Stepanova, T. V.

2002-11-01

The direction-sensitive method of microflow velocity measurements based on the space — time correlation properties of the dynamic speckle field is described and used for in vivo monitoring of lymph flow in the vessels of rat mesentery. The results of measurements are compared with the data obtained from functional video microscopy of the microvessel region.

The inhibitor of 20-HETE synthesis, TS-011, improves cerebral microcirculatory autoregulation impaired by middle cerebral artery occlusion in mice.

PubMed

Marumo, Toshiyuki; Eto, Kei; Wake, Hiroaki; Omura, Tomohiro; Nabekura, Junichi

2010-11-01

20-Hydroxyeicosatetraenoic acid is a potent vasoconstrictor that contributes to cerebral ischaemia. An inhibitor of 20-Hydroxyeicosatetraenoic acid synthesis, TS-011, reduces infarct volume and improves neurological deficits in animal stroke models. However, little is known about how TS-011 affects the microvessels in ischaemic brain. Here, we investigated the effect of TS-011 on microvessels after cerebral ischaemia. TS-011 (0.3 mg·kg(-1) ) or a vehicle was infused intravenously for 1 h every 6 h in a mouse model of stroke, induced by transient occlusion of the middle cerebral artery occlusion following photothrombosis. The cerebral blood flow velocity and the vascular perfusion area of the peri-infarct microvessels were measured using in vivo two-photon imaging. The cerebral blood flow velocities in the peri-infarct microvessels decreased at 1 and 7 h after reperfusion, followed by an increase at 24 h after reperfusion in the vehicle-treated mice. We found that TS-011 significantly inhibited both the decrease and the increase in the blood flow velocities in the peri-infarct microvessels seen in the vehicle-treated mice after reperfusion. In addition, TS-011 significantly inhibited the reduction in the microvascular perfusion area after reperfusion, compared with the vehicle-treated group. Moreover, TS-011 significantly reduced the infarct volume by 40% at 72 h after middle cerebral artery occlusion. These findings demonstrated that infusion of TS-011 improved defects in the autoregulation of peri-infarct microcirculation and reduced the infarct volume. Our results could be relevant to the treatment of cerebral ischaemia. © 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society.

A Simple and Reproducible Method to Prepare Membrane Samples from Freshly Isolated Rat Brain Microvessels.

PubMed

Brzica, Hrvoje; Abdullahi, Wazir; Reilly, Bianca G; Ronaldson, Patrick T

2018-05-07

The blood-brain barrier (BBB) is a dynamic barrier tissue that responds to various pathophysiological and pharmacological stimuli. Such changes resulting from these stimuli can greatly modulate drug delivery to the brain and, by extension, cause considerable challenges in the treatment of central nervous system (CNS) diseases. Many BBB changes that affect pharmacotherapy, involve proteins that are localized and expressed at the level of endothelial cells. Indeed, such knowledge on BBB physiology in health and disease has sparked considerable interest in the study of these membrane proteins. From a basic science research standpoint, this implies a requirement for a simple but robust and reproducible method for isolation of microvessels from brain tissue harvested from experimental animals. In order to prepare membrane samples from freshly isolated microvessels, it is essential that sample preparations be enriched in endothelial cells but limited in the presence of other cell types of the neurovascular unit (i.e., astrocytes, microglia, neurons, pericytes). An added benefit is the ability to prepare samples from individual animals in order to capture the true variability of protein expression in an experimental population. In this manuscript, details regarding a method that is utilized for isolation of rat brain microvessels and preparation of membrane samples are provided. Microvessel enrichment, from samples derived, is achieved by using four centrifugation steps where dextran is included in the sample buffer. This protocol can easily be adapted by other laboratories for their own specific applications. Samples generated from this protocol have been shown to yield robust experimental data from protein analysis experiments that can greatly aid the understanding of BBB responses to physiological, pathophysiological, and pharmacological stimuli.

Cardioprotective effects of red wine and vodka in a model of endothelial dysfunction

PubMed Central

Lassaletta, Antonio D; Chu, Louis M; Elmadhun, Nassrene Y; Burgess, Thomas A; Feng, Jun; Robich, Michael P; Sellke, Frank W

2012-01-01

Background Moderate alcohol consumption is largely believed to be cardioprotective, while red wine is hypothesized to offer benefit in part due to the pro-angiogenic and antioxidant properties of polyphenols. We investigated the cardiovascular effects of both red wine and vodka in a swine model of endothelial dysfunction. Methods Twenty-seven male Yorkshire swine fed a high-fat/cholesterol diet were divided into three groups and received either no alcohol (Control), red wine, or vodka. After seven weeks, myocardial perfusion was measured, and ventricular tissue was analyzed for microvascular reactivity, and immunohistochemical studies. Results There were no differences in myocardial perfusion, in arteriolar or capillary density, or in VEGF expression among groups. Total protein oxidation as well as expression of superoxide dismutase-1 and -2 (SOD1, SOD2) and NADPH-oxidase (NOX2) was decreased in both treatment groups compared to controls. Endothelium-dependent microvessel relaxation, however, was significantly improved only in the red wine-supplemented group. Conclusions Supplementation with both red wine and vodka decreased oxidative stress by several measures, implicating the effects of ethanol in reducing oxidative stress in the myocardium. However, it was only in the red wine-supplemented group that an improvement in microvessel function was observed. This suggests that a component of red wine, independent of ethanol, possibly a polyphenol such as resveratrol, may confer cardioprotection by normalizing endothelial dysfunction induced by an atherogenic diet. PMID:22748601

Microvascular dysfunction with increased vascular leakage response in mice systemically exposed to arsenic.

PubMed

Chen, Shih-Chieh; Huang, Shin-Yin; Lu, Chi-Yu; Hsu, Ya-Hung; Wang, Dean-Chuan

2014-09-01

The mechanisms underlying cardiovascular disease induced by arsenic exposure are not completely understood. The objectives of this study were to investigate whether arsenic-fed mice have an increased vascular leakage response to vasoactive agents and whether enhanced type-2 protein phosphatase (PP2A) activity is involved in mustard oil-induced leakage. ICR mice were fed water or sodium arsenite (20 mg/kg) for 4 or 8 weeks. The leakage response to vasoactive agents was quantified using the Evans blue (EB) technique or vascular labeling with carbon particles. Increased EB leakage and high density of carbon-labeled microvessels were detected in arsenic-fed mice treated with mustard oil. Histamine induced significantly higher vascular leakage in arsenic-fed mice than in water-fed mice. Pretreatment with the PP2A inhibitor okadaic acid or the neurokinin 1 receptor (NK1R) blocker RP67580 significantly reduced mustard oil-induced vascular leakage in arsenic-fed mice. The protein levels of PP2Ac and NK1R were similar in both groups. PP2A activity was significantly higher in the arsenic-fed mice compared with the control group. These findings indicate that microvessels generally respond to vasoactive agents, and that the increased PP2A activity is involved in mustard oil-induced vascular leakage in arsenic-fed mice. Arsenic may initiate endothelial dysfunction, resulting in vascular leakage in response to vasoactive agents.

Prognostic significance of anaplasia and angiogenesis in childhood medulloblastoma: a pediatric oncology group study.

PubMed

Ozer, Erdener; Sarialioglu, Faik; Cetingoz, Riza; Yüceer, Nurullah; Cakmakci, Handan; Ozkal, Sermin; Olgun, Nur; Uysal, Kamer; Corapcioglu, Funda; Canda, Serefettin

2004-01-01

The purpose of this study was to investigate whether quantitative assessment of cytologic anaplasia and angiogenesis may predict the clinical prognosis in medulloblastoma and stratify the patients to avoid both undertreatment and overtreatment. Medulloblastomas from 23 patients belonging to the Pediatric Oncology Group were evaluated with respect to some prognostic variables, including histologic assessment of nodularity and desmoplasia, grading of anaplasia, measurement of nuclear size, mitotic cell count, quantification of angiogenesis, including vascular surface density (VSD) and microvessel number (NVES), and immunohistochemical scoring of vascular endothelial growth factor (VEGF) expression. Univariate and multivariate analyses for prognostic indicators for survival were performed. Univariate analysis revealed that extensive nodularity was a significant favorable prognostic factor, whereas the presence of anaplasia, increased nuclear size, mitotic rate, VSD, and NVES were significant unfavorable prognostic factors. Using multivariate analysis, increased nuclear size was found to be an independent unfavorable prognostic factor for survival. Neither the presence of desmoplasia nor VEGF expression was significantly related to patient survival. Although care must be taken not to overstate the importance of the results of this single-institution preliminary report, pathologic grading of medulloblastomas with respect to grading of anaplasia and quantification of nodularity, nuclear size, and microvessel profiles may be clinically useful for the treatment of medulloblastomas. Further validation of the independent prognostic significance of nuclear size in stratifying patients is required.

Tc17 Cells in Patients with Uterine Cervical Cancer

PubMed Central

Zhang, Yan; Hou, Fei; Liu, Xin; Ma, Daoxin; Zhang, Youzhong; Kong, Beihua; Cui, Baoxia

2014-01-01

Background The existence of Tc17 cells was recently shown in several types of infectious and autoimmune diseases, but their distribution and functions in uterine cervical cancer (UCC) have not been fully elucidated. Methods The frequency of Tc17 cells in peripheral blood samples obtained from UCC patients, cervical intraepithelial neoplasia (CIN) patients and healthy controls was determined by flow cytometry. Besides, the prevalence of Tc17 cells and their relationships to Th17 cells and Foxp3-expressing T cells as well as microvessels in tissue samples of the patients were assessed by immunohistochemistry staining. Results Compared to controls, patients with UCC or CIN had a higher proportion of Tc17 cells in both peripheral blood and cervical tissues, but the level of Tc17 cells in UCC tissues was significantly higher than that in CIN tissues. Besides, the increased level of Tc17 in UCC patients was associated with the status of pelvic lymph node metastases and increased microvessel density. Finally, significant correlations of infiltration between Tc17 cells and Th17 cells or Foxp3-expressing T cells were observed in UCC and CIN tissues. Conclusions This study indicates that Tc17 cell infiltration in cervical cancers is associated with cancer progression accompanied by increased infiltrations of Th17 cells and regulatory T cells as well as promoted tumor vasculogenesis. PMID:24523865

In vivo endoscopic Doppler optical coherence tomography imaging of mouse colon

NASA Astrophysics Data System (ADS)

Welge, Weston A.; Barton, Jennifer K.

2016-03-01

Colorectal cancer remains the second deadliest cancer in the United States, despite the high sensitivity and specificity of colonoscopy and sigmoidoscopy. While these standard imaging procedures can accurately detect medium and large polyps, some studies have shown miss rates up to 25% for polyps less than 5 mm in diameter. An imaging modality capable of detecting small lesions could potentially improve patient outcomes. Optical coherence tomography (OCT) has been shown to be a powerful imaging modality for adenoma detection in a mouse model of colorectal cancer. While previous work has focused on analyzing the structural OCT images based on thickening of the mucosa and changes in light attenuation in depth, imaging the microvasculature of the colon may enable earlier detection of polyps. The structure and function of vessels grown to support tumor growth are markedly different from healthy vessels. Doppler OCT is capable of imaging microvessels in vivo. We developed a method of processing raw fringe data from a commercial swept-source OCT system using a lab-built miniature endoscope to extract microvessels. This method can be used to measure vessel count and density and to measure flow velocities. This may improve early detection and aid in the development of new chemopreventive and chemotherapeutic drugs. We present, to the best of our knowledge, the first endoscopic Doppler OCT images of in vivo mouse colon.

Intravital lectin perfusion analysis of vascular permeability in human micro- and macro- blood vessels.

PubMed

Debbage, P L; Sölder, E; Seidl, S; Hutzler, P; Hugl, B; Ofner, D; Kreczy, A

2001-10-01

We previously applied intravital lectin perfusion in mouse models to elucidate mechanisms underlying vascular permeability. The present work transfers this technique to human models, analysing vascular permeability in macro- and microvessels. Human vascular endothelial surface carbohydrate biochemistry differs significantly from its murine counterpart, lacking alpha-galactosyl epitopes and expressing the L-fucose moiety in the glycocalyx; the poly-N-lactosamine glycan backbone is common to all mammals. We examined extensively lectin binding specificities in sections and in vivo, and then applied the poly-N-lactosamine-specific lectin LEA and the L-fucose-specific lectin UEA-I in human intravital perfusions. Transendothelial transport differed in macrovessels and microvessels. In microvessels of adult human fat tissue, rectal wall and rectal carcinomas, slow transendothelial transport by vesicles was followed by significant retention at the subendothelial basement membrane; paracellular passage was not observed. Passage time exceeded 1 h. Thus we found barrier mechanisms resembling those we described previously in murine tissues. In both adult and fetal macrovessels, the vena saphena magna and the umbilical vein, respectively, rapid passage across the endothelial lining was observed, the tracer localising completely in the subendothelial tissues within 15 min; vesicular transport was more rapid than in microvessels, and retention at the subendothelial basement membrane briefer.

Sox10+ adult stem cells contribute to biomaterial encapsulation and microvascularization

PubMed Central

Wang, Dong; Wang, Aijun; Wu, Fan; Qiu, Xuefeng; Li, Ye; Chu, Julia; Huang, Wen-Chin; Xu, Kang; Gong, Xiaohua; Li, Song

2017-01-01

Implanted biomaterials and biomedical devices generally induce foreign body reaction and end up with encapsulation by a dense avascular fibrous layer enriched in extracellular matrix. Fibroblasts/myofibroblasts are thought to be the major cell type involved in encapsulation, but it is unclear whether and how stem cells contribute to this process. Here we show, for the first time, that Sox10+ adult stem cells contribute to both encapsulation and microvessel formation. Sox10+ adult stem cells were found sparsely in the stroma of subcutaneous loose connective tissues. Upon subcutaneous biomaterial implantation, Sox10+ stem cells were activated and recruited to the biomaterial scaffold, and differentiated into fibroblasts and then myofibroblasts. This differentiation process from Sox10+ stem cells to myofibroblasts could be recapitulated in vitro. On the other hand, Sox10+ stem cells could differentiate into perivascular cells to stabilize newly formed microvessels. Sox10+ stem cells and endothelial cells in three-dimensional co-culture self-assembled into microvessels, and platelet-derived growth factor had chemotactic effect on Sox10+ stem cells. Transplanted Sox10+ stem cells differentiated into smooth muscle cells to stabilize functional microvessels. These findings demonstrate the critical role of adult stem cells in tissue remodeling and unravel the complexity of stem cell fate determination. PMID:28071739

Retooling Laser Speckle Contrast Analysis Algorithm to Enhance Non-Invasive High Resolution Laser Speckle Functional Imaging of Cutaneous Microcirculation

NASA Astrophysics Data System (ADS)

Gnyawali, Surya C.; Blum, Kevin; Pal, Durba; Ghatak, Subhadip; Khanna, Savita; Roy, Sashwati; Sen, Chandan K.

2017-01-01

Cutaneous microvasculopathy complicates wound healing. Functional assessment of gated individual dermal microvessels is therefore of outstanding interest. Functional performance of laser speckle contrast imaging (LSCI) systems is compromised by motion artefacts. To address such weakness, post-processing of stacked images is reported. We report the first post-processing of binary raw data from a high-resolution LSCI camera. Sharp images of low-flowing microvessels were enabled by introducing inverse variance in conjunction with speckle contrast in Matlab-based program code. Extended moving window averaging enhanced signal-to-noise ratio. Functional quantitative study of blood flow kinetics was performed on single gated microvessels using a free hand tool. Based on detection of flow in low-flow microvessels, a new sharp contrast image was derived. Thus, this work presents the first distinct image with quantitative microperfusion data from gated human foot microvasculature. This versatile platform is applicable to study a wide range of tissue systems including fine vascular network in murine brain without craniotomy as well as that in the murine dorsal skin. Importantly, the algorithm reported herein is hardware agnostic and is capable of post-processing binary raw data from any camera source to improve the sensitivity of functional flow data above and beyond standard limits of the optical system.

Retooling Laser Speckle Contrast Analysis Algorithm to Enhance Non-Invasive High Resolution Laser Speckle Functional Imaging of Cutaneous Microcirculation

PubMed Central

Gnyawali, Surya C.; Blum, Kevin; Pal, Durba; Ghatak, Subhadip; Khanna, Savita; Roy, Sashwati; Sen, Chandan K.

2017-01-01

Cutaneous microvasculopathy complicates wound healing. Functional assessment of gated individual dermal microvessels is therefore of outstanding interest. Functional performance of laser speckle contrast imaging (LSCI) systems is compromised by motion artefacts. To address such weakness, post-processing of stacked images is reported. We report the first post-processing of binary raw data from a high-resolution LSCI camera. Sharp images of low-flowing microvessels were enabled by introducing inverse variance in conjunction with speckle contrast in Matlab-based program code. Extended moving window averaging enhanced signal-to-noise ratio. Functional quantitative study of blood flow kinetics was performed on single gated microvessels using a free hand tool. Based on detection of flow in low-flow microvessels, a new sharp contrast image was derived. Thus, this work presents the first distinct image with quantitative microperfusion data from gated human foot microvasculature. This versatile platform is applicable to study a wide range of tissue systems including fine vascular network in murine brain without craniotomy as well as that in the murine dorsal skin. Importantly, the algorithm reported herein is hardware agnostic and is capable of post-processing binary raw data from any camera source to improve the sensitivity of functional flow data above and beyond standard limits of the optical system. PMID:28106129

Plasma membrane localization of multidrug resistance-associated protein homologs in brain capillary endothelial cells.

PubMed

Zhang, Yan; Schuetz, John D; Elmquist, William F; Miller, Donald W

2004-11-01

Several multidrug resistance-associated protein (MRP) homologs are expressed in brain microvessel endothelial cells forming the blood-brain barrier (BBB). The influence of these MRP transporters on BBB permeability will be dependent on their localization within the brain microvessel endothelial cells. Using two different and complementary approaches, the localization of various MPR homologs (MRP1, MRP4, and MRP5) was examined in primary cultured bovine brain microvessel endothelial cells (BBMECs). The first approach involved centrifugal separation of apical and basolateral plasma membranes of cultured BBMECs. The membrane fractions were then subjected to Western blot analysis for MRPs. The second approach used confocal laser scanning microscopy to determine membrane localization of MRPs in BBMECs. Results show a predominantly apical plasma membrane distribution for MRP1 and MRP5, and an almost equal distribution of MRP4 on the apical and basolateral plasma membrane of BBMECs. These studies provide the first demonstration of the localization of MRP1, MRP4, and MRP5 homologs in brain microvessel endothelial cells. The present studies also indicate that the localization of MRPs in the endothelial cells forming the BBB is different from that observed in polarized epithelial cells and thus may contribute to the reduced entry and enhanced elimination of organic anions and nucleotides in the brain.

Global epidemiology of invasive meningococcal disease

PubMed Central

2013-01-01

Neisseria meningitidis is one of the leading causes of bacterial meningitis globally and can also cause sepsis, pneumonia, and other manifestations. In countries with high endemic rates, the disease burden places an immense strain on the public health system. The worldwide epidemiology of invasive meningococcal disease (IMD) varies markedly by region and over time. This review summarizes the burden of IMD in different countries and identifies the highest-incidence countries where routine preventive programs against Neisseria meningitidis would be most beneficial in providing protection. Available epidemiological data from the past 20 years in World Health Organization and European Centre for Disease Prevention and Control collections and published articles are included in this review, as well as direct communications with leading experts in the field. Countries were grouped into high-, moderate-, and low-incidence countries. The majority of countries in the high-incidence group are found in the African meningitis belt; many moderate-incidence countries are found in the European and African regions, and Australia, while low-incidence countries include many from Europe and the Americas. Priority countries for vaccine intervention are high- and moderate-incidence countries where vaccine-preventable serogroups predominate. Epidemiological data on burden of IMD are needed in countries where this is not known, particularly in South- East Asia and Eastern Mediterranean regions, so evidence-based decisions about the use of meningococcal vaccines can be made. PMID:24016339

Global epidemiology of invasive meningococcal disease.

PubMed

Jafri, Rabab Z; Ali, Asad; Messonnier, Nancy E; Tevi-Benissan, Carol; Durrheim, David; Eskola, Juhani; Fermon, Florence; Klugman, Keith P; Ramsay, Mary; Sow, Samba; Zhujun, Shao; Bhutta, Zulfiqar A; Abramson, Jon

2013-09-10

Neisseria meningitidis is one of the leading causes of bacterial meningitis globally and can also cause sepsis, pneumonia, and other manifestations. In countries with high endemic rates, the disease burden places an immense strain on the public health system. The worldwide epidemiology of invasive meningococcal disease (IMD) varies markedly by region and over time. This review summarizes the burden of IMD in different countries and identifies the highest-incidence countries where routine preventive programs against Neisseria meningitidis would be most beneficial in providing protection. Available epidemiological data from the past 20 years in World Health Organization and European Centre for Disease Prevention and Control collections and published articles are included in this review, as well as direct communications with leading experts in the field. Countries were grouped into high-, moderate-, and low-incidence countries. The majority of countries in the high-incidence group are found in the African meningitis belt; many moderate-incidence countries are found in the European and African regions, and Australia, while low-incidence countries include many from Europe and the Americas. Priority countries for vaccine intervention are high- and moderate-incidence countries where vaccine-preventable serogroups predominate. Epidemiological data on burden of IMD are needed in countries where this is not known, particularly in South- East Asia and Eastern Mediterranean regions, so evidence-based decisions about the use of meningococcal vaccines can be made.

Influence of deprivation on health care use, health care costs, and mortality in COPD.

PubMed

Collins, Peter F; Stratton, Rebecca J; Kurukulaaratchy, Ramesh J; Elia, Marinos

Deprivation is associated with the incidence of COPD, but its independent impact on clinical outcomes is still relatively unknown. This study aimed to explore the influence of deprivation on health care use, costs, and survival. A total of 424 outpatients with COPD were assessed for deprivation across two hospitals. The English Index of Multiple Deprivation (IMD) was used to establish a deprivation score for each patient. The relationship between deprivation and 1-year health care use, costs, and mortality was examined, controlling for potential confounding variables (age, malnutrition risk, COPD severity, and smoking status). IMD was significantly and independently associated with emergency hospitalization (β-coefficient 0.022, SE 0.007; p =0.001), length of hospital stay, secondary health care costs (β-coefficient £101, SE £30; p =0.001), and mortality (HR 1.042, 95% CI 1.015-1.070; p =0.002). IMD was inversely related to participation in exercise rehabilitation (OR 0.961, 95% CI 0.930-0.994; p =0.002) and secondary care appointments. Deprivation was also significantly related to modifiable risk factors (smoking status and malnutrition risk). Deprivation in patients with COPD is associated with increased emergency health care use, health care costs, and mortality. Tackling deprivation is complex; however, strategies targeting high-risk groups and modifiable risk factors, such as malnutrition and smoking, could reduce the clinical and economic burden.

A Member of the p38 Mitogen-Activated Protein Kinase Family Is Responsible for Transcriptional Induction of Dopa decarboxylase in the Epidermis of Drosophila melanogaster during the Innate Immune Response▿ †

PubMed Central

Davis, Monica M.; Primrose, David A.; Hodgetts, Ross B.

2008-01-01

Drosophila innate immunity is controlled primarily by the activation of IMD (immune deficiency) or Toll signaling leading to the production of antimicrobial peptides (AMPs). IMD signaling also activates the JUN N-terminal kinase (JNK) cascade, which is responsible for immune induction of non-antimicrobial peptide immune gene transcription though the transcription factor AP-1. Transcription of the Dopa decarboxylase (Ddc) gene is induced in response to gram-negative and gram-positive septic injury, but not aseptic wounding. Transcription is induced throughout the epidermis and not specifically at the site of infection. Ddc transcripts are detectible within 2 h and remain high for several hours following infection with either gram-negative or gram-positive bacteria. Using Ddc-green fluorescent protein (GFP) reporter gene constructs, we show that a conserved consensus AP-1 binding site upstream of the Ddc transcription start site is required for induction. However, neither the Toll, IMD, nor JNK pathway is involved. Rather, Ddc transcription depends on a previously uncharacterized member of the p38 mitogen-activated protein kinase family, p38c. We propose that the involvement of DDC in a new pathway involved in Drosophila immunity increases the levels of dopamine, which is metabolized to produce reactive quinones that exert an antimicrobial effect on invading bacteria. PMID:18519585

Wireless Power Transfer Strategies for Implantable Bioelectronics.

PubMed

Agarwal, Kush; Jegadeesan, Rangarajan; Guo, Yong-Xin; Thakor, Nitish V

2017-01-01

Neural implants have emerged over the last decade as highly effective solutions for the treatment of dysfunctions and disorders of the nervous system. These implants establish a direct, often bidirectional, interface to the nervous system, both sensing neural signals and providing therapeutic treatments. As a result of the technological progress and successful clinical demonstrations, completely implantable solutions have become a reality and are now commercially available for the treatment of various functional disorders. Central to this development is the wireless power transfer (WPT) that has enabled implantable medical devices (IMDs) to function for extended durations in mobile subjects. In this review, we present the theory, link design, and challenges, along with their probable solutions for the traditional near-field resonant inductively coupled WPT, capacitively coupled short-ranged WPT, and more recently developed ultrasonic, mid-field, and far-field coupled WPT technologies for implantable applications. A comparison of various power transfer methods based on their power budgets and WPT range follows. Power requirements of specific implants like cochlear, retinal, cortical, and peripheral are also considered and currently available IMD solutions are discussed. Patient's safety concerns with respect to electrical, biological, physical, electromagnetic interference, and cyber security from an implanted neurotech device are also explored in this review. Finally, we discuss and anticipate future developments that will enhance the capabilities of current-day wirelessly powered implants and make them more efficient and integrable with other electronic components in IMDs.

Effect of heat transfer on rotating electroosmotic flow through a micro-vessel: haemodynamical applications

NASA Astrophysics Data System (ADS)

Sinha, A.; Mondal, A.; Shit, G. C.; Kundu, P. K.

2016-08-01

This paper theoretically analyzes the heat transfer characteristics associated with electroosmotic flow of blood through a micro-vessel having permeable walls. The analysis is based on the Debye-Hückel approximation for charge distributions and the Navier-Stokes equations are assumed to represent the flow field in a rotating system. The velocity slip condition at the vessel walls is taken into account. The essential features of the rotating electroosmotic flow of blood and associated heat transfer characteristics through a micro-vessel are clearly highlighted by the variation in the non-dimensional flow velocity, volumetric flow rate and non-dimensional temperature profiles. Moreover, the effect of Joule heating parameter and Prandtl number on the thermal transport characteristics are discussed thoroughly. The study reveals that the flow of blood is appreciably influenced by the elctroosmotic parameter as well as rotating Reynolds number.

Three-Dimensional Arrangement of Human Bone Marrow Microvessels Revealed by Immunohistology in Undecalcified Sections

PubMed Central

Wilhelmi, Verena; Seiler, Anja; Lampp, Katrin; Neff, Andreas; Guthe, Michael; Lobachev, Oleg

2016-01-01

The arrangement of microvessels in human bone marrow is so far unknown. We combined monoclonal antibodies against CD34 and against CD141 to visualise all microvessel endothelia in 21 serial sections of about 1 cm2 size derived from a human iliac crest. The specimen was not decalcified and embedded in Technovit® 9100. In different regions of interest, the microvasculature was reconstructed in three dimensions using automatic methods. The three-dimensional models were subject to a rigid semiautomatic and manual quality control. In iliac crest bone marrow, the adipose tissue harbours irregularly distributed haematopoietic areas. These are fed by networks of large sinuses, which are loosely connected to networks of small capillaries prevailing in areas of pure adipose tissue. Our findings are compatible with the hypothesis that capillaries and sinuses in human iliac crest bone marrow are partially arranged in parallel. PMID:27997569

Modelling nonlinearity in superconducting split ring resonator and its effects on metamaterial structures

NASA Astrophysics Data System (ADS)

Mazdouri, Behnam; Mohammad Hassan Javadzadeh, S.

2017-09-01

Superconducting materials are intrinsically nonlinear, because of nonlinear Meissner effect (NLME). Considering nonlinear behaviors, such as harmonic generation and intermodulation distortion (IMD) in superconducting structures, are very important. In this paper, we proposed distributed nonlinear circuit model for superconducting split ring resonators (SSRRs). This model can be analyzed by using Harmonic Balance method (HB) as a nonlinear solver. Thereafter, we considered a superconducting metamaterial filter which was based on split ring resonators and we calculated fundamental and third-order IMD signals. There are good agreement between nonlinear results from proposed model and measured ones. Additionally, based on the proposed nonlinear model and by using a novel method, we considered nonlinear effects on main parameters in the superconducting metamaterial structures such as phase constant (β) and attenuation factor (α).

Magnetically tunable graphene-based reflector under linear polarized incidence at room temperature

NASA Astrophysics Data System (ADS)

Yang, Liang; Tian, Jing; Giddens, Henry; Poumirol, Jean-Marie; Wu, JingBo; Kuzmenko, Alexey B.; Hao, Yang

2018-04-01

At the terahertz spectrum, the 2D material graphene has diagonal and Hall conductivities in the presence of a magnetic field. These peculiar properties provide graphene-based structures with a magnetically tunable response to electromagnetic waves. In this work, the absolute reflection intensity was measured for a graphene-based reflector illuminated by linearly polarized incident waves at room temperature, which demonstrated the intensity modulation depth (IMD) under different magnetostatic biases by up to 15%. Experimental data were fitted and analyzed by a modified equivalent circuit model. In addition, as an important phenomenon of the graphene gyrotropic response, Kerr rotation is discussed according to results achieved from full-wave simulations. It is concluded that the IMD is reduced for the best Kerr rotation in the proposed graphene-based reflector.

MR Imaging-derived Oxygen Metabolism and Neovascularization Characterization for Grading and IDH Gene Mutation Detection of Gliomas.

PubMed

Stadlbauer, Andreas; Zimmermann, Max; Kitzwögerer, Melitta; Oberndorfer, Stefan; Rössler, Karl; Dörfler, Arnd; Buchfelder, Michael; Heinz, Gertraud

2017-06-01

Purpose To explore the diagnostic performance of physiological magnetic resonance (MR) imaging of oxygen metabolism and neovascularization activity for grading and characterization of isocitrate dehydrogenase (IDH) gene mutation status of gliomas. Materials and Methods This retrospective study had institutional review board approval; written informed consent was obtained from all patients. Eighty-three patients with histopathologically proven glioma (World Health Organization [WHO] grade II-IV) were examined with quantitative blood oxygen level-dependent imaging and vascular architecture mapping. Biomarker maps of neovascularization activity (microvessel radius, microvessel density, and microvessel type indicator [MTI]) and oxygen metabolism (oxygen extraction fraction [OEF] and cerebral metabolic rate of oxygen [CMRO 2 ]) were calculated. Receiver operating characteristic analysis was used to determine diagnostic performance for grading and detection of IDH gene mutation status. Results Low-grade (WHO grade II) glioma showed areas with increased OEF (+18%, P < .001, n = 20), whereas anaplastic glioma (WHO grade III) and glioblastoma (WHO grade IV) showed decreased OEF when compared with normal brain tissue (-54% [P < .001, n = 21] and -49% [P < .001, n = 41], respectively). This allowed clear differentiation between low- and high-grade glioma (area under the receiver operating characteristic curve [AUC], 1) for the patient cohort. MTI had the highest diagnostic performance (AUC, 0.782) for differentiation between gliomas of grades III and IV among all biomarkers. CMRO 2 was decreased (P = .037) in low-grade glioma with a mutated IDH gene, and MTI was significantly increased in glioma grade III with IDH mutation (P = .013) when compared with the IDH wild-type counterparts. CMRO 2 showed the highest diagnostic performance for IDH gene mutation detection in low-grade glioma (AUC, 0.818) and MTI in high-grade glioma (AUC, 0.854) and for all WHO grades (AUC, 0.899) among all biomarkers. Conclusion MR imaging-derived oxygen metabolism and neovascularization characterization may be useful for grading and IDH mutation detection of gliomas and requires only 7 minutes of extra imaging time. © RSNA, 2016 Online supplemental material is available for this article.

Pooled analysis of large and long-term safety data from the human papillomavirus-16/18-AS04-adjuvanted vaccine clinical trial programme

PubMed Central

Angelo, Maria-Genalin; David, Marie-Pierre; Zima, Julia; Baril, Laurence; Dubin, Gary; Arellano, Felix; Struyf, Frank

2014-01-01

Purpose The purpose of this study is to further evaluate the safety of the human papillomavirus (HPV)-16/18-AS04-adjuvanted vaccine (HPV-16/18-vaccine Cervarix®, GlaxoSmithKline, Belgium) through a pooled analysis of data from 42 completed/ongoing clinical studies. Methods Unsolicited adverse events (AEs) were reported for 30 days after each dose. Medically significant conditions, serious AEs (SAEs), potential immune-mediated diseases (pIMDs) and pregnancy outcomes were captured until study completion. Events leading to subject withdrawal were reviewed. Relative risks compared incidences of spontaneous abortion and pIMDs in controlled studies. Results Thirty one thousand one hundred seventy-three adolescent girls/women received HPV-16/18-vaccine alone (HPV group), 2166 received HPV-16/18-vaccine coadministered with another vaccine and 24 241 were controls. Mean follow-up was 39 months (range 0–113.3). Incidences of unsolicited AEs reported within 30 days after any dose were similar between HPV and Control groups (30.8%/29.7%). During the entire study period, reports of medically significant conditions (25.0%/28.3%) and SAEs (7.9%/9.3%) were also similarly distributed between groups. Deaths were rare: HPV (alone/coadministered) n = 25, controls n = 20 (n = 18 in blinded groups). pIMDs within 1 year were reported by 0.2% of HPV-16/18 vaccinees and controls. For each pIMD event category, no increased relative risks were reported for HPV-16/18 vaccinees versus controls. Coadministration did not change the overall safety profile. Pregnancy outcomes and withdrawal rates were similar between groups. Conclusions Analysis of safety data arising from 57 580 subjects and 96 704 HPV-16/18-vaccine doses shows that the incidences and distribution of AEs were similar among HPV-16/18-vaccine recipients and controls. No new safety signals were identified. The data confirm previous findings that HPV-16/18-vaccine has an acceptable benefit-risk profile in adolescent girls and adult women. PMID:24644063

Impact of socioeconomic deprivation on screening for cardiovascular disease risk in a primary prevention population: a cross-sectional study.

PubMed

Lang, Sarah-Jane; Abel, Gary A; Mant, Jonathan; Mullis, Ricky

2016-03-21

Investigate the association between socioeconomic deprivation and completeness of cardiovascular disease (CVD) risk factor recording in primary care, uptake of screening in people with incomplete risk factor recording and with actual CVD risk within the screened subgroup. Cross-sectional study. Nine UK general practices. 7987 people aged 50-74 years with no CVD diagnosis. CVD risk was estimated using the Framingham equation from data extracted from primary care electronic health records. Where there was insufficient information to calculate risk, patients were invited to attend a screening assessment. Proportion of patients for whom clinical data were sufficiently complete to enable CVD risk to be calculated; proportion of patients invited to screening who attended; proportion of patients who attended screening whose 10-year risk of a cardiovascular event was high (>20%). For each outcome, a set of logistic regression models were run. Crude and adjusted ORs were estimated for person-level deprivation, age, gender and smoking status. We included practice-level deprivation as a continuous variable and practice as a random effect to account for clustering. People who had lower Indices of Multiple Deprivation (IMD) scores (less deprived) had significantly worse routine CVD risk factor recording (adjusted OR 0.97 (0.95 to 1.00) per IMD decile; p=0.042). Screening attendance was poorer in those with more deprivation (adjusted OR 0.89 (0.86 to 0.91) per IMD decile; p<0.001). Among those who attended screening, the most deprived were more likely to have CVD risk >20% (OR 1.09 (1.03 to 1.15) per IMD decile; p=0.004). Our data suggest that those who had the most to gain from screening were least likely to attend, potentially exacerbating existing health inequalities. Future research should focus on tailoring the delivery of CVD screening to ensure engagement of socioeconomically deprived groups. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Association between breastfeeding duration, non-nutritive sucking habits and dental arch dimensions in deciduous dentition: a cross-sectional study.

PubMed

Agarwal, Shiv Shankar; Nehra, Karan; Sharma, Mohit; Jayan, Balakrishna; Poonia, Anish; Bhattal, Hiteshwar

2014-10-31

This cross-sectional retrospective study was conducted to determine association between breastfeeding duration, non-nutritive sucking habits, dental arch transverse diameters, posterior crossbite and anterior open bite in deciduous dentition. 415 children (228 males and 187 females), 4 to 6 years old, from a mixed Indian population were clinically examined. Based on written questionnaire answered by parents, children were divided into two groups: group 1 (breastfed for <6 months (n = 158)) and group 2 (breastfed for ≥6 months (n = 257)). The associations were analysed using chi-square test (P < 0.05 taken as statistically significant). Odds ratio (OR) was calculated to determine the strength of associations tested. Multivariate logistic regression analysis was done for obtaining independent predictors of posterior crossbite and maxillary and mandibular IMD (Inter-molar distance) and ICD (Inter-canine distance). Non-nutritive sucking (NNS) was present in 15.18% children (20.3% in group 1 as compared to 12.1% in group 2 (P = 0.024)). The average ICD and IMD in maxilla and average IMD in mandible were significantly higher among group 2 as compared to group 1 (P < 0.01). In mandible, average ICD did not differ significantly between the two groups (P = 0.342). The distribution of anterior open bite did not differ significantly between the two groups (P = 0.865). The distribution of posterior crossbite was significantly different between the two groups (P = 0.001). OR assessment (OR = 1.852) revealed that group 1 had almost twofold higher prevalence of NNS habits than group 2. Multivariate logistic regression analysis revealed that the first group had independently fourfold increased risk of developing crossbite compared to the second group (OR = 4.3). Multivariate linear regression analysis also revealed that age and breastfeeding duration were the most significant determinants of ICD and IMD. An increased prevalence of NNS in the first group suggests that NNS is a dominant variable in the association between breastfeeding duration and reduced intra-arch transverse diameters which leads to increased prevalence of posterior crossbites as seen in our study. Mandibular inter-canine width is however unaffected due to a lowered tongue posture seen in these children.

Cyclo-oxygenase 2 expression is associated with angiogenesis and lymph node metastasis in human breast cancer.

PubMed

Costa, C; Soares, R; Reis-Filho, J S; Leitão, D; Amendoeira, I; Schmitt, F C

2002-06-01

Cyclo-oxygenases 1 and 2 (COX-1 and COX-2) are key enzymes in prostaglandin biosynthesis. COX-2 is induced by a wide variety of stimuli, and present during inflammation. COX-2 overexpression has been observed in colon, head and neck, lung, prostate, stomach, and breast cancer. In colon and gastric cancer, COX-2 expression was associated with angiogenesis. The aim of this study was to determine the relation between COX-2 expression and angiogenesis in breast cancer, and to correlate the expression of this enzyme with classic clinicopathological parameters. COX-2 expression was investigated by immunohistochemistry and western blotting analysis. The expression of COX-2 was then related to age, histological grade, nodal status, oestrogen receptor status, p53 expression,c-erb-B2 overexpression, mitotic counts, MIB-1 labelling index, apoptotic index, sialyl-Tn expression, transforming growth factor alpha expression, microvessel density, and disease free survival in 46 patients with invasive ductal breast carcinoma. By means of immunohistochemistry, COX-2 expression was detected in eight of the 46 carcinomas studied. Western blotting showed COX-2 protein expression in the same breast tumours, but not in normal adjacent tissues. The density of microvessels immunostained with anti-F-VIII related antigen was significantly higher in patients with COX-2 expression than in those without expression (p = 0.03). In addition, COX-2 was significantly associated with the presence of sialyl-Tn expression (p = 0.02), lymph node metastasis (p = 0.03), a high apoptotic index (p = 0.03), and a short disease free survival (p = 0.03) in univariate analyses. These data suggest that COX-2 expression is associated with angiogenesis, lymph node metastasis, and apoptosis in human breast cancer. Moreover, these results warrant further studies with larger series of patients to confirm the association with short disease free survival in patients with breast cancer.

Role of Neuropilin-1/Semaphorin-3A signaling in the functional and morphological integrity of the cochlea

PubMed Central

Salehi, Pezhman; Gundimeda, Usha; Lael Cantu, Homero; Lavinsky, Joel; Myint, Anthony; Wang, Juemei; Abdala, Carolina; Ohyama, Takahiro; Coate, Thomas Matthew

2017-01-01

Neuropilin-1 (Nrp1) encodes the transmembrane cellular receptor neuropilin-1, which is associated with cardiovascular and neuronal development and was within the peak SNP interval on chromosome 8 in our prior GWAS study on age-related hearing loss (ARHL) in mice. In this study, we generated and characterized an inner ear-specific Nrp1 conditional knockout (CKO) mouse line because Nrp1 constitutive knockouts are embryonic lethal. In situ hybridization demonstrated weak Nrp1 mRNA expression late in embryonic cochlear development, but increased expression in early postnatal stages when cochlear hair cell innervation patterns have been shown to mature. At postnatal day 5, Nrp1 CKO mice showed disorganized outer spiral bundles and enlarged microvessels of the stria vascularis (SV) but normal spiral ganglion cell (SGN) density and presynaptic ribbon body counts; however, we observed enlarged SV microvessels, reduced SGN density, and a reduction of presynaptic ribbons in the outer hair cell region of 4-month-old Nrp1 CKO mice. In addition, we demonstrated elevated hearing thresholds of the 2-month-old and 4-month-old Nrp1 CKO mice at frequencies ranging from 4 to 32kHz when compared to 2-month-old mice. These data suggest that conditional loss of Nrp1 in the inner ear leads to progressive hearing loss in mice. We also demonstrated that mice with a truncated variant of Nrp1 show cochlear axon guidance defects and that exogenous semaphorin-3A, a known neuropilin-1 receptor agonist, repels SGN axons in vitro. These data suggest that Neuropilin-1/Semaphorin-3A signaling may also serve a role in neuronal pathfinding in the developing cochlea. In summary, our results here support a model whereby Neuropilin-1/Semaphorin-3A signaling is critical for the functional and morphological integrity of the cochlea and that Nrp1 may play a role in ARHL. PMID:29059194

An analysis of microvessel density, androgen receptor, p53 and HER-2/neu expression and Gleason score in prostate cancer . preliminary results and therapeutic implications.

PubMed

Mydlo, J H; Kral, J G; Volpe, M; Axotis, C; Macchia, R J; Pertschuk, L P

1998-01-01

To investigate relationships between microvessel density (MVD), androgen receptors (AR), mutant p53 and HER-2/neu expression and Gleason score (GS) to further understand the tumor biology of prostate cancer (CAP). Slides of CAP from patients who underwent radical prostatectomy or channel transurethral resection of the prostate (TURP) were tested for androgen receptors by immunocytochemical assay and MVD was analyzed by staining with antibodies to the endothelial cell membrane molecule PECAM-1/CD-31. The p53 monoclonal antibody D07 and HER-2 9G6 mouse monoclonal antibody were used to assess p53 and HER-2/neu expression, respectively. The results were correlated with GS and clinical stage by multivariate analysis. We found a fourfold greater expression of MVD in prostate cancer specimens compared to neighboring normal prostate tissue. We observed a greater concentration of MVD in the higher Gleason scores (r = 0.40, p = 0. 06), and a correlation of Gleason score with mutant p53 expression (r = 0.57, p <0.05). We did not observe any associations between AR or HER-2/neu to Gleason score. More than half of the patients with specimens with 50% or greater expression of mutant p53 were in stage D2 (T4NxM1b) at the time of biopsy. We observed a correlation between mutant p53 and GS, and a greater concentration of MVD in the higher GS. Since the neovascularity of prostate tumors can be attenuated by radiation and hormones, while mutant p53 may confer resistance to such treatment, it appears that p53 expression may also play an important role in addition to angiogenesis in the virulence of prostate cancer. These data may aid in allocating patients to different treatment modalities.

Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenografts

PubMed Central

Zhu, Yin; Cheng, Ming; Yang, Zhen; Zeng, Chun-Yan; Chen, Jiang; Xie, Yong; Luo, Shi-Wen; Zhang, Kun-He; Zhou, Shu-Feng; Lu, Nong-Hua

2014-01-01

Mesenchymal stem cells (MSCs) have been recognized as promising delivery vehicles for gene therapy of tumors. Gastric cancer is the third leading cause of worldwide cancer mortality, and novel treatment modalities are urgently needed. NK4 is an antagonist of hepatocyte growth factor receptors (Met) which are often aberrantly activated in gastric cancer and thus represent a useful candidate for targeted therapies. This study investigated MSC-delivered NK4 gene therapy in nude mice bearing gastric cancer xenografts. MSCs were transduced with lentiviral vectors carrying NK4 complementary DNA or enhanced green fluorescent protein (GFP). Such transduction did not change the phenotype of MSCs. Gastric cancer xenografts were established in BALB/C nude mice, and the mice were treated with phosphate-buffered saline (PBS), MSCs-GFP, Lenti-NK4, or MSCs-NK4. The tropism of MSCs toward gastric cancer cells was determined by an in vitro migration assay using MKN45 cells, GES-1 cells and human fibroblasts and their presence in tumor xenografts. Tumor growth, tumor cell apoptosis and intratumoral microvessel density of tumor tissue were measured in nude mice bearing gastric cancer xenografts treated with PBS, MSCs-GFP, Lenti-NK4, or MSCs-NK4 via tail vein injection. The results showed that MSCs migrated preferably to gastric cancer cells in vitro. Systemic MSCs-NK4 injection significantly suppressed the growth of gastric cancer xenografts. MSCs-NK4 migrated and accumulated in tumor tissues after systemic injection. The microvessel density of tumor xenografts was decreased, and tumor cellular apoptosis was significantly induced in the mice treated with MSCs-NK4 compared to control mice. These findings demonstrate that MSC-based NK4 gene therapy can obviously inhibit the growth of gastric cancer xenografts, and MSCs are a better vehicle for NK4 gene therapy than lentiviral vectors. Further studies are warranted to explore the efficacy and safety of the MSC-based NK4 gene therapy in animals and cancer patients. PMID:25525335

5-fluorouracil enhances the antitumor effect of sorafenib and sunitinib in a xenograft model of human renal cell carcinoma.

PubMed

Miyake, Makito; Anai, Satoshi; Fujimoto, Kiyohide; Ohnishi, Sayuri; Kuwada, Masaomi; Nakai, Yasushi; Inoue, Takeshi; Tomioka, Atsushi; Tanaka, Nobumichi; Hirao, Yoshihiko

2012-06-01

Sorafenib and sunitinib are multi-kinase inhibitors with antitumor activity in patients with advanced renal cell carcinoma (RCC). Several studies have evaluated the effect of sorafenib/sunitinib in combination with chemotherapeutic agents in different types of tumor. However, few studies have addressed the activity of fluorinated pyrimidine in combination with sorafenib/sunitinib. In this study, we examined the potential of combination therapy with 5FU and sorafenib/sunitinib in human RCC cell lines. Three human RCC cell lines, ACHN, Caki-1 and Caki-2, were used to assess sensitivity to 5-fluorouracil (5FU), sorafenib and sunitinib alone or in combination using an in vitro cell survival assay. Caki-2 cells demonstrated significantly higher resistance to 5FU and sorafenib as compared to ACHN and Caki-1. Additive antitumor effects of the combination therapy were observed in the in vitro study. There was a tendency for a positive correlation between the sensitivity to sunitinib and platelet-derived growth factor β (PDGFR-β) expression levels, which were examined by reverse transcription polymerase chain reaction. Caki-1 xenograft models were prepared by inoculating cells subcutaneously into nude mice, which were divided randomly into six groups: control, 5FU (8 mg/kg/day, intraperitoneally), sorafenib (15 mg/kg/day, orally), sunitinib (20 mg/kg/day, orally), and 5FU with sorafenib or sunitinib. The treatments were administered on 5 days each week, and tumor growth was monitored for 42 days following inoculation of cells. Synergistic antitumor effects of the combination therapy were observed in an in vivo study. The resected tumors were evaluated using the Ki-67 labeling index and microvessel density. Both the Ki-67 labeling index and microvessel density were decreased in tumors treated with the combination therapy compared to those treated with sorafenib/sunitinib alone. These findings suggest that the combination therapy of 5FU with sorafenib/sunitinib may be an effective therapeutic modality for advanced RCC patients.

A mathematical model for filtration and macromolecule transport across capillary walls.

PubMed

Facchini, L; Bellin, A; Toro, E F

2014-07-01

Metabolic substrates, such as oxygen and glucose, are rapidly delivered to the cells of large organisms through filtration across microvessels walls. Modelling this important process is complicated by the strong coupling between flow and transport equations, which are linked through the osmotic pressure induced by the colloidal plasma proteins. The microvessel wall is a composite media with the internal glycocalyx layer exerting a strong sieving effect on macromolecules, with respect to the external layer composed by the endothelial cells. The physiological structure of the microvessel is represented as the superimposition of two membranes with different properties; the inner membrane represents the glycocalyx, while the outer membrane represents the surrounding endothelial cells. Application of the mass conservation principle and thermodynamic considerations lead to a model composed of two coupled second-order ordinary differential equations for the hydrostatic and osmotic pressures, one, expressing volumetric mass conservation and the other, which is non-linear in the unknown osmotic pressure, expressing macromolecules mass conservation. Despite the complexity of the system, the assumption that the properties of the layers are piece-wise constant allows us to obtain analytical solutions for the two pressures. This solution is in agreement with experimental observations, which contrary to common belief, show that flow reversal cannot occur in steady-state conditions unless the hydrostatic pressure in the lumen drops below physiologically plausible values. The observed variations of the volumetric flux and the solute mass flux in case of a significant reduction of the hydrostatic pressure at the lumen are in qualitative agreement with observed variations during detailed experiments reported in the literature. On the other hand, homogenising the microvessel wall into a single-layer membrane with equivalent properties leads to a very different distribution of pressure across the microvessel walls, not consistent with observations. Copyright © 2014 Elsevier Inc. All rights reserved.

Expression of protease-activated receptor-2 (PAR-2) in patients with nasopharyngeal carcinoma: correlation with clinicopathological features and prognosis.

PubMed

Li, Zhi; Bian, Li-Juan; Li, Yang; Liang, Ying-Jie; Liang, Hui-Zhen

2009-01-01

We aimed at determining whether the expression of protease-activated receptor 2 (PAR-2) is involved in the progression of nasopharyngeal carcinoma (NPC) and correlated with latent membrane protein 1 (LMP-1), matrix metalloproteinases-9 (MMP9), and angiogenesis of tumor. PAR-2, LMP-1, and MMP9 expressions were detected in 57 biopsies of primary NPC by immunohistochemistry. The presence of Epstein-Barr virus (EBV) was determined using EBER in situ hybridization, and intratumoral microvessels were highlighted by staining endothelial cells for anti-CD34. The correlations with immunostainings and clinicopathological factors, as well as the follow-up data of patients, were analyzed statistically. Strong expression of PAR-2 in 61.4% (35/57) of the biopsies was correlated with extensive lymph node metastasis and advanced stage of NPC. The patients with PAR-2/LMP-1 or PAR-2/MMP9 dual high-expression tumors had a significant worse prognosis than those with single protein high expression and dual low or negative expression tumors (P=0.013 and 0.004, respectively). Angiogenesis in the tumor is related to overall survival of NPC patients (P=0.001), and exhibits strong PAR-2 expression or LMP-1 expression in tumors associated with increased intratumoral microvessel density (P=0.026 and 0.006, respectively). PAR-2 is a possible mediator cooperating with LMP-1 and MMP9 to influence the progression of NPC by inducing angiogenesis and promoting lymph node metastasis.

Expression of lactoferrin receptors is increased in the mesencephalon of patients with Parkinson disease.

PubMed Central

Faucheux, B A; Nillesse, N; Damier, P; Spik, G; Mouatt-Prigent, A; Pierce, A; Leveugle, B; Kubis, N; Hauw, J J; Agid, Y

1995-01-01

The degeneration of nigral dopaminergic neurons in Parkinson disease is believed to be associated with oxidative stress. Since iron levels are increased in the substantia nigra of parkinsonian patients and this metal catalyzes the formation of free radicals, it may be involved in the mechanisms of nerve cell death. The cause of nigral iron increase is not understood. Iron acquisition by neurons may occur from iron-transferrin complexes with a direct interaction with specific membrane receptors, but recent results have shown a low density of transferrin receptors in the substantia nigra. To investigate whether neuronal death in Parkinson disease may be associated with changes in a pathway supplementary to that of transferrin, lactoferrin (lactotransferrin) receptor expression was studied in the mesencephalon. In this report we present evidence from immunohistochemical staining of postmortem human brain tissue that lactoferrin receptors are localized on neurons (perikarya, dendrites, axons), cerebral microvasculature, and, in some cases, glial cells. In parkinsonian patients, lactoferrin receptor immunoreactivity on neurons and microvessels was increased and more pronounced in those regions of the mesencephalon where the loss of dopaminergic neurons is severe. Moreover, in the substantia nigra, the intensity of immunoreactivity on neurons and microvessels was higher for patients with higher nigral dopaminergic loss. These data suggest that lactoferrin receptors on vulnerable neurons may increase intraneuronal iron levels and contribute to the degeneration of nigral dopaminergic neurons in Parkinson disease. Images Fig. 1 Fig. 2 PMID:7568181

An alternative marker for the effectiveness of water fluoridation: hospital extraction rates for dental decay, a two-region study.

PubMed

Elmer, T B; Langford, J W; Morris, A J

2014-03-01

Contemporary evidence for the effectiveness of water fluoridation schemes in the U.K. is sparse. The utility of routinely collected data in providing evidence warrants further research. To examine inpatient hospital episodes statistics for dental extractions as an alternative population marker for the effectiveness of water fluoridation by comparing hospital admissions between two major strategic health authority (SHA) areas, the West Midlands SHA-largely fluoridated--and the North West SHA--largely unfluoridated. Hospital episodes statistics (HES) were interrogated to provide data on admissions for simple and surgical dental extractions, which had a primary diagnostic code of either dental caries or diseases of pulp and periapical tissues for financial years 2006/7, 2007/8 and 2008/9. Data was aggregated by SHA area and quinary age group. Directly standardised rates (DSR) of admissions purchased for each primary care trust (PCT) were calculated and ranked by index of multiple deprivation (IMD). A significant difference in DSRs of admission between PCTs in the West Midlands and North West was observed (Mann-Whitney U test [p <0.0001]) irrespective of IMD ranking. The difference in rates between the two most deprived PCTs was 27-fold. After ranking by IMD, DSRs of hospital admissions for the extraction of decayed or pulpally/periapically involved teeth is lower in areas with a fluoridated water supply. The analysis of routinely collected HES data may help identify the impact of water fluoridation schemes.

Occlusion and rupture of ex vivo capillary bifurcation due to acoustic droplet vaporization

NASA Astrophysics Data System (ADS)

Feng, Yi; Qin, Dui; Zhang, Jun; Zhang, Lei; Bouakaz, Ayache; Wan, Mingxi

2018-06-01

Gas embolotherapy (GE) consists in the occlusion of tumor blood vessels using gas emboli induced by acoustic droplet vaporization (ADV), to create tumor starvation and localized drug delivery. Therefore, the occlusion and rupture of capillary bifurcation due to ADV was investigated in an ex vivo rat mesentery model using a confocal acousto-optical high-speed microscope system. Following ADV bubble formation, coalescence, and translational movement, the growing bubbles lodged in and then occluded two different capillary bifurcations. Capillary rupture was induced at the bubble lodging area, immediately followed by gas extravasation and bubble dislodging. Before and after bubble lodgment/occlusion, a local microvessel invagination was observed due to the interactions between ADV bubbles and the microvessel itself, indicating a contribution to the capillary rupture. Understanding the transient dynamics of ADV bubble, the bubble-microvessel interaction and the consequent mechanical bio-effects in GE is of the paramount importance for developing and applying this approach in clinical practice.

Brain-endocrine interactions: a microvascular route in the mediobasal hypothalamus.

PubMed

Ciofi, Philippe; Garret, Maurice; Lapirot, Olivier; Lafon, Pierrette; Loyens, Anne; Prévot, Vincent; Levine, Jon E

2009-12-01

Blood-borne hormones acting in the mediobasal hypothalamus, like those controlling food intake, require relatively direct access to target chemosensory neurons of the arcuate nucleus (ARC). An anatomical substrate for this is a permeable microvasculature with fenestrated endothelial cells in the ARC, a system that has awaited comprehensive documentation. Here, the immunofluorescent detection of endothelial fenestral diaphragms in the rat ARC allowed us to quantitate permeable microvessels throughout its rostrocaudal extent. We have determined that permeable microvessels are part of the subependymal plexus irrigating exclusively the ventromedial (vm) ARC from the subadjacent neuroendocrine median eminence. Unexpectedly, permeable microvessels were concentrated proximal to the pituitary stalk. This marked topography strongly supports the functional importance of retrograde blood flow from the pituitary to the vmARC, therefore making a functional relationship between peripheral long-loop, pituitary short-loop, and neuroendocrine ultra-short loop feedback, altogether converging for integration in the vmARC (formerly known as the hypophysiotrophic area), thereby so pivotal as a multicompetent brain endocrinostat.

AutoTag and AutoSnap: Standardized, semi-automatic capture of regions of interest from whole slide images

PubMed Central

Marien, Koen M.; Andries, Luc; De Schepper, Stefanie; Kockx, Mark M.; De Meyer, Guido R.Y.

2015-01-01

Tumor angiogenesis is measured by counting microvessels in tissue sections at high power magnification as a potential prognostic or predictive biomarker. Until now, regions of interest1 (ROIs) were selected by manual operations within a tumor by using a systematic uniform random sampling2 (SURS) approach. Although SURS is the most reliable sampling method, it implies a high workload. However, SURS can be semi-automated and in this way contribute to the development of a validated quantification method for microvessel counting in the clinical setting. Here, we report a method to use semi-automated SURS for microvessel counting: • Whole slide imaging with Pannoramic SCAN (3DHISTECH) • Computer-assisted sampling in Pannoramic Viewer (3DHISTECH) extended by two self-written AutoHotkey applications (AutoTag and AutoSnap) • The use of digital grids in Photoshop® and Bridge® (Adobe Systems) This rapid procedure allows traceability essential for high throughput protein analysis of immunohistochemically stained tissue. PMID:26150998

Hemodynamic and proinflammatory actions of endothelin-1 in guinea pig small intestine submucosal microcirculation.

PubMed

King-VanVlack, C E; Mewburn, J D; Chapler, C K; MacDonald, P H

2003-06-01

The hemodynamic and proinflammatory effects of endothelin-1 (ET-1) in proximal (1st/2nd order) and terminal (3rd/4th order) arterioles and venules were examined in small intestine submucosa of anesthetized guinea pigs. Vessel diameter (D), red blood cell velocity, and blood flow (Q) were determined in eight proximal and eight terminal microvessels before and at 20 min of ET-1 suffusion (10(-10), 10(-9), and 10(-8) M) and then with endothelin-A (ET(A))-receptor blockade with BQ-123 (10(-5) M). This protocol was repeated with platelet-activating factor (PAF) inhibition (WEB-2086, 1.0 mg/kg iv; n = 16). The ET-1-mediated microvascular responses were also examined with endothelin-B (ET(B))-receptor blockade using BQ-788 (10(-5) M; n = 11) alone or with ET(A+B)-receptor blockade with BQ-123 + BQ-788 (n = 10). Microvascular permeability was assessed by FITC-albumin (25 mg/kg iv) extravasation in seven series: 1) buffered modified Krebs solution suffusion (n = 6), 2) histamine suffusion (HIS; 10(-3) M, n = 5), 3) ET-1 suffusion (10(-8) M, n = 5), 4) BQ-123 (10(-5) M) plus ET-1 suffusion (n = 5), 5) PAF inhibition before ET-1 suffusion (n = 5), 6) histamine-1 (H1)-receptor blockade (diphenhydramine, 20 mg/kg iv) before ET-1 suffusion (n = 5), and 7) ET(B)-receptor blockade before (BQ-788 10(-5) M; n = 3) or with ET-1 suffusion (n = 3). D and Q decreased at 10(-8) M ET-1 and returned to control values with BQ-123 and BQ-123+BQ788 but not with BQ-788 in proximal microvessels. D did not change in terminal microvessels with ET-1 (10(-8) M) but decreased with BQ-788 and increased with BQ-123. PAF inhibition did not affect the D and Q responses of proximal microvessels to ET-1 but prevented the fall in Q in terminal microvessels with ET-1. ET-1 increased vascular permeability to approximately 1/3 of that with HIS; this response was prevented with BQ-123 and WEB-2086 but not with H1-receptor blockade. This is the first evidence that submucosal terminal microvessel flow is reduced with ET-1 independent of vessel diameter changes and that this response is associated with increased microvascular permeability mediated via ET(A)-receptor stimulation and PAF activation.

The prevalence, serogroup distribution and risk factors of meningococcal carriage in adolescents and young adults in Turkey

PubMed Central

Tekin, Rahmi Tuna; Dinleyici, Ener Cagri; Ceyhan, Mehmet; Karbuz, Adem; Salman, Nuran; Sutçu, Murat; Kurugol, Zafer; Balliel, Yasemin; Celik, Melda; Hacimustafaoglu, Mustafa; Kuyucu, Necdet; Kondolot, Meda; Sensoy, Gülnar; Metin, Ozge; Kara, Soner Sertan; Dinleyici, Meltem; Kılıç, Omer; Bayhan, Cihangul; Gurbuz, Venhar; Aycan, Emre; Memedova, Aygun; Karli, Arzu; Bozlu, Gulçin; Celebi, Solmaz

2017-01-01

ABSTRACT The serogroup epidemiology of invasive meningococcal disease (IMD), which varies considerably by geographic region and immunization schedule, changes continuously. Meningococcal carriage data are crucial for assessing IMD epidemiology and designing f potential vaccination strategies. Meningococcal seroepidemiology in Turkey differs from that in other countries: serogroups W and B are the predominant strains for IMD during childhood, whereas no serogroup C cases were identified over the last 10 y and no adolescent peak for IMD was found. There is a lack of data on meningococcal carriage that represents the whole population. The aims of this multicenter study (12 cities in Turkey) were to evaluate the prevalence of Neisseria meningitidis carriage, the serogroup distribution and the related risk factors (educational status, living in a dormitory or student house, being a household contact with Hajj pilgrims, smoking, completion of military service, attending bars/clubs) in 1518 adolescents and young adults aged 10–24 y. The presence of N. meningitidis DNA was tested, and a serogroup analysis was performed using polymerase chain reaction. The overall meningococcal carriage rate was 6.3% (n = 96) in the study population. A serogroup distribution of the 96 N. meningitidis strains isolated from the nasopharyngeal specimens revealed serogroup A in 5 specimens (5.2%), serogroup B in 9 specimens (9.4%), serogroup W in 64 specimens (66.6%), and serogroup Y in 4 specimens (4.2%); 14 were classified as non-grouped (14.4%). No serogroup C cases were detected. The nasopharyngeal meningococcal carriage rate was 5% in the 10–14 age group, 6.4% in the 15–17 age-group, and 4.7% in the 18–20 age group; the highest carriage rate was found in the 21–24 age group (9.1%), which was significantly higher than those of the other age groups (p < 0.05). The highest carriage rate was found in 17-year-old adolescents (11%). The carriage rate was higher among the participants who had had close contact with Hajj/Umrah pilgrims (p < 0.01) or a history of upper respiratory tract infections over the past 3 months (p < 0.05). The nasopharyngeal carriage rate was 6.3% among adolescents and young adults in Turkey and was similar to the recent rates observed in the same age groups in other countries. The most prevalent serogroup was W, and no serogroup C cases were found. In conclusion, the present study found that meningococcal carriage reaches its peak level by age 17, the highest carriage rate was found in 21 - to 24 - year-olds and the majority of the carriage cases were due to serogroup W. Adolescents and young adult carriers seem to be a potential reservoir for the disease, and further immunization strategies, including adolescent immunization, may play a role in the control of IMD. PMID:28140784

The prevalence, serogroup distribution and risk factors of meningococcal carriage in adolescents and young adults in Turkey.

PubMed

Tekin, Rahmi Tuna; Dinleyici, Ener Cagri; Ceyhan, Mehmet; Karbuz, Adem; Salman, Nuran; Sutçu, Murat; Kurugol, Zafer; Balliel, Yasemin; Celik, Melda; Hacimustafaoglu, Mustafa; Kuyucu, Necdet; Kondolot, Meda; Sensoy, Gülnar; Metin, Ozge; Kara, Soner Sertan; Dinleyici, Meltem; Kılıç, Omer; Bayhan, Cihangul; Gurbuz, Venhar; Aycan, Emre; Memedova, Aygun; Karli, Arzu; Bozlu, Gulçin; Celebi, Solmaz

2017-05-04

The serogroup epidemiology of invasive meningococcal disease (IMD), which varies considerably by geographic region and immunization schedule, changes continuously. Meningococcal carriage data are crucial for assessing IMD epidemiology and designing f potential vaccination strategies. Meningococcal seroepidemiology in Turkey differs from that in other countries: serogroups W and B are the predominant strains for IMD during childhood, whereas no serogroup C cases were identified over the last 10 y and no adolescent peak for IMD was found. There is a lack of data on meningococcal carriage that represents the whole population. The aims of this multicenter study (12 cities in Turkey) were to evaluate the prevalence of Neisseria meningitidis carriage, the serogroup distribution and the related risk factors (educational status, living in a dormitory or student house, being a household contact with Hajj pilgrims, smoking, completion of military service, attending bars/clubs) in 1518 adolescents and young adults aged 10-24 y. The presence of N. meningitidis DNA was tested, and a serogroup analysis was performed using polymerase chain reaction. The overall meningococcal carriage rate was 6.3% (n = 96) in the study population. A serogroup distribution of the 96 N. meningitidis strains isolated from the nasopharyngeal specimens revealed serogroup A in 5 specimens (5.2%), serogroup B in 9 specimens (9.4%), serogroup W in 64 specimens (66.6%), and serogroup Y in 4 specimens (4.2%); 14 were classified as non-grouped (14.4%). No serogroup C cases were detected. The nasopharyngeal meningococcal carriage rate was 5% in the 10-14 age group, 6.4% in the 15-17 age-group, and 4.7% in the 18-20 age group; the highest carriage rate was found in the 21-24 age group (9.1%), which was significantly higher than those of the other age groups (p < 0.05). The highest carriage rate was found in 17-year-old adolescents (11%). The carriage rate was higher among the participants who had had close contact with Hajj/Umrah pilgrims (p < 0.01) or a history of upper respiratory tract infections over the past 3 months (p < 0.05). The nasopharyngeal carriage rate was 6.3% among adolescents and young adults in Turkey and was similar to the recent rates observed in the same age groups in other countries. The most prevalent serogroup was W, and no serogroup C cases were found. In conclusion, the present study found that meningococcal carriage reaches its peak level by age 17, the highest carriage rate was found in 21 - to 24 - year-olds and the majority of the carriage cases were due to serogroup W. Adolescents and young adult carriers seem to be a potential reservoir for the disease, and further immunization strategies, including adolescent immunization, may play a role in the control of IMD.

Active and Passive Supplier Assessment Program (ASAP & PSAP) WWW Sites http://nepp.nasa.gov/imd/asap http://nepp.nasa.gov/imd/psap

NASA Technical Reports Server (NTRS)

Brusse, Jay

2000-01-01

The Active and Passive Supplier Assessment Programs (ASAP and PSAP) WWW Sites provide general information to the electronic parts community regarding the availability of electronic parts. They also provide information to NASA regarding modifications to commonly used procurement specifications and test methods. The ASAP and PSAP www sites are ongoing resources produced by Code 562 in support of the NASA HQ funded NASA Electronic Parts and Packaging (NEPP) Program. These WWW sites do not provide information pertaining to patented or proprietary information. All of the information contained in these www sites is available through various other public domain resources such as US Military Qualified Producers Listings (QPLs) and Qualified Manufacturer Listings (QMLs) and industry working groups such as the Electronics Industry Alliance (EIA) and the Space Parts Working Group (SPWG).

Heteroleptic complexes of Zn(II) based on 1-(5-bromo-2-hydroxybenzylidene)-4-phenylthiosemicarbazide: Synthesis, structural characterization, theoretical studies and antibacterial activity

NASA Astrophysics Data System (ADS)

Azarkish, Mohammad; Akbari, Alireza; Sedaghat, Tahereh; Simpson, Jim

2017-04-01

Four new ternary complexes, [ZnL (2,2‧-bipy)] (1), Zn2L2(4,4‧-bipy)] (2), [ZnL(Imd)]·H2O (3) and [ZnL3(MeImd)] (4), have been synthesized from the reaction of Zn(II) acetate with 1-(5-bromo-2-hydroxybenzylidene)-4-phenylthiosemicarbazide (H2L) in the presence of a heterocyclic base, 2,2‧-bipyridine, 4,4‧-bipyridine, imidazole or 2-methylimidazole, as an auxiliary ligand. The complexes have been investigated by elemental analysis and FT-IR, UV-Vis and 1HNMR spectroscopy. These data show that the thiosemicarbazone acts as a tridentate dianionic ligand and coordinates via the thiol group, imine nitrogen, and phenolic oxygen. The coordination sphere was completed by the nitrogen atom(s) of the secondary ligand. The structure of 1 was also confirmed by X-ray crystallography and shown to be a five coordinate complex with coordination geometry between the square-pyramidal and trigonal-bipyramidal. Density functional theory (DFT) calculations including geometry optimization, vibrational frequencies and electronic absorptions have been performed for 1 with the B3LYP functional at the TZP(6-311G*) basis set using the Gaussian 03 or ADF 2009 packages. The optimization calculation showed that the crystallographically determined geometry parameters can be reproduced with that basis set. Experimental IR frequencies and calculated vibration frequencies also support each other. The in vitro antibacterial activities of the ligand and complexes have been evaluated against Gram-positive (B. subtilis and S. aureus) and Gram-negative (P. aeruginosa) bacteria and compared with the standard antibacterial drugs. The results reveal that all of the complexes show much better activity in comparison to the individual thiosemoicarbazone ligand (H2L), against all bacterial strains used, with complex 3 showing the most promising results.

The bacterium Wolbachia exploits host innate immunity to establish a symbiotic relationship with the dengue vector mosquito Aedes aegypti.

PubMed

Pan, Xiaoling; Pike, Andrew; Joshi, Deepak; Bian, Guowu; McFadden, Michael J; Lu, Peng; Liang, Xiao; Zhang, Fengrui; Raikhel, Alexander S; Xi, Zhiyong

2018-01-01

A host's immune system plays a central role in shaping the composition of the microbiota and, in return, resident microbes influence immune responses. Symbiotic associations of the maternally transmitted bacterium Wolbachia occur with a wide range of arthropods. It is, however, absent from the dengue and Zika vector mosquito Aedes aegypti in nature. When Wolbachia is artificially forced to form symbiosis with this new mosquito host, it boosts the basal immune response and enhances the mosquito's resistance to pathogens, including dengue, Zika virus and malaria parasites. The mechanisms involved in establishing a symbiotic relationship between Wolbachia and A. aegypti, and the long-term outcomes of this interaction, are not well understood. Here, we have demonstrated that both the immune deficiency (IMD) and Toll pathways are activated by the Wolbachia strain wAlbB upon its introduction into A. aegypti. Silencing the Toll and IMD pathways via RNA interference reduces the wAlbB load. Notably, wAlbB induces peptidoglycan recognition protein (PGRP)-LE expression in the carcass of A. aegypti, and its silencing results in a reduction of symbiont load. Using transgenic mosquitoes with stage-specific induction of the IMD and Toll pathways, we have shown that elevated wAlbB infection in these mosquitoes is maintained via maternal transmission. These results indicate that host innate immunity is utilized to establish and promote host-microbial symbiosis. Our results will facilitate a long-term projection of the stability of the Wolbachia-A. aegypti mosquito system that is being developed to control dengue and Zika virus transmission to humans.

Pseudomonas aeruginosa RhlR is required to neutralize the cellular immune response in a Drosophila melanogaster oral infection model

PubMed Central

Limmer, Stefanie; Haller, Samantha; Drenkard, Eliana; Lee, Janice; Yu, Shen; Kocks, Christine; Ausubel, Frederick M.; Ferrandon, Dominique

2011-01-01

An in-depth mechanistic understanding of microbial infection necessitates a molecular dissection of host–pathogen relationships. Both Drosophila melanogaster and Pseudomonas aeruginosa have been intensively studied. Here, we analyze the infection of D. melanogaster by P. aeruginosa by using mutants in both host and pathogen. We show that orally ingested P. aeruginosa crosses the intestinal barrier and then proliferates in the hemolymph, thereby causing the infected flies to die of bacteremia. Host defenses against ingested P. aeruginosa included an immune deficiency (IMD) response in the intestinal epithelium, systemic Toll and IMD pathway responses, and a cellular immune response controlling bacteria in the hemocoel. Although the observed cellular and intestinal immune responses appeared to act throughout the course of the infection, there was a late onset of the systemic IMD and Toll responses. In this oral infection model, P. aeruginosa PA14 did not require its type III secretion system or other well-studied virulence factors such as the two-component response regulator GacA or the protease AprA for virulence. In contrast, the quorum-sensing transcription factor RhlR, but surprisingly not LasR, played a key role in counteracting the cellular immune response against PA14, possibly at an early stage when only a few bacteria are present in the hemocoel. These results illustrate the power of studying infection from the dual perspective of host and pathogen by revealing that RhlR plays a more complex role during pathogenesis than previously appreciated. PMID:21987808

Spaceflight and Simulated Microgravity Increases Virulence of the Known Bacterial Pathogen S. Marcescens

NASA Technical Reports Server (NTRS)

Clemens-Grisham, Rachel Andrea; Bhattacharya, Sharmila; Wade, William

2016-01-01

After spaceflight, the number of immune cells is reduced in humans. In other research models, including Drosophila, not only is there a reduction in the number of plasmatocytes, but expression of immune-related genes is also changed after spaceflight. These observations suggest that the immune system is compromised after exposure to microgravity. It has also been reported that there is a change in virulence of some bacterial pathogens after spaceflight. We recently observed that samples of gram-negative S. marcescens retrieved from spaceflight is more virulent than ground controls, as determined by reduced survival and increased bacterial growth in the host. We were able to repeat this finding of increased virulence after exposure to simulated microgravity using the rotating wall vessel, a ground based analog to microgravity. With the ground and spaceflight samples, we looked at involvement of the Toll and Imd pathways in the Drosophila host in fighting infection by ground and spaceflight samples. We observed that Imd-pathway mutants were more susceptible to infection by the ground bacterial samples, which aligns with the known role of this pathway in fighting infections by gram-negative bacteria. When the Imd-pathway mutants were infected with the spaceflight sample, however, they exhibited the same susceptibility as seen with the ground control bacteria. Interestingly, all mutant flies show the same susceptibility to the spaceflight bacterial sample as do wild type flies. This suggests that neither humoral immunity pathway is effectively able to counter the increased pathogenicity of the space-flown S. marcescens bacteria.

Genome of Rhodnius prolixus, an insect vector of Chagas disease, reveals unique adaptations to hematophagy and parasite infection

PubMed Central

Mesquita, Rafael D.; Vionette-Amaral, Raquel J.; Lowenberger, Carl; Rivera-Pomar, Rolando; Monteiro, Fernando A.; Minx, Patrick; Spieth, John; Carvalho, A. Bernardo; Panzera, Francisco; Lawson, Daniel; Torres, André Q.; Ribeiro, Jose M. C.; Sorgine, Marcos H. F.; Waterhouse, Robert M.; Abad-Franch, Fernando; Alves-Bezerra, Michele; Amaral, Laurence R.; Araujo, Helena M.; Aravind, L.; Atella, Georgia C.; Azambuja, Patricia; Berni, Mateus; Bittencourt-Cunha, Paula R.; Braz, Gloria R. C.; Calderón-Fernández, Gustavo; Carareto, Claudia M. A.; Christensen, Mikkel B.; Costa, Igor R.; Costa, Samara G.; Dansa, Marilvia; Daumas-Filho, Carlos R. O.; De-Paula, Iron F.; Dias, Felipe A.; Dimopoulos, George; Emrich, Scott J.; Esponda-Behrens, Natalia; Fampa, Patricia; Fernandez-Medina, Rita D.; da Fonseca, Rodrigo N.; Fontenele, Marcio; Fronick, Catrina; Fulton, Lucinda A.; Gandara, Ana Caroline; Garcia, Eloi S.; Genta, Fernando A.; Giraldo-Calderón, Gloria I.; Gomes, Bruno; Gondim, Katia C.; Granzotto, Adriana; Guarneri, Alessandra A.; Guigó, Roderic; Harry, Myriam; Hughes, Daniel S. T.; Jablonka, Willy; Jacquin-Joly, Emmanuelle; Juárez, M. Patricia; Koerich, Leonardo B.; Lange, Angela B.; Latorre-Estivalis, José Manuel; Lavore, Andrés; Lawrence, Gena G.; Lazoski, Cristiano; Lazzari, Claudio R.; Lopes, Raphael R.; Lorenzo, Marcelo G.; Lugon, Magda D.; Marcet, Paula L.; Mariotti, Marco; Masuda, Hatisaburo; Megy, Karine; Missirlis, Fanis; Mota, Theo; Noriega, Fernando G.; Nouzova, Marcela; Nunes, Rodrigo D.; Oliveira, Raquel L. L.; Oliveira-Silveira, Gilbert; Ons, Sheila; Orchard, Ian; Pagola, Lucia; Paiva-Silva, Gabriela O.; Pascual, Agustina; Pavan, Marcio G.; Pedrini, Nicolás; Peixoto, Alexandre A.; Pereira, Marcos H.; Pike, Andrew; Polycarpo, Carla; Prosdocimi, Francisco; Ribeiro-Rodrigues, Rodrigo; Robertson, Hugh M.; Salerno, Ana Paula; Salmon, Didier; Santesmasses, Didac; Schama, Renata; Seabra-Junior, Eloy S.; Silva-Cardoso, Livia; Silva-Neto, Mario A. C.; Souza-Gomes, Matheus; Sterkel, Marcos; Taracena, Mabel L.; Tojo, Marta; Tu, Zhijian Jake; Tubio, Jose M. C.; Ursic-Bedoya, Raul; Venancio, Thiago M.; Walter-Nuno, Ana Beatriz; Wilson, Derek; Warren, Wesley C.; Wilson, Richard K.; Huebner, Erwin; Dotson, Ellen M.; Oliveira, Pedro L.

2015-01-01

Rhodnius prolixus not only has served as a model organism for the study of insect physiology, but also is a major vector of Chagas disease, an illness that affects approximately seven million people worldwide. We sequenced the genome of R. prolixus, generated assembled sequences covering 95% of the genome (∼702 Mb), including 15,456 putative protein-coding genes, and completed comprehensive genomic analyses of this obligate blood-feeding insect. Although immune-deficiency (IMD)-mediated immune responses were observed, R. prolixus putatively lacks key components of the IMD pathway, suggesting a reorganization of the canonical immune signaling network. Although both Toll and IMD effectors controlled intestinal microbiota, neither affected Trypanosoma cruzi, the causal agent of Chagas disease, implying the existence of evasion or tolerance mechanisms. R. prolixus has experienced an extensive loss of selenoprotein genes, with its repertoire reduced to only two proteins, one of which is a selenocysteine-based glutathione peroxidase, the first found in insects. The genome contained actively transcribed, horizontally transferred genes from Wolbachia sp., which showed evidence of codon use evolution toward the insect use pattern. Comparative protein analyses revealed many lineage-specific expansions and putative gene absences in R. prolixus, including tandem expansions of genes related to chemoreception, feeding, and digestion that possibly contributed to the evolution of a blood-feeding lifestyle. The genome assembly and these associated analyses provide critical information on the physiology and evolution of this important vector species and should be instrumental for the development of innovative disease control methods. PMID:26627243

Epstein-Barr Virus DNA Enhances Diptericin Expression and Increases Hemocyte Numbers in Drosophila melanogaster via the Immune Deficiency Pathway.

PubMed

Sherri, Nour; Salloum, Noor; Mouawad, Carine; Haidar-Ahmad, Nathaline; Shirinian, Margret; Rahal, Elias A

2018-01-01

Infection with the Epstein-Barr virus (EBV) is associated with several malignancies and autoimmune diseases in humans. The following EBV infection and establishment of latency, recurrences frequently occur resulting in potential viral DNA shedding, which may then trigger the activation of immune pathways. We have previously demonstrated that levels of the pro-inflammatory cytokine IL-17, which is associated with several autoimmune diseases, are increased in response to EBV DNA injection in mice. Whether other pro-inflammatory pathways are induced in EBV DNA pathobiology remains to be investigated. The complexity of mammalian immune systems presents a challenge to studying differential activities of their intricate immune pathways in response to a particular immune stimulus. In this study, we used Drosophila melanogaster to identify innate humoral and cellular immune pathways that are activated in response to EBV DNA. Injection of wild-type adult flies with EBV DNA induced the immune deficiency (IMD) pathway resulting in enhanced expression of the antimicrobial peptide diptericin. Furthermore, EBV DNA increased the number of hemocytes in flies. Conditional silencing of the IMD pathway decreased diptericin expression in addition to curbing of hemocyte proliferation in response to challenge with EBV DNA. Comparatively, upon injecting mice with EBV DNA, we detected enhanced expression of tumor necrosis factor-α (TNFα); this enhancement is rather comparable to IMD pathway activation in flies. This study hence indicates that D. melanogaster could possibly be utilized to identify immune mediators that may also play a role in the response to EBV DNA in higher systems.

Gut microbiota in early pediatric multiple sclerosis: a case-control study.

PubMed

Tremlett, Helen; Fadrosh, Douglas W; Faruqi, Ali A; Zhu, Feng; Hart, Janace; Roalstad, Shelly; Graves, Jennifer; Lynch, Susan; Waubant, Emmanuelle

2016-08-01

Alterations in the gut microbial community composition may be influential in neurological disease. Microbial community profiles were compared between early onset pediatric multiple sclerosis (MS) and control children similar for age and sex. Children ≤18 years old within 2 years of MS onset or controls without autoimmune disorders attending a University of California, San Francisco, USA, pediatric clinic were examined for fecal bacterial community composition and predicted function by 16S ribosomal RNA sequencing and phylogenetic reconstruction of unobserved states (PICRUSt) analysis. Associations between subject characteristics and the microbiota, including beta diversity and taxa abundance, were identified using non-parametric tests, permutational multivariate analysis of variance and negative binomial regression. Eighteen relapsing-remitting MS cases and 17 controls (mean age 13 years; range 4-18) were studied. Cases had a short disease duration (mean 11 months; range 2-24) and half were immunomodulatory drug (IMD) naïve. Whilst overall gut bacterial beta diversity was not significantly related to MS status, IMD exposure was (Canberra, P < 0.02). However, relative to controls, MS cases had a significant enrichment in relative abundance for members of the Desulfovibrionaceae (Bilophila, Desulfovibrio and Christensenellaceae) and depletion in Lachnospiraceae and Ruminococcaceae (all P and q < 0.000005). Microbial genes predicted as enriched in MS versus controls included those involved in glutathione metabolism (Mann-Whitney, P = 0.017), findings that were consistent regardless of IMD exposure. In recent onset pediatric MS, perturbations in the gut microbiome composition were observed, in parallel with predicted enrichment of metabolic pathways associated with neurodegeneration. Findings were suggestive of a pro-inflammatory milieu. © 2016 EAN.

Modeling photodegradation kinetics of three systemic neonicotinoids-dinotefuran, imidacloprid, and thiamethoxam-in aqueous and soil environment.

PubMed

Kurwadkar, Sudarshan; Evans, Amanda; DeWinne, Dustan; White, Peter; Mitchell, Forrest

2016-07-01

Environmental presence and retention of commonly used neonicotinoid insecticides such as dinotefuran (DNT), imidacloprid (IMD), and thiamethoxam (THM) are a cause for concern and prevention because of their potential toxicity to nontarget species. In the present study the kinetics of the photodegradation of these insecticides were investigated in water and soil compartments under natural light conditions. The results suggest that these insecticides are fairly unstable in both aqueous and soil environments when exposed to natural sunlight. All 3 insecticides exhibit strong first-order degradation rate kinetics in the aqueous phase, with rate constants kDNT , kIMD , and kTHM of 0.20 h(-1) , 0.30 h(-1) , and 0.18 h(-1) , respectively. However, in the soil phase, the modeled photodegradation kinetics appear to be biphasic, with optimal rate constants k1DNT and k2DNT of 0.0198 h(-1) and 0.0022 h(-1) and k1THM and k2THM of 0.0053 h(-1) and 0.0014 h(-1) , respectively. Differentially, in the soil phase, imidacloprid appears to follow the first-order rate kinetics with a kIMD of 0.0013 h(-1) . These results indicate that all 3 neonicotinoids are photodegradable, with higher degradation rates in aqueous environments relative to soil environments. In addition, soil-encapsulated imidacloprid appears to degrade slowly compared with dinotefuran and thiamethoxam and does not emulate the faster degradation rates observed in the aqueous phase. Environ Toxicol Chem 2016;35:1718-1726. © 2015 SETAC. © 2015 SETAC.

Relative Roles of the Cellular and Humoral Responses in the Drosophila Host Defense against Three Gram-Positive Bacterial Infections

PubMed Central

Cho, Ju Hyun; Lee, Janice; Lafarge, Marie-Céline; Kocks, Christine; Ferrandon, Dominique

2011-01-01

Background Two NF-kappaB signaling pathways, Toll and immune deficiency (imd), are required for survival to bacterial infections in Drosophila. In response to septic injury, these pathways mediate rapid transcriptional activation of distinct sets of effector molecules, including antimicrobial peptides, which are important components of a humoral defense response. However, it is less clear to what extent macrophage-like hemocytes contribute to host defense. Methodology/Principal Findings In order to dissect the relative importance of humoral and cellular defenses after septic injury with three different Gram-positive bacteria (Micrococcus luteus, Enterococcus faecalis, Staphylococcus aureus), we used latex bead pre-injection to ablate macrophage function in flies wildtype or mutant for various Toll and imd pathway components. We found that in all three infection models a compromised phagocytic system impaired fly survival – independently of concomitant Toll or imd pathway activation. Our data failed to confirm a role of the PGRP-SA and GNBP1 Pattern Recognition Receptors for phagocytosis of S. aureus. The Drosophila scavenger receptor Eater mediates the phagocytosis by hemocytes or S2 cells of E. faecalis and S. aureus, but not of M. luteus. In the case of M. luteus and E. faecalis, but not S. aureus, decreased survival due to defective phagocytosis could be compensated for by genetically enhancing the humoral immune response. Conclusions/Significance Our results underscore the fundamental importance of both cellular and humoral mechanisms in Drosophila immunity and shed light on the balance between these two arms of host defense depending on the invading pathogen. PMID:21390224

Genome of Rhodnius prolixus, an insect vector of Chagas disease, reveals unique adaptations to hematophagy and parasite infection.

PubMed

Mesquita, Rafael D; Vionette-Amaral, Raquel J; Lowenberger, Carl; Rivera-Pomar, Rolando; Monteiro, Fernando A; Minx, Patrick; Spieth, John; Carvalho, A Bernardo; Panzera, Francisco; Lawson, Daniel; Torres, André Q; Ribeiro, Jose M C; Sorgine, Marcos H F; Waterhouse, Robert M; Montague, Michael J; Abad-Franch, Fernando; Alves-Bezerra, Michele; Amaral, Laurence R; Araujo, Helena M; Araujo, Ricardo N; Aravind, L; Atella, Georgia C; Azambuja, Patricia; Berni, Mateus; Bittencourt-Cunha, Paula R; Braz, Gloria R C; Calderón-Fernández, Gustavo; Carareto, Claudia M A; Christensen, Mikkel B; Costa, Igor R; Costa, Samara G; Dansa, Marilvia; Daumas-Filho, Carlos R O; De-Paula, Iron F; Dias, Felipe A; Dimopoulos, George; Emrich, Scott J; Esponda-Behrens, Natalia; Fampa, Patricia; Fernandez-Medina, Rita D; da Fonseca, Rodrigo N; Fontenele, Marcio; Fronick, Catrina; Fulton, Lucinda A; Gandara, Ana Caroline; Garcia, Eloi S; Genta, Fernando A; Giraldo-Calderón, Gloria I; Gomes, Bruno; Gondim, Katia C; Granzotto, Adriana; Guarneri, Alessandra A; Guigó, Roderic; Harry, Myriam; Hughes, Daniel S T; Jablonka, Willy; Jacquin-Joly, Emmanuelle; Juárez, M Patricia; Koerich, Leonardo B; Lange, Angela B; Latorre-Estivalis, José Manuel; Lavore, Andrés; Lawrence, Gena G; Lazoski, Cristiano; Lazzari, Claudio R; Lopes, Raphael R; Lorenzo, Marcelo G; Lugon, Magda D; Majerowicz, David; Marcet, Paula L; Mariotti, Marco; Masuda, Hatisaburo; Megy, Karine; Melo, Ana C A; Missirlis, Fanis; Mota, Theo; Noriega, Fernando G; Nouzova, Marcela; Nunes, Rodrigo D; Oliveira, Raquel L L; Oliveira-Silveira, Gilbert; Ons, Sheila; Orchard, Ian; Pagola, Lucia; Paiva-Silva, Gabriela O; Pascual, Agustina; Pavan, Marcio G; Pedrini, Nicolás; Peixoto, Alexandre A; Pereira, Marcos H; Pike, Andrew; Polycarpo, Carla; Prosdocimi, Francisco; Ribeiro-Rodrigues, Rodrigo; Robertson, Hugh M; Salerno, Ana Paula; Salmon, Didier; Santesmasses, Didac; Schama, Renata; Seabra-Junior, Eloy S; Silva-Cardoso, Livia; Silva-Neto, Mario A C; Souza-Gomes, Matheus; Sterkel, Marcos; Taracena, Mabel L; Tojo, Marta; Tu, Zhijian Jake; Tubio, Jose M C; Ursic-Bedoya, Raul; Venancio, Thiago M; Walter-Nuno, Ana Beatriz; Wilson, Derek; Warren, Wesley C; Wilson, Richard K; Huebner, Erwin; Dotson, Ellen M; Oliveira, Pedro L

2015-12-01

Rhodnius prolixus not only has served as a model organism for the study of insect physiology, but also is a major vector of Chagas disease, an illness that affects approximately seven million people worldwide. We sequenced the genome of R. prolixus, generated assembled sequences covering 95% of the genome (∼ 702 Mb), including 15,456 putative protein-coding genes, and completed comprehensive genomic analyses of this obligate blood-feeding insect. Although immune-deficiency (IMD)-mediated immune responses were observed, R. prolixus putatively lacks key components of the IMD pathway, suggesting a reorganization of the canonical immune signaling network. Although both Toll and IMD effectors controlled intestinal microbiota, neither affected Trypanosoma cruzi, the causal agent of Chagas disease, implying the existence of evasion or tolerance mechanisms. R. prolixus has experienced an extensive loss of selenoprotein genes, with its repertoire reduced to only two proteins, one of which is a selenocysteine-based glutathione peroxidase, the first found in insects. The genome contained actively transcribed, horizontally transferred genes from Wolbachia sp., which showed evidence of codon use evolution toward the insect use pattern. Comparative protein analyses revealed many lineage-specific expansions and putative gene absences in R. prolixus, including tandem expansions of genes related to chemoreception, feeding, and digestion that possibly contributed to the evolution of a blood-feeding lifestyle. The genome assembly and these associated analyses provide critical information on the physiology and evolution of this important vector species and should be instrumental for the development of innovative disease control methods.

Complex molecular assemblies at hand via interactive simulations.

PubMed

Delalande, Olivier; Férey, Nicolas; Grasseau, Gilles; Baaden, Marc

2009-11-30

Studying complex molecular assemblies interactively is becoming an increasingly appealing approach to molecular modeling. Here we focus on interactive molecular dynamics (IMD) as a textbook example for interactive simulation methods. Such simulations can be useful in exploring and generating hypotheses about the structural and mechanical aspects of biomolecular interactions. For the first time, we carry out low-resolution coarse-grain IMD simulations. Such simplified modeling methods currently appear to be more suitable for interactive experiments and represent a well-balanced compromise between an important gain in computational speed versus a moderate loss in modeling accuracy compared to higher resolution all-atom simulations. This is particularly useful for initial exploration and hypothesis development for rare molecular interaction events. We evaluate which applications are currently feasible using molecular assemblies from 1900 to over 300,000 particles. Three biochemical systems are discussed: the guanylate kinase (GK) enzyme, the outer membrane protease T and the soluble N-ethylmaleimide-sensitive factor attachment protein receptors complex involved in membrane fusion. We induce large conformational changes, carry out interactive docking experiments, probe lipid-protein interactions and are able to sense the mechanical properties of a molecular model. Furthermore, such interactive simulations facilitate exploration of modeling parameters for method improvement. For the purpose of these simulations, we have developed a freely available software library called MDDriver. It uses the IMD protocol from NAMD and facilitates the implementation and application of interactive simulations. With MDDriver it becomes very easy to render any particle-based molecular simulation engine interactive. Here we use its implementation in the Gromacs software as an example. Copyright 2009 Wiley Periodicals, Inc.

42 CFR 456.600 - Purpose.

Code of Federal Regulations, 2010 CFR

2010-10-01

... ASSISTANCE PROGRAMS UTILIZATION CONTROL Inspections of Care in Intermediate Care Facilities and Institutions for Mental Diseases § 456.600 Purpose. This subpart prescribes requirements for periodic inspections of care and services intermediate care facilities (ICF's), and institutions for mental diseases (IMD...

A method for modelling GP practice level deprivation scores using GIS

PubMed Central

Strong, Mark; Maheswaran, Ravi; Pearson, Tim; Fryers, Paul

2007-01-01

Background A measure of general practice level socioeconomic deprivation can be used to explore the association between deprivation and other practice characteristics. An area-based categorisation is commonly chosen as the basis for such a deprivation measure. Ideally a practice population-weighted area-based deprivation score would be calculated using individual level spatially referenced data. However, these data are often unavailable. One approach is to link the practice postcode to an area-based deprivation score, but this method has limitations. This study aimed to develop a Geographical Information Systems (GIS) based model that could better predict a practice population-weighted deprivation score in the absence of patient level data than simple practice postcode linkage. Results We calculated predicted practice level Index of Multiple Deprivation (IMD) 2004 deprivation scores using two methods that did not require patient level data. Firstly we linked the practice postcode to an IMD 2004 score, and secondly we used a GIS model derived using data from Rotherham, UK. We compared our two sets of predicted scores to "gold standard" practice population-weighted scores for practices in Doncaster, Havering and Warrington. Overall, the practice postcode linkage method overestimated "gold standard" IMD scores by 2.54 points (95% CI 0.94, 4.14), whereas our modelling method showed no such bias (mean difference 0.36, 95% CI -0.30, 1.02). The postcode-linked method systematically underestimated the gold standard score in less deprived areas, and overestimated it in more deprived areas. Our modelling method showed a small underestimation in scores at higher levels of deprivation in Havering, but showed no bias in Doncaster or Warrington. The postcode-linked method showed more variability when predicting scores than did the GIS modelling method. Conclusion A GIS based model can be used to predict a practice population-weighted area-based deprivation measure in the absence of patient level data. Our modelled measure generally had better agreement with the population-weighted measure than did a postcode-linked measure. Our model may also avoid an underestimation of IMD scores in less deprived areas, and overestimation of scores in more deprived areas, seen when using postcode linked scores. The proposed method may be of use to researchers who do not have access to patient level spatially referenced data. PMID:17822545

Sialic acids regulate microvessel permeability, revealed by novel in vivo studies of endothelial glycocalyx structure and function

PubMed Central

Betteridge, Kai B.; Arkill, Kenton P.; Neal, Christopher R.; Harper, Steven J.; Foster, Rebecca R.; Satchell, Simon C.; Bates, David O.

2017-01-01

Key points We have developed novel techniques for paired, direct, real‐time in vivo quantification of endothelial glycocalyx structure and associated microvessel permeability.Commonly used imaging and analysis techniques yield measurements of endothelial glycocalyx depth that vary by over an order of magnitude within the same vessel.The anatomical distance between maximal glycocalyx label and maximal endothelial cell plasma membrane label provides the most sensitive and reliable measure of endothelial glycocalyx depth.Sialic acid residues of the endothelial glycocalyx regulate glycocalyx structure and microvessel permeability to both water and albumin. Abstract The endothelial glycocalyx forms a continuous coat over the luminal surface of all vessels, and regulates multiple vascular functions. The contribution of individual components of the endothelial glycocalyx to one critical vascular function, microvascular permeability, remains unclear. We developed novel, real‐time, paired methodologies to study the contribution of sialic acids within the endothelial glycocalyx to the structural and functional permeability properties of the same microvessel in vivo. Single perfused rat mesenteric microvessels were perfused with fluorescent endothelial cell membrane and glycocalyx labels, and imaged with confocal microscopy. A broad range of glycocalyx depth measurements (0.17–3.02 μm) were obtained with different labels, imaging techniques and analysis methods. The distance between peak cell membrane and peak glycocalyx label provided the most reliable measure of endothelial glycocalyx anatomy, correlating with paired, numerically smaller values of endothelial glycocalyx depth (0.078 ± 0.016 μm) from electron micrographs of the same portion of the same vessel. Disruption of sialic acid residues within the endothelial glycocalyx using neuraminidase perfusion decreased endothelial glycocalyx depth and increased apparent solute permeability to albumin in the same vessels in a time‐dependent manner, with changes in all three true vessel wall permeability coefficients (hydraulic conductivity, reflection coefficient and diffusive solute permeability). These novel technologies expand the range of techniques that permit direct studies of the structure of the endothelial glycocalyx and dependent microvascular functions in vivo, and demonstrate that sialic acid residues within the endothelial glycocalyx are critical regulators of microvascular permeability to both water and albumin. PMID:28524373

PPARδ agonist GW501516 prevents uncoupling of endothelial nitric oxide synthase in cerebral microvessels of hph-1 mice

PubMed Central

Santhanam, Anantha Vijay R.; d’Uscio, Livius V.; He, Tongrong; Katusic, Zvonimir S.

2012-01-01

Peroxisome proliferator-activated receptor delta (PPARδ) is ubiquitously expressed in the vasculature, including cerebral circulation. The role of PPARδ in metabolism of tetrahydrobiopterin (BH4) has not been studied in the cerebral microvasculature. In the present study, the effects of PPARδ agonist GW501516 on uncoupling of endothelial nitric oxide synthase (eNOS) were determined in cerebral microvessels of BH4-deficient hph-1 mice. Wild-type (B6CBA) and hph-1 mice were orally gavaged with a selective PPARδ activator, GW501516 (2 mg/kg/day) for 14 days, and thereafter, cerebral microvessels were isolated and studied. Treatment of hph-1 mice with GW501516 significantly reduced oxidation of BH4 and increased the ratio of BH4 to 7,8-BH2 (P<0.05, n=6–9). Attenuation of L-NAME-inhibitable superoxide anion levels by GW501516 demonstrated that activation of PPARδ might prevent uncoupling of endothelial nitric oxide synthase (eNOS, P<0.05, n=6–9). Western blotting studies demonstrated that GW501516 selectively increased the endothelial expressions of CuZn superoxide dismutase (P<0.05, n=6–9) and catalase (P<0.05, n=6–8). PPARδ activation increased the total nitrite and nitrate (NO2 + NO3) content in cerebral microvessels (P<0.05, n=6). Obtained results suggest that in vivo activation of PPARδ prevents eNOS uncoupling, restores bioavailability of NO and may help preserve endothelial function in the BH4-deficient cerebral circulation. PMID:22982594

PPARδ agonist GW501516 prevents uncoupling of endothelial nitric oxide synthase in cerebral microvessels of hph-1 mice.

PubMed

Santhanam, Anantha Vijay R; d'Uscio, Livius V; He, Tongrong; Katusic, Zvonimir S

2012-11-05

Peroxisome proliferator-activated receptor delta (PPARδ) is ubiquitously expressed in the vasculature, including cerebral circulation. The role of PPARδ in metabolism of tetrahydrobiopterin (BH₄) has not been studied in the cerebral microvasculature. In the present study, the effects of PPARδ agonist GW501516 on uncoupling of endothelial nitric oxide synthase (eNOS) were determined in cerebral microvessels of BH₄-deficient hph-1 mice. Wild-type (B6CBA) and hph-1 mice were orally gavaged with a selective PPARδ activator, GW501516 (2 mg/kg/day) for 14 days, and thereafter, cerebral microvessels were isolated and studied. Treatment of hph-1 mice with GW501516 significantly reduced oxidation of BH₄ and increased the ratio of BH₄ to 7,8-BH₂ (P<0.05, n=6-9). Attenuation of L-NAME-inhibitable superoxide anion levels by GW501516 demonstrated that activation of PPARδ might prevent uncoupling of endothelial nitric oxide synthase (eNOS, P<0.05, n=6-9). Western blotting studies demonstrated that GW501516 selectively increased the endothelial expressions of CuZn superoxide dismutase (P<0.05, n=6-9) and catalase (P<0.05, n=6-8). PPARδ activation increased the total nitrite and nitrate (NO₂+NO₃) content in cerebral microvessels (P<0.05, n=6). Obtained results suggest that in vivo activation of PPARδ prevents eNOS uncoupling, restores bioavailability of NO and may help preserve endothelial function in the BH₄-deficient cerebral circulation. Copyright © 2012 Elsevier B.V. All rights reserved.

Data-driven sampling method for building 3D anatomical models from serial histology

NASA Astrophysics Data System (ADS)

Salunke, Snehal Ulhas; Ablove, Tova; Danforth, Theresa; Tomaszewski, John; Doyle, Scott

2017-03-01

In this work, we investigate the effect of slice sampling on 3D models of tissue architecture using serial histopathology. We present a method for using a single fully-sectioned tissue block as pilot data, whereby we build a fully-realized 3D model and then determine the optimal set of slices needed to reconstruct the salient features of the model objects under biological investigation. In our work, we are interested in the 3D reconstruction of microvessel architecture in the trigone region between the vagina and the bladder. This region serves as a potential avenue for drug delivery to treat bladder infection. We collect and co-register 23 serial sections of CD31-stained tissue images (6 μm thick sections), from which four microvessels are selected for analysis. To build each model, we perform semi-automatic segmentation of the microvessels. Subsampled meshes are then created by removing slices from the stack, interpolating the missing data, and re-constructing the mesh. We calculate the Hausdorff distance between the full and subsampled meshes to determine the optimal sampling rate for the modeled structures. In our application, we found that a sampling rate of 50% (corresponding to just 12 slices) was sufficient to recreate the structure of the microvessels without significant deviation from the fullyrendered mesh. This pipeline effectively minimizes the number of histopathology slides required for 3D model reconstruction, and can be utilized to either (1) reduce the overall costs of a project, or (2) enable additional analysis on the intermediate slides.

Butter feeding enhances TNF-alpha production from macrophages and lymphocyte adherence in murine small intestinal microvessels.

PubMed

Fujiyama, Yoichi; Hokari, Ryota; Miura, Soichiro; Watanabe, Chikako; Komoto, Shunsuke; Oyama, Tokushige; Kurihara, Chie; Nagata, Hiroshi; Hibi, Toshifumi

2007-11-01

Dietary fat is known to modulate immune functions. Intake of an animal fat-rich diet has been linked to increased risk of inflammation; however, little is known about how animal fat ingestion directly affects intestinal immune function. The objective of this study was to assess the effect of butter feeding on lymphocyte migration in intestinal mucosa and the changes in adhesion molecules and cytokines involved in this effect. T-lymphocytes isolated from the spleen were fluorescence-labeled and injected into recipient mice. Butter was administered into the duodenum, and villus microvessels of the small intestinal mucosa were observed under an intravital microscope. mRNA expression of adhesion molecules and cytokines in the intestinal mucosa were determined by quantitative PCR. The effect of butter feeding on tumor necrosis factor (TNF)-alpha mRNA expression of intestinal macrophages was also determined. Intraluminal butter administration significantly increased lymphocyte adherence to intestinal microvessels accompanied by increases in expression levels of adhesion molecules ICAM-1, MAdCAM-1 and VCAM-1. This accumulation was significantly attenuated by anti-MAdCAM-1 and anti-ICAM-1 antibodies. Butter administration significantly increased TNF-alpha in the lamina proprial macrophages but not interleukin-6. Anti-TNF-alpha treatment attenuated the enhanced expression of adhesion molecules induced by butter administration. T-lymphocyte adherence to microvessels of the small intestinal mucosa was significantly enhanced after butter ingestion. This enhancement is due to increase in expression levels of adhesion molecules of the intestinal mucosa, which is mediated by TNF-alpha from macrophages in the intestinal lamina propria.

Bioprinted Amniotic Fluid-Derived Stem Cells Accelerate Healing of Large Skin Wounds

PubMed Central

Skardal, Aleksander; Mack, David; Kapetanovic, Edi; Atala, Anthony; Jackson, John D.; Yoo, James

2012-01-01

Stem cells obtained from amniotic fluid show high proliferative capacity in culture and multilineage differentiation potential. Because of the lack of significant immunogenicity and the ability of the amniotic fluid-derived stem (AFS) cells to modulate the inflammatory response, we investigated whether they could augment wound healing in a mouse model of skin regeneration. We used bioprinting technology to treat full-thickness skin wounds in nu/nu mice. AFS cells and bone marrow-derived mesenchymal stem cells (MSCs) were resuspended in fibrin-collagen gel and “printed” over the wound site. At days 0, 7, and 14, AFS cell- and MSC-driven wound closure and re-epithelialization were significantly greater than closure and re-epithelialization in wounds treated by fibrin-collagen gel only. Histological examination showed increased microvessel density and capillary diameters in the AFS cell-treated wounds compared with the MSC-treated wounds, whereas the skin treated only with gel showed the lowest amount of microvessels. However, tracking of fluorescently labeled AFS cells and MSCs revealed that the cells remained transiently and did not permanently integrate in the tissue. These observations suggest that the increased wound closure rates and angiogenesis may be due to delivery of secreted trophic factors, rather than direct cell-cell interactions. Accordingly, we performed proteomic analysis, which showed that AFS cells secreted a number of growth factors at concentrations higher than those of MSCs. In parallel, we showed that AFS cell-conditioned media induced endothelial cell migration in vitro. Taken together, our results indicate that bioprinting AFS cells could be an effective treatment for large-scale wounds and burns. PMID:23197691

Transfection of the Human Heme Oxygenase Gene Into Rabbit Coronary Microvessel Endothelial Cells: Protective Effect Against Heme and Hemoglobin Toxicity

NASA Astrophysics Data System (ADS)

Abraham, N. G.; Lavrovsky, Y.; Schwartzman, M. L.; Stoltz, R. A.; Levere, R. D.; Gerritsen, M. E.

1995-07-01

Heme oxygenase (HO) is a stress protein and has been suggested to participate in defense mechanisms against agents that may induce oxidative injury such as metals, endotoxin, heme/hemoglobin, and various cytokines. Overexpression of HO in cells might therefore protect against oxidative stress produced by certain of these agents, specifically heme and hemoglobin, by catalyzing their degradation to bilirubin, which itself has antioxidant properties. We report here the successful in vitro transfection of rabbit coronary microvessel endothelial cells with a functioning gene encoding the human HO enzyme. A plasmid containing the cytomegalovirus promoter and the human HO cDNA complexed to cationic liposomes (Lipofectin) was used to transfect rabbit endothelial cells. Cells transfected with human HO exhibited an ≈3.0-fold increase in enzyme activity and expressed a severalfold induction of human HO mRNA as compared with endogenous rabbit HO mRNA. Transfected and nontransfected cells expressed factor VIII antigen and exhibited similar acetylated low-density lipoprotein uptake (two important features that characterize endothelial cells) with >85% of cells staining positive for each marker. Moreover, cells transfected with the human HO gene acquired substantial resistance to toxicity produced by exposure to recombinant hemoglobin and heme as compared with nontransfected cells. The protective effect of HO overexpression against heme/hemoglobin toxicity in endothelial cells shown in these studies provides direct evidence that the inductive response of human HO to such injurious stimuli represents an important tissue adaptive mechanism for moderating the severity of cell damage produced by these blood components.

Aberrant expression of decoy receptor 3 in human breast cancer: relevance to lymphangiogenesis.

PubMed

Wu, Qiuwan; Zheng, Yahong; Chen, Donghan; Li, Xiaohong; Lu, Chuanhui; Zhang, Zhiming

2014-05-15

Decoy receptor 3 (DcR3), a decoy receptor against Fas ligand belonging to the tumor necrosis factor receptor superfamily, is overexpressed in some forms of cancer. It was recently reported that DcR3 could protect endothelial cells from apoptosis, implying a potential role in the development of vessels, whereas its role in the lymphangiogenesis remains unclear. In the present study, we studied the DcR3 expression and its relationship with the lymphatic microvessel density (LMVD) to investigate if it played a role in the lymph metastasis of human breast cancer. Real-time polymerase chain reaction and immunohistochemistry were performed to measure the messenger RNA and protein expression of DcR3 in the breast cancer tissues, noncancerous counterparts, and axillary lymph node from 63 patients. LMVD in these specimens was assessed by counting the D2-40 labeled-microvessels. Furthermore, the correlations between DcR3 expression and LMVD and other clinicopathologic parameters were analyzed. DcR3 was overexpressed in the breast cancer tissue of 58 patients (92.1%) and was also expressed in vascular endothelial cells and tumor cells in the lymph nodes. LMVD in cancer tissue and lymph nodes were both positively correlated to the aberrant expression of DcR3. The relevance between DcR3 overexpression and LMVD revealed the existence of possible links between DcR3 and lymphangiogenesis. Based on these findings, it is important to further explore the regulation of lymphangiogenesis operated by the reverse tumor necrosis factor signaling of DcR3. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Microvascular Perfusion Changes following Transarterial Hepatic Tumor Embolization

PubMed Central

Johnson, Carmen Gacchina; Sharma, Karun V.; Levy, Elliot B.; Woods, David L.; Morris, Aaron H.; Bacher, John D.; Lewis, Andrew L.; Wood, Bradford J.; Dreher, Matthew R.

2015-01-01

Purpose To quantify changes in tumor microvascular (< 1 mm) perfusion relative to commonly used angiographic endpoints. Materials and Methods Rabbit Vx2 liver tumors were embolized with 100–300-µm LC Bead particles to endpoints of substasis or complete stasis (controls were not embolized). Microvascular perfusion was evaluated by delivering two different fluorophore-conjugated perfusion markers (ie, lectins) through the catheter before embolization and 5 min after reaching the desired angiographic endpoint. Tumor microvasculature was labeled with an anti-CD31 antibody and analyzed with fluorescence microscopy for perfusion marker overlap/mismatch. Data were analyzed by analysis of variance and post hoc test (n = 3–5 per group; 18 total). Results Mean microvascular density was 70 vessels/mm2 ± 17 (standard error of the mean), and 81% ± 1 of microvasculature (ie, CD31+ structures) was functionally perfused within viable Vx2 tumor regions. Embolization to the extent of substasis eliminated perfusion in 37% ± 9 of perfused microvessels (P > .05 vs baseline), whereas embolization to the extent of angiographic stasis eliminated perfusion in 56% ± 8 of perfused microvessels. Persistent microvascular perfusion following embolization was predominantly found in the tumor periphery, adjacent to normal tissue. Newly perfused microvasculature was evident following embolization to substasis but not when embolization was performed to complete angiographic stasis. Conclusions Nearly half of tumor microvasculature remained patent despite embolization to complete angiographic stasis. The observed preservation of tumor microvasculature perfusion with angiographic endpoints of substasis and stasis may have implications for tumor response to embolotherapy. PMID:26321051

Numerical Simulation of Thrombotic Occlusion in Tortuous Arterioles

PubMed Central

Feng, Zhi-Gang; Cortina, Miguel; Chesnutt, Jennifer KW; Han, Hai-Chao

2017-01-01

Tortuous microvessels alter blood flow and stimulate thrombosis but the physical mechanisms are poorly understood. Both tortuous microvessels and abnormally large platelets are seen in diabetic patients. Thus, the objective of this study was to determine the physical effects of arteriole tortuosity and platelet size on the microscale processes of thrombotic occlusion in microvessels. A new lattice-Boltzmann method-based discrete element model was developed to simulate the fluid flow field with fluid-platelet coupling, platelet interactions, thrombus formation, and thrombotic occlusion in tortuous arterioles. Our results show that vessel tortuosity creates high shear stress zones that activate platelets and stimulate thrombus formation. The growth rate depends on the level of tortuosity and the pressure and flow boundary conditions. Once thrombi began to form, platelet collisions with thrombi and subsequent activations were more important than tortuosity level. Thrombus growth narrowed the channel and reduced the flow rate. Larger platelet size leads to quicker decrease of flow rate due to larger thrombi that occluded the arteriole. This study elucidated the important roles that tortuosity and platelet size play in thrombus formation and occlusion in arterioles. PMID:29327739

Stromal-dependent tumor promotion by MIF family members.

PubMed

Mitchell, Robert A; Yaddanapudi, Kavitha

2014-12-01

Solid tumors are composed of a heterogeneous population of cells that interact with each other and with soluble and insoluble factors that, when combined, strongly influence the relative proliferation, differentiation, motility, matrix remodeling, metabolism and microvessel density of malignant lesions. One family of soluble factors that is becoming increasingly associated with pro-tumoral phenotypes within tumor microenvironments is that of the migration inhibitory factor family which includes its namesake, MIF, and its only known family member, D-dopachrome tautomerase (D-DT). This review seeks to highlight our current understanding of the relative contributions of a variety of immune and non-immune tumor stromal cell populations and, within those contexts, will summarize the literature associated with MIF and/or D-DT. Copyright © 2014 Elsevier Inc. All rights reserved.

CXC chemokine ligand 4 (CXCL4) is predictor of tumour angiogenic activity and prognostic biomarker in non-small cell lung cancer (NSCLC) patients undergoing surgical treatment.

PubMed

Spaks, Artjoms; Svirina, Darja; Spaka, Irina; Jaunalksne, Inta; Breiva, Donats; Tracums, Ilmars; Krievins, Dainis

2016-07-01

To evaluate the association of CXC chemokine ligand 4 (CXCL4) plasma levels with tumour angiogenesis in non-small cell lung cancer (NSCLC) and to assess association of CXCL4 with clinical outcomes. Fifty patients with early stage NSCLC who underwent pulmonary resection. CXCL4 levels were analysed by ELISA. Angiogenesis was assessed by immunohistochemistry, and microvessel density (MVD) count. There was positive correlation between MVD and CXCL4 levels. Patients with higher CXCL4 levels had worse overall and disease-free survival. Plasma levels of CXCL4 are associated with tumour vascularity. Increased CXCL4 levels in NSCLC patients undergoing treatment may indicate active cancer-induced angiogenesis associated with relapse and worse outcome.

RNA Interference Directed against the Transglutaminase Gene Triggers Dysbiosis of Gut Microbiota in Drosophila*

PubMed Central

Sekihara, Sanae; Shibata, Toshio; Hyakkendani, Mai; Kawabata, Shun-ichiro

2016-01-01

We recently reported that transglutaminase (TG) suppresses immune deficiency pathway-controlled antimicrobial peptides (IMD-AMPs), thereby conferring immune tolerance to gut microbes, and that RNAi of the TG gene in flies decreases the lifespan compared with non-TG-RNAi flies. Here, analysis of the bacterial composition of the Drosophila gut by next-generation sequencing revealed that gut microbiota comprising one dominant genus of Acetobacter in non-TG-RNAi flies was shifted to that comprising two dominant genera of Acetobacter and Providencia in TG-RNAi flies. Four bacterial strains, including Acetobacter persici SK1 and Acetobacter indonesiensis SK2, Lactobacillus pentosus SK3, and Providencia rettgeri SK4, were isolated from the midgut of TG-RNAi flies. SK1 exhibited the highest resistance to the IMD-AMPs Cecropin A1 and Diptericin among the isolated bacteria. In contrast, SK4 exhibited considerably lower resistance against Cecropin A1, whereas SK4 exhibited high resistance to hypochlorous acid. The resistance of strains SK1–4 against IMD-AMPs in in vitro assays could not explain the shift of the microbiota in the gut of TG-RNAi flies. The lifespan was reduced in gnotobiotic flies that ingested both SK4 and SK1, concomitant with the production of reactive oxygen species and apoptosis in the midgut, whereas the survival rate was not altered in gnotobiotic flies that mono-ingested either SK4 or SK1. Interestingly, significant amounts of reactive oxygen species were detected in the midgut of gnotobiotic flies that ingested SK4 and SK2, concomitant with no significant apoptosis in the midgut. In gnotobiotic flies that co-ingested SK4 and SK1, an additional unknown factor(s) may be required to cause midgut apoptosis. PMID:27760824

Area-Level Deprivation and Overall and Cause-Specific Mortality: 12 Years’ Observation on British Women and Systematic Review of Prospective Studies

PubMed Central

Sánchez-Santos, Maria T.; Mesa-Frias, Marco; Choi, Minkyoung; Nüesch, Eveline; Asunsolo-Del Barco, Angel; Amuzu, Antoinette; Smith, George Davey; Ebrahim, Shah; Prieto-Merino, David; Casas, Juan P.

2013-01-01

Background Prospective studies have suggested a negative impact of area deprivation on overall mortality, but its effect on cause-specific mortality and the mechanisms that account for this association remain unclear. We investigate the association of area deprivation, using Index of Multiple deprivation (IMD), with overall and cause-specific mortality, contextualising findings within a systematic review. Methods And Findings We used data from 4,286 women from the British Women’s Heart Health Study (BWHHS) recruited at 1999-2001 to examine the association of IMD with overall and cause-specific mortality using Cox regression models. One standard deviation (SD) increase in the IMD score had a hazard ratio (HR) of 1.21 (95% CI: 1.13-1.30) for overall mortality after adjustment for age and lifecourse individual deprivation, which was attenuated to 1.15 (95% CI: 1.04-1.26) after further inclusion of mediators (health behaviours, biological factors and use of statins and blood pressure-lowering medications). A more pronounced association was observed for respiratory disease and vascular deaths. The meta-analysis, based on 20 published studies plus the BWHHS (n=21), yielded a summary relative risk (RR) of 1.15 (95% CI: 1.11-1.19) for area deprivation (top [least deprived; reference] vs. bottom tertile) with overall mortality in an age and sex adjusted model, which reduced to 1.06 (95% CI: 1.04-1.08) in a fully adjusted model. Conclusions Health behaviours mediate the association between area deprivation and cause-specific mortality. Efforts to modify health behaviours may be more successful if they are combined with measures that tackle area deprivation. PMID:24086262

Optimal Ranking Regime Analysis of TreeFlow Dendrohydrological Reconstructions

NASA Astrophysics Data System (ADS)

Mauget, S. A.

2017-12-01

The Optimal Ranking Regime (ORR) method was used to identify 6-100 year time windows containing significant ranking sequences in 55 western U.S. streamflow reconstructions, and reconstructions of the level of the Great Salt Lake and San Francisco Bay salinity during 1500-2007. The method's ability to identify optimally significant and non-overlapping runs of low and high rankings allows it to re-express a reconstruction time series as a simplified sequence of regime segments marking intra- to multi-decadal (IMD) periods of low or high streamflow, lake level, or salinity. Those ORR sequences, referred to here as Z-lines, can be plotted to identify consistent regime patterns in the analysis of numerous reconstructions. The Z-lines for the 57 reconstructions evaluated here show a common pattern of IMD cycles of drought and pluvial periods during the late 16th and 17th centuries, a relatively dormant period during the 18th century, and the reappearance of alternating dry and wet IMD periods during the 19th and early 20th centuries. Although this pattern suggests the possibility of similarly active and inactive oceanic modes in the North Pacific and North Atlantic, such centennial-scale patterns are not evident in the ORR analyses of reconstructed Pacific Decadal Oscillation (PDO), El Niño-Southern Oscillation, and North Atlantic seas-surface temperature variation. But given the inconsistency in the analyses of four PDO reconstructions the possible role of centennial-scale oceanic mechanisms is uncertain. In future research the ORR method might be applied to climate reconstructions around the Pacific Basin to try to resolve this uncertainty. Given its ability to compare regime patterns in climate reconstructions derived using different methods and proxies, the method may also be used in future research to evaluate long-term regional temperature reconstructions.

Pneumonia treated in the internal medicine department: focus on healthcare-associated pneumonia.

PubMed

Giannella, M; Pinilla, B; Capdevila, J A; Martínez Alarcón, J; Muñoz, P; López Álvarez, J; Bouza, E

2012-08-01

Patients with pneumonia treated in the internal medicine department (IMD) are often at risk of healthcare-associated pneumonia (HCAP). The importance of HCAP is controversial. We invited physicians from 72 IMDs to report on all patients with pneumonia hospitalized in their department during 2 weeks (one each in January and June 2010) to compare HCAP with community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP). We analysed 1002 episodes of pneumonia: 58.9% were CAP, 30.6% were HCAP and 10.4% were HAP. A comparison between CAP, HCAP and HAP showed that HCAP patients were older (77, 83 and 80.5 years; p < 0.001), had poorer functional status (Barthel 100, 30 and 65; p < 0.001) and had more risk factors for aspiration pneumonia (18, 50 and 34%; p < 0.001). The frequency of testing to establish an aetiological diagnosis was lower among HCAP patients (87, 72 and 79; p < 0.001), as was adherence to the therapeutic recommendations of guidelines (70, 23 and 56%; p < 0.001). In-hospital mortality increased progressively between CAP, HCAP and HAP (8, 19 and 27%; p < 0.001). Streptococcus pneumoniae was the main pathogen in CAP and HCAP. Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) caused 17 and 12.3% of HCAP. In patients with a confirmed aetiological diagnosis, the independent risk factors for pneumonia due do difficult-to-treat microorganisms (Enterobacteriaceae, P. aeruginosa or MRSA) were HCAP, chronic obstructive pulmonary diseases and higher Port Severity Index. Our data confirm the importance of maintaining high awareness of HCAP among patients treated in IMDs, because of the different aetiologies, therapy requirements and prognosis of this population. © 2011 The Authors. Clinical Microbiology and Infection © 2011 European Society of Clinical Microbiology and Infectious Diseases.

LOCALIZATION OF CALCITONIN RECEPTOR-LIKE RECEPTOR (CLR) AND RECEPTOR ACTIVITY-MODIFYING PROTEIN 1 (RAMP1) IN HUMAN GASTROINTESTINAL TRACT

PubMed Central

Cottrell, Graeme S.; Alemi, Farzad; Kirkland, Jacob G.; Grady, Eileen F.; Corvera, Carlos U.; Bhargava, Aditi

2012-01-01

Calcitonin gene-related peptide (CGRP) exerts its diverse effects on vasodilation, nociception, secretion, and motor function through a heterodimeric receptor comprising of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1). Despite the importance of CLR•RAMP1 in human disease, little is known about its distribution in the human gastrointestinal (GI) tract, where it participates in inflammation and pain. In this study, we determined that CLR and RAMP1 mRNAs are expressed in normal human stomach, ileum and colon by RT-PCR. We next characterized antibodies that we generated to rat CLR and RAMP1 in transfected HEK cells. Having characterized these antibodies in vitro, we then localized CLR-, RAMP1-, CGRP- and intermedin-immunoreactivity (IMD-IR) in various human GI segments. In the stomach, nerve bundles in the myenteric plexus and nerve fibers throughout the circular and longitudinal muscle had prominent CLR-IR. In the proximal colon and ileum, CLR was found in nerve varicosities of the myenteric plexus and surrounding submucosal neurons. Interestingly, CGRP expressing fibers did not co-localize, but were in close proximity to CLR. However, CLR and RAMP1, the two subunits of a functional CGRP receptor were clearly localized in myenteric plexus, where they may form functional cell-surface receptors. IMD, another member of calcitonin peptide family was also found in close proximity to CLR, and like CGRP, did not co-localize with either CLR or RAMP1 receptors. Thus, CGRP and IMD appear to be released locally, where they can mediate their effect on their receptors regulating diverse functions such as inflammation, pain and motility. PMID:22484227

The missing link: family physician perspectives on barriers and enablers to prescribing a new Meningococcal B vaccine and other recommended, non-government funded vaccines.

PubMed

Taylor, Kathryn A; Stocks, Nigel; Marshall, Helen S

2014-07-16

To determine factors influencing Family Physician (FP) uptake of non government-funded vaccines, and to explore FP attitudes towards the introduction and use of a new vaccine to protect against serogroup B meningococcal disease to inform its future introduction into the Australian Immunisation Schedule. Quantitative, self-administered state-wide questionnaire mailed to all FPs in South Australia (n=1786). Results from 523 FP respondents in South Australia, collected between June and October 2013. Self-reported immunisation counselling practices; and knowledge, attitudes and barriers to prescribing of Meningococcal B (Men B) vaccine and other recommended, non-funded immunisations. The response rate was 30% (n=523). While most (59%) respondents had worked in general practice for over 20 years, only 39% of all respondents had ever had personal or professional experience with a case of invasive meningococcal disease (IMD). Most FPs (63%) were aware that a meningococcal B vaccine was being developed, and 93% of respondents agreed that this vaccine should be government-funded. FPs ranked Men B vaccine as the highest priority to receive funding of eight currently non-funded immunisation strategies. High vaccine cost and low patient socioeconomic status were identified as definite barriers to prescribing non-funded vaccines by 59% of respondents. Past IMD experience significantly affected attitudes and prescribing practices. IMD, while encountered rarely in clinical practice, is considered an important disease to vaccinate against by FPs. Cost and perceived low socioeconomic status of patients are substantial barriers to FPs prescribing Men B and other non-funded vaccines, and inclusion of such vaccines on the National Immunisation Program is likely to improve equity of access. Copyright © 2014 Elsevier Ltd. All rights reserved.

Outcomes by area of residence deprivation in a cohort of oral cancer patients: Survival, health-related quality of life, and place of death.

PubMed

Rylands, Joseph; Lowe, Derek; Rogers, Simon N

2016-01-01

Oral cancer patients from lower socio-economic backgrounds have worse outcomes of survival and health related quality of life. The mechanism of cause is not fully understood. The purpose of the paper is to report treatment selection, survival, health related quality of life, cause and place of death in relation to deprivation status. 553 patients treated for oral cancer between 2008 and 2012 were identified from records at University hospital. Mortality was tracked via the Office of National Statistics (ONS) and health-related quality of life was measured using the University Washington quality of life questionnaire (UW-QoLv4). Postcodes of residence at diagnosis were used to obtain index of multiple deprivation (IMD) 2010 scores. Nearly half of the sample (47%) lived in the 'most deprived' IMD 2010 quartile of residential areas in England and such patients when treated with curative intent using surgery with or without adjuvant radiotherapy had worse survival than patients living elsewhere, p=0.01 after adjusting for pathological staging and age group. There were no notable differences by IMD group in cancer being mentioned anywhere in part 1 or part 2 of the death certificate or in place of death. After adjustment for patient and clinical factors patients residing in more deprived areas had worse quality of life outcomes in regard to social-emotional functioning and overall quality of life but not in regard to physical oral function. Addressing inequalities in health care related to deprivation is a priority for patients with oral cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

Peroxiredoxin 5 modulates immune response in Drosophila

PubMed Central

Radyuk, Svetlana N.; Michalak, Katarzyna; Klichko, Vladimir I.; Benes, Judith; Orr, William C.

2010-01-01

Background Peroxiredoxins are redox-sensing enzymes with multiple cellular functions. Previously, we reported on the potent antioxidant function of Drosophila peroxiredoxin 5 (dPrx5). Studies with mammalian and human cells suggest that peroxiredoxins can modulate immune-related signaling. Methods Survivorship studies and bacteriological analysis were used to determine resistance of flies to fungal and bacterial infections. RT-PCR and immunoblot analyses determined expression of dPrx5 and immunity factors in response to bacterial challenge. Double mutants for dprx5 gene and genes comprising the Imd/Relish and dTak1/Basket branches of the immune signaling pathways were used in epistatic analysis. Results The dprx5 mutant flies were more resistant to bacterial infection than controls, while flies overexpressing dPrx5 were more susceptible. The enhanced resistance to bacteria was accompanied by rapid induction of the Imd-dependent antimicrobial peptides, phosphorylation of the JNK kinase Basket and altered transcriptional profiling of the transient response genes, puckered, ets21C and relish, while the opposite effects were observed in flies over-expressing dPrx5. Epistatic analysis of double mutants, using attacin D and Puckered as read outs of activation of the Imd and JNK pathways, implicated dPrx5 function in the control of the dTak1-JNK arm of immune signaling. Conclusions Differential effects on fly survivorship suggested a trade-off between the antioxidant and immune functions of dPrx5. Molecular and epistatic analyses identified dPrx5 as a negative regulator in the dTak1-JNK arm of immune signaling. General significance Our findings suggest that peroxiredoxins play an important modulatory role in the Drosophila immune response. PMID:20600624

Monitoring of the biological response to murine hindlimb ischemia with 64Cu-labeled vascular endothelial growth factor-121 positron emission tomography.

PubMed

Willmann, Jürgen K; Chen, Kai; Wang, Hui; Paulmurugan, Ramasamy; Rollins, Mark; Cai, Weibo; Wang, David S; Chen, Ian Y; Gheysens, Olivier; Rodriguez-Porcel, Martin; Chen, Xiaoyuan; Gambhir, Sanjiv S

2008-02-19

Vascular endothelial growth factor-121 (VEGF121), an angiogenic protein secreted in response to hypoxic stress, binds to VEGF receptors (VEGFRs) overexpressed on vessels of ischemic tissue. The purpose of this study was to evaluate 64Cu-VEGF121 positron emission tomography for noninvasive spatial, temporal, and quantitative monitoring of VEGFR2 expression in a murine model of hindlimb ischemia with and without treadmill exercise training. 64Cu-labeled VEGF121 and a VEGF mutant were tested for VEGFR2 binding specificity in cell culture. Mice (n=58) underwent unilateral ligation of the femoral artery, and postoperative tissue ischemia was assessed with laser Doppler imaging. Longitudinal VEGFR2 expression in exercised and nonexercised mice was quantified with 64Cu-VEGF121 positron emission tomography at postoperative day 8, 15, 22, and 29 and correlated with postmortem gamma-counting. Hindlimbs were excised for immunohistochemistry, Western blotting, and microvessel density measurements. Compared with the VEGF mutant, VEGF121 showed specific binding to VEGFR2. Perfusion in ischemic hindlimbs fell to 9% of contralateral hindlimb on postoperative day 1 and recovered to 82% on day 29. 64Cu-VEGF121 uptake in ischemic hindlimbs increased significantly (P < 0.001) from a control level of 0.61+/-0.17% ID/g (percentage of injected dose per gram) to 1.62+/-0.35% ID/g at postoperative day 8, gradually decreased over the following 3 weeks (0.59+/-0.14% ID/g at day 29), and correlated with gamma-counting (R2 = 0.99). Compared with nonexercised mice, 64Cu-VEGF121 uptake was increased significantly (P < or = 0.0001) in exercised mice (at day 15, 22, and 29) and correlated with VEGFR2 levels as obtained by Western blotting (R2 = 0.76). Ischemic hindlimb tissue stained positively for VEGFR2. In exercised mice, microvessel density was increased significantly (P<0.001) compared with nonexercised mice. 64Cu-VEGF121 positron emission tomography allows longitudinal spatial and quantitative monitoring of VEGFR2 expression in murine hindlimb ischemia and indirectly visualizes enhanced angiogenesis stimulated by treadmill exercise training.

High eIF4E, VEGF, and Microvessel Density in Stage I to III Breast Cancer

PubMed Central

Byrnes, Kerry; White, Stephen; Chu, Quyen; Meschonat, Carol; Yu, Herbert; Johnson, Lester W.; DeBenedetti, Arrigo; Abreo, Fleurette; Turnage, Richard H.; McDonald, John C.; Li, Benjamin D.

2006-01-01

Objective: In a prospective trial, to determine if eIF4E overexpression in breast cancer specimens is correlated with VEGF elevation, increased tumor microvessel density (MVD) counts, and a worse clinical outcome irrespective of nodal status. Summary and Background Data: In vitro, the overexpression of eukaryotic initiation factor 4E (eIF4E) up-regulates the translation of mRNAs with long 5′-untranslated regions (5′-UTRs). One such gene product is the vascular endothelial growth factor (VEGF). Methods: A total of 114 stage I to III breast cancer patients were prospectively accrued and followed with a standardized clinical surveillance protocol. Cancer specimens were quantified for eIF4E, VEGF, and MVD. Outcome endpoints were cancer recurrence and cancer-related death. Results: eIF4E overexpression was found in all cancer specimens (mean ± SD, 12.5 ± 7.6-fold). Increasing eIF4E overexpression correlated with increasing VEGF elevation (r = 0.24, P = 0.01, Spearman's coefficient), and increasing MVD counts (r = 0.35, P < 0.0002). Patients whose tumor had high eIF4E overexpression had shorter disease-free survival (P = 0.004, log-rank test) and higher cancer-related deaths (P = 0.002) than patients whose tumors had low eIF4E overexpression. Patients with high eIF4E had a hazard ratio for cancer recurrence and cancer-related death of 1.8 and 2.1 times that of patients with low eIF4E (respectively, P = 0.009 and P = 0.002, Cox proportional hazard model). Conclusions: In breast cancer patients, increasing eIF4E overexpression in the cancer specimens correlates with higher VEGF levels and MVD counts. Patients whose tumors had high eIF4E overexpression had a worse clinical outcome, independent of nodal status. Thus, eIF4E overexpression in breast cancer appears to predict increased tumor vascularity and perhaps cancer dissemination by hematogenous means. PMID:16633004

Combined cetuximab and genistein treatment shows additive anti-cancer effect on oral squamous cell carcinoma.

PubMed

Park, Sung-Jin; Kim, Myung-Jin; Kim, Yu-Kyoung; Kim, Soung-Min; Park, Ju-Yong; Myoung, Hoon

2010-06-01

The purpose of this study was to evaluate the potency of EGFR pathway inhibition achieved by combining cetuximab, an anti-EGFR monoclonal antibody, and genistein, a tyrosine kinase inhibitor, which target extracellular and intracellular domains of the receptor, respectively, in oral squamous cell carcinoma (OSCC) in vitro and in vivo. Two OSCC cell lines, HSC3 and KB, were treated with cetuximab (C, 0-400mug/ml), genistein (G, 0-80muM), or a combination of both at a range of concentrations. Downstream protein expression of EGFR, p-EGFR, and p-Akt were evaluated by Western blot. Cell proliferation and apoptosis indices were calculated to assess anti-cancer effects in vitro. The in vivo effects of cetuximab and genistein on tumor cell growth were examined using an OSCC xenografted nude mouse model and immunohistochemical analyses of proliferation (PCNA) and microvessel density (CD31). Treatment of cells with dual anti-EGFR agents reduced the expressions of p-EGFR, and p-Akt in HSC3 cell line, but there was no significant difference in downregulation between cetuximab alone and in combination with genistein in KB cells. Both HSC3 and KB cells showed a dose-dependent decrease in cell proliferation significantly with single agent treatment and combination (p<0.05). In low concentration, combined cetuximab and genistein therapy resulted in additive growth inhibition and more apoptosis compared to that achieved with single-agent exposure in both cell lines. A combination of cetuximab and genistein significantly inhibited tumor growth and caused a substantial growth delay in in vivo models of both cell lines while each single-agent exposure caused no delay of tumor growth. Immunohistochemical staining with PCNA revealed that the group receiving combined cetuximab and genistein exhibited the lowest number of proliferating cells and microvessel density (p<0.05). Combined therapy with genistein and cetuximab can add the potency of EGFR signaling inhibition. Because not all OSCC cell types appear to respond uniformly, however, selective targeting of distinct molecular pathways is required for effective clinical response. Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.

2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-Glucoside Attenuates Ischemia/Reperfusion-Induced Brain Injury in Rats by Promoting Angiogenesis.

PubMed

Mu, Ying; Xu, Zhaohui; Zhou, Xuanxuan; Zhang, Huinan; Yang, Qian; Zhang, Yunlong; Xie, Yanhua; Kang, Juan; Li, Feng; Wang, Siwang

2017-05-01

Cerebral ischemia can cause brain infarcts, which are difficult to recover due to poor angiogenesis. 2,3,5,4'-Tetrahydroxystilbene-2-O- β -D-glucoside is a natural polyphenol, has antioxidant and anti-inflammatory activity, and can protect from ischemic neuronal injury. However, little is known about the effect of 2,3,5,4'-tetrahydroxystilbene-2-O- β -D-glucoside on brain microcirculation after stroke. This study aimed at investigating the influence of 2,3,5,4'-tetrahydroxystilbene-2-O- β -D-glucoside on brain lesions and angiogenesis after stroke. Sprague-Dawley rats were subjected to right middle cerebral artery occlusion and treated with vehicle, nimodipine, or different doses of 2,3,5,4'-tetrahydroxystilbene-2-O- β -D-glucoside daily beginning at 6 h post-middle cerebral artery occlusion for 14 days. The volume of cerebral infarcts, degree of neurological dysfunction, and level of microvessel density were determined longitudinally. The levels of vascular endothelial growth factor, angiopoietin 1, and angiopoietin receptor-2 expression in the brain lesions were characterized by immunohistochemistry and Western blot assays at 14 days post-middle cerebral artery occlusion. We found that 2,3,5,4'-tetrahydroxystilbene-2-O- β -D-glucoside significantly promoted postoperative recovery in rats by minimizing the volume of cerebral infarcts and improving neurological dysfunction in a dose- and time-dependent manner. Additionally, 2,3,5,4'-tetrahydroxystilbene-2-O- β -D-glucoside significantly increased the microvessel density in the brain and upregulated CD31 expression in ischemic penumbra, relative to that in the control. Finally, treatment with 2,3,5,4'-tetrahydroxystilbene-2-O- β -D-glucoside significantly upregulated the relative levels of vascular endothelial growth factor, angiopoietin 1, and angiopoietin receptor-2 expression in the brain lesions of rats. Therefore, these data indicated that 2,3,5,4'-tetrahydroxystilbene-2-O- β -D-glucoside treatment promoted angiogenesis and recovery from ischemia/reperfusion-induced brain injury in rats. Georg Thieme Verlag KG Stuttgart · New York.

Effect of peritoneal dialysis on expression of vascular endothelial growth factor, basic fibroblast growth factor and endostatin of the peritoneum in peritoneal dialysis patients.

PubMed

Gao, Dan; Zhao, Zhan-Zheng; Liang, Xian-Hui; Li, Yan; Cao, Ying; Liu, Zhang-Suo

2011-11-01

The aim of this study is to investigate the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and endostatin (ES) in human peritoneum and investigate the relationship between them and peritoneum neoangiogensis in the patients with uraemia and peritoneal dialysis (PD). Peritoneal biopsies were obtained from normal subjects (n = 8), uraemic predialysis patients (n = 12) and PD patients (n = 10). The mRNA expression of VEGF, bFGF and ES in peritoneal tissues were measured through real-time polymerase chain reaction. The protein expression of VEGF, bFGF and ES in peritoneal tissues were determined through western blot. Microvessel density (MVD) of peritoneal tissue was assessed using immunohistochemistry with CD34 monoclonal antibody. The mRNA and protein of VEGF, bFGF and ES were expressed in all peritoneal samples. Compared with the normal control group, the mRNA and protein expression of VEGF and bFGF in peritoneal tissues were all significantly upregulated in the uraemic predialysis and PD group (all P < 0.05). Compared with the normal control group, the protein expression of ES were significantly upregulated in the uraemic predialysis and PD group (all (P < 0.05), but the mRNA expression of ES did not have obvious differences in the uraemic predialysis and PD group as compared to the normal control group (P > 0.05). MVD of peritoneal tissue were increased in the uraemic predialysis and PD group compared with the normal group (all P < 0.05). A significant positive correlation was found between VEGF mRNA expression and MVD, bFGF mRNA expression and MVD. The mRNA expression of VEGF and bFGF, the protein expression of VEGF, bFGF, and ES and microvessel density (MVD) are increased both in the uraemic predialysis and PD patients. These results show that uraemia circumstances and non-physiological compatibility of peritoneal dialysis solution might increase VEGF, bFGF and ES expression and MVD, which might participate in the increment of the peritoneum neoangiogensis and ultrafiltration failure in PD patients. © 2011 The Authors. Nephrology © 2011 Asian Pacific Society of Nephrology.

Slit2 promotes tumor growth and invasion in chemically induced skin carcinogenesis.

PubMed

Qi, Cuiling; Lan, Haimei; Ye, Jie; Li, Weidong; Wei, Ping; Yang, Yang; Guo, Simei; Lan, Tian; Li, Jiangchao; Zhang, Qianqian; He, Xiaodong; Wang, Lijing

2014-07-01

Slit, a neuronal guidance cue, binds to Roundabout (Robo) receptors to modulate neuronal, leukocytic, and endothelial migration. Slit has been reported to have an important effect on tumor growth and metastasis. In the current study, we evaluated the role of Slit2 in skin tumor growth and invasion in mice using a two-step chemical carcinogenesis protocol. We found that Slit2 expression correlated with the loss of basement membrane in the samples of human skin squamous cell carcinoma at different stages of disease progression. Slit2-Tg mice developed significantly more skin tumors than wild-type mice. Furthermore, the skin tumors that occurred in Slit2-Tg mice were significantly larger than those in the wild-type mice 10 weeks after 7,12-dimethylbenz[a]anthracene initiation until the end of the experiment. We also found that pathological development of the wild-type mice was delayed compared with that of Slit2-Tg mice. To further investigate the mechanism of increasing tumors in Slit2-Tg mice, we analyzed the expression of 5-bromo-2'-deoxyuridine (BrdU) in mouse skin lesions and found that the number of BrdU-positive cells and microvessel density in skin lesions were significantly higher in Slit2-Tg mice than in wild-type mice. Histological staining of PAS and type IV collagen and the colocalization of Slit2 and type IV collagen demonstrated varying degrees of loss of the basement membrane in the skin lesions from Slit2-Tg mice that were at the stage of carcinoma in situ. However, the basement membrane was well defined in the wild-type mice. In addition, MMP2, but not MMP9, was upregulated in the skin tissue of Slit2-Tg mice. Interruption of Slit2-Robo1 signaling by the antibody R5 significantly repressed the invasive capability of the squamous cell carcinoma cell line A431. Taken together, our findings reveal that Slit2 promotes DMBA/TPA-induced skin tumorigenesis by increasing cell proliferation, microvessel density, and invasive behavior of cutaneous squamous cell carcinoma, along with loss of basement membrane, by upregulation of MMP2 expression.

The associations between serum VEGF, bFGF and endoglin levels with microvessel density and expression of proangiogenic factors in malignant and benign ovarian tumors.

PubMed

Szubert, Sebastian; Moszynski, Rafal; Michalak, Slawomir; Nowicki, Michal; Sajdak, Stefan; Szpurek, Dariusz

2016-09-01

To investigate whether serum levels of VEGF, bFGF and endoglin correlate with tumor VEGF and bFGF expression or microvessel density (MVD) in ovarian cancer. Forty five patients with epithelial ovarian cancers (EOCs) and 38 patients with benign ovarian tumors (BOTs) were included into the study. Serum levels of VEGF, bFGF and endoglin were assessed using ELISA. The expression of VEGF and bFGF in tumor samples were evaluated using ELISA of supernatants obtained from tumor homogenization. MVD was analyzed using immunohistochemistry with antibodies against CD31, CD34 and CD105. Serum VEGF levels were significantly higher in EOCs than in BOTs (436.6pg/ml [19.67-2860] vs 295.5pg/ml [123-539], P=0.025). Serum endoglin levels were lowered in the group EOCs when compared to BOTs (33,720g/ml [12,220-73,940] vs 42,390pg/ml [19,380-56,910], P=0.015). There were no differences in bFGF levels between studied groups. EOCs have significantly higher CD105 MVD (25 vessels/mm2 [0-57] vs 6 vessels/mm2 [0-70], P<0.001) and tumor VEGF (405.9pg/mg protein [0-3000] vs 2.225 [0-634.7], P<0.001) expression than BOTs, while, bFGF expression was higher in BOTs than in EOCs (2076pg/mg protein [668.1-8718] vs 847.3pg/mg protein [188.9-8333], P=0.003). In patients with EOCs we have observed negative correlation between serum VEGF concentration and its tissue expression (r Spearman=-0.571, P=0.0261), and serum VEGF concentration correlated positively with CD34-MVD (r Spearman=0.545, P=0.0289). In a multiple regression analysis we have observed only the negative correlation between serum VEGF and CD105-MVD (r=-0.5288, P=0.0427). Serum VEGF is a useful marker for prediction of ovarian cancer MVD and tumor VEGF expression. Copyright © 2016 Elsevier Inc. All rights reserved.

The contribution of CXCL12-expressing radial glia cells to neuro-vascular patterning during human cerebral cortex development

PubMed Central

Errede, Mariella; Girolamo, Francesco; Rizzi, Marco; Bertossi, Mirella; Roncali, Luisa; Virgintino, Daniela

2014-01-01

This study was conducted on human developing brain by laser confocal and transmission electron microscopy (TEM) to make a detailed analysis of important features of blood-brain barrier (BBB) microvessels and possible control mechanisms of vessel growth and differentiation during cerebral cortex vascularization. The BBB status of cortex microvessels was examined at a defined stage of cortex development, at the end of neuroblast waves of migration, and before cortex lamination, with BBB-endothelial cell markers, namely tight junction (TJ) proteins (occludin and claudin-5) and influx and efflux transporters (Glut-1 and P-glycoprotein), the latter supporting evidence for functional effectiveness of the fetal BBB. According to the well-known roles of astroglia cells on microvessel growth and differentiation, the early composition of astroglia/endothelial cell relationships was analyzed by detecting the appropriate astroglia, endothelial, and pericyte markers. GFAP, chemokine CXCL12, and connexin 43 (Cx43) were utilized as markers of radial glia cells, CD105 (endoglin) as a marker of angiogenically activated endothelial cells (ECs), and proteoglycan NG2 as a marker of immature pericytes. Immunolabeling for CXCL12 showed the highest level of the ligand in radial glial (RG) fibers in contact with the growing cortex microvessels. These specialized contacts, recognizable on both perforating radial vessels and growing collaterals, appeared as CXCL12-reactive en passant, symmetrical and asymmetrical, vessel-specific RG fiber swellings. At the highest confocal resolution, these RG varicosities showed a CXCL12-reactive dot-like content whose microvesicular nature was confirmed by ultrastructural observations. A further analysis of RG varicosities reveals colocalization of CXCL12 with Cx43, which is possibly implicated in vessel-specific chemokine signaling. PMID:25360079

Reproducibility of Retinal Microvascular Traits Decoded by the Singapore I Vessel Assessment Software Across the Human Age Range.

PubMed

Huang, Qi-Fang; Wei, Fang-Fei; Zhang, Zhen-Yu; Raaijmakers, Anke; Asayama, Kei; Thijs, Lutgarde; Yang, Wen-Yi; Mujaj, Blerim; Allegaert, Karel; Verhamme, Peter; Struijker-Boudier, Harry A J; Li, Yan; Staessen, Jan A

2018-03-10

Retinal microvascular traits predict adverse health outcomes. The Singapore I Vessel Assessment (SIVA) software improved automated postprocessing of retinal photographs. In addition to microvessel caliber, it generates measures of arteriolar and venular geometry. Few studies addressed the reproducibility of SIVA measurements across a wide age range. In the current study, 2 blinded graders read images obtained by nonmydriatic retinal photography twice in 20 11-year-old children, born prematurely (n = 10) or at term (n = 10) and in 60 adults (age range, 18.9-86.1 years). Former preterm compared with term children had lower microvessel diameter and disorganized vessel geometry with no differences in intraobserver and interobserver variability. Among adults, microvessel caliber decreased with age and blood pressure and arteriolar geometry was inversely correlated with female sex and age. Intraobserver differences estimated by the Bland-Altman method did not reach significance for any measurement. Across measurements, median reproducibility (RM) expressed as percent of the average trait value was 8.8% in children (median intraclass correlation coefficient [ICC], 0.94) and 8.0% (0.97) in adults. Likewise, interobserver differences did not reach significance with RM (ICC) of 10.6% (0.85) in children and 10.4% (0.93) in adults. Reproducibility was best for microvessel caliber (intraobserver/interobserver RM, 4.7%/6.0%; ICC, 0.98/0.96), worst for venular geometry (17.0%/18.8%; 0.93/0.84), and intermediate for arteriolar geometry (10.9%/14.9%; 0.95/0.86). SIVA produces repeatable measures of the retinal microvasculature in former preterm and term children and in adults, thereby proving its usability from childhood to old age.

IDH1 mutation is associated with lower expression of VEGF but not microvessel formation in glioblastoma multiforme

PubMed Central

Polívka, Jiří; Pešta, Martin; Pitule, Pavel; Hes, Ondřej; Holubec, Luboš; Polívka, Jiří; Kubíková, Tereza; Tonar, Zbyněk

2018-01-01

Introduction Glioblastoma multiforme (GBM) represents the most malignant primary brain tumor characterized by pathological vascularization. Mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) were observed in GBM. We aimed to assess the intra-tumor hypoxia, angiogenesis and microvessel formation in GBM and to find their associations with IDH1 mutation status and patients prognosis. Methods 52 patients with a diagnosis of GBM were included into the study. IDH1 R132H mutation was assessed by RT-PCR from FFPE tumor samples obtained during surgery. The expression of markers of hypoxia (HIF2α), angiogenesis (VEGF), tumor microvascularity (CD31, CD34, vWF, CD105), and proliferation (Ki-67) were assessed immunohistochemically (IHC). IDH1 mutation and IHC markers were correlated with the patient survival. Results 20 from 52 GBM tumor samples comprised IDH1 R132H mutation (38.5%). The majority of mutated tumors were classified as secondary glioblastomas (89.9%). Patients with IDH1 mutated tumors experienced better progression-free survival (P = 0.037) as well as overall survival (P = 0.035) compared with wild type tumors. The significantly lower expression of VEGF was observed in GBM with IDH1 mutation than in wild type tumors (P = 0.01). No such association was found for microvascular markers. The increased expression of newly-formed microvessels (ratio CD105/CD31) in tumor samples was associated with worse patient’s progression-free survival (P = 0.026). Summary No increase in HIF/VEGF-mediated angiogenesis was observed in IDH1-mutated GBM compared with IDH1 wild type tumors. The histological assessment of the portion of newly-formed microvessels in tumor tissue can be used for the prediction of GBM patient’s prognosis. PMID:29662659

42 CFR 456.612 - Copies of reports.

Code of Federal Regulations, 2011 CFR

2011-10-01

... function, including, if inspection reports concern IMD's, the appropriate State mental health authorities. ... 42 Public Health 4 2011-10-01 2011-10-01 false Copies of reports. 456.612 Section 456.612 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED...

42 CFR 456.612 - Copies of reports.

Code of Federal Regulations, 2012 CFR

2012-10-01

... function, including, if inspection reports concern IMD's, the appropriate State mental health authorities. ... 42 Public Health 4 2012-10-01 2012-10-01 false Copies of reports. 456.612 Section 456.612 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED...

42 CFR 456.612 - Copies of reports.

Code of Federal Regulations, 2010 CFR

2010-10-01

... function, including, if inspection reports concern IMD's, the appropriate State mental health authorities. ... 42 Public Health 4 2010-10-01 2010-10-01 false Copies of reports. 456.612 Section 456.612 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED...

42 CFR 456.612 - Copies of reports.

Code of Federal Regulations, 2014 CFR

2014-10-01

... function, including, if inspection reports concern IMD's, the appropriate State mental health authorities. ... 42 Public Health 4 2014-10-01 2014-10-01 false Copies of reports. 456.612 Section 456.612 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED...

42 CFR 456.612 - Copies of reports.

Code of Federal Regulations, 2013 CFR

2013-10-01

... function, including, if inspection reports concern IMD's, the appropriate State mental health authorities. ... 42 Public Health 4 2013-10-01 2013-10-01 false Copies of reports. 456.612 Section 456.612 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED...

Splenic cyst and its management in a 21-month-old boy: a rare complication of invasive meningococcal disease.

PubMed

Pratt, Jeremy John; Connell, Tom G; Bekhit, Elhamy; Crawford, Nigel W

2018-05-04

Splenic complications of invasive meningococcal disease (IMD) are well recognised, though cyst formation is rare, particularly in paediatric populations. The best approach to their management is not yet established. This case outlines the management of a splenic cyst in a 21-month-old boy following severe IMD. The case took place in the context of an acute emergence of serogroup W prompting significant media attention and subsequent change in vaccination practice at a jurisdictional level in Australia. The patient was critically unwell early in the illness, then later a collection in the left upper quadrant was detected, shown on ultrasound to be a 11.6×7.7 cm splenic cyst. In this case, the cyst was managed by ultrasound-guided drainage tube insertion. The residual collection was small and stable on subsequent imaging. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

[Clinical application of mass spectrometry in the pediatric field: current topics].

PubMed

Yamaguchi, Seiji

2013-09-01

Mass spectrometry, including tandem mass spectrometry (MS/MS) and gas chromatography-mass spectrometry (GC/MS), is becoming prominent in the diagnosis of metabolic disorders in the pediatric field. It enables biochemical diagnosis of metabolic disorders from the metabolic profiles obtained by MS/MS and/or GC/MS. In neonatal mass screening for inherited metabolic disease (IMD) using MS/MS, amino acids and acylcarnitines on dried blood spots are analyzed. The target diseases include amino acidemia, urea cycle disorder, organic acidemia, and fatty acid oxidation disorder. In the MS/MS screening, organic acid analysis using GC/MS is required for differential and/or definite diagnosis of the IMDs. GC/MS data processing, however, is difficult, and metabolic diagnosis often requires the necessary skills and expertize. We developed an automated system of GC/MS data processing and autodiagnosis, and the biochemical diagnosis using GC/MS became markedly easier and user-friendly. Mass spectrometric techniques will expand from research laboratories to clinical laboratories in the near future.

Recent Progress on Piezoelectric and Triboelectric Energy Harvesters in Biomedical Systems

PubMed Central

Zheng, Qiang; Shi, Bojing; Wang, Zhong Lin

2017-01-01

Implantable medical devices (IMDs) have become indispensable medical tools for improving the quality of life and prolonging the patient's lifespan. The minimization and extension of lifetime are main challenges for the development of IMDs. Current innovative research on this topic is focused on internal charging using the energy generated by the physiological environment or natural body activity. To harvest biomechanical energy efficiently, piezoelectric and triboelectric energy harvesters with sophisticated structural and material design have been developed. Energy from body movement, muscle contraction/relaxation, cardiac/lung motions, and blood circulation is captured and used for powering medical devices. Other recent progress in this field includes using PENGs and TENGs for our cognition of the biological processes by biological pressure/strain sensing, or direct intervention of them for some special self‐powered treatments. Future opportunities lie in the fabrication of intelligent, flexible, stretchable, and/or fully biodegradable self‐powered medical systems for monitoring biological signals and treatment of various diseases in vitro and in vivo. PMID:28725529

Two-dimensional distribution of carbon nanotubes in copper flake powders.

PubMed

Tan, Zhanqiu; Li, Zhiqiang; Fan, Genlian; Li, Wenhuan; Liu, Qinglei; Zhang, Wang; Zhang, Di

2011-06-03

We report an approach of flake powder metallurgy to the uniform, two-dimensional (2D) distribution of carbon nanotubes (CNTs) in Cu flake powders. It consists of the preparation of Cu flakes by ball milling in an imidazoline derivative (IMD) aqueous solution, surface modification of Cu flakes with polyvinyl alcohol (PVA) hydrosol and adsorption of CNTs from a CNT aqueous suspension. During ball milling, a hydrophobic monolayer of IMD is adsorbed on the surface of the Cu flakes, on top of which a hydrophilic PVA film is adsorbed subsequently. This PVA film could further interact with the carboxyl-group functionalized CNTs and act to lock the CNTs onto the surfaces of the Cu flakes. The CNT volume fraction is controlled easily by adjusting the concentration/volume of CNT aqueous suspension and Cu flake thickness. The as-prepared CNT/Cu composite flakes will serve as suitable building blocks for the self-assembly of CNT/Cu laminated composites that enable the full potential of 2D distributed CNTs to achieve high thermal conductivity.

[Polyvalent meningococcal vaccines: within or outside our agenda?].

PubMed

Abad, R; Vázquez, J A

2014-11-01

The development of tetravalent vaccines against Invasive Meningococcal Disease (IMD) has been driven mainly due to the increase of the prevalence and geographic expansion of several serogroups considered unusual, but also because of the need for vaccines that offer broad spectrum protection in a devastating disease such as IMD. These changes in serogroups considered usual (B and C) have been detected for both serogroup Y and W, which has led to the multivalent vaccines being used by a number of countries with different strategies that will be discussed in the article. Epidemiological data in Spain, currently do not justify its use in immunization schedules, but there is a potential risk for the introduction of virulent clones of those uncommon serogroups (Y and W), and this would lead us to open a discussion of their potential use, particularly in the adolescent/pre-teen population as a target group for intervention. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

Microbial fuel cell as power supply for implantable medical devices: a novel configuration design for simulating colonic environment.

PubMed

Dong, Kun; Jia, Boyang; Yu, Chaoling; Dong, Wenbo; Du, Fangzhou; Liu, Hong

2013-03-15

This study focused on providing power for implantable medical devices (IMDs) using a microbial fuel cell (MFC) implanted in human transverse colon. Considering the condition of colonic environment, a continuous-flow single-chamber MFC without membrane was set up. The performance of the MFC was investigated. The power output of 1.6 mW under the steady state was not rich enough for some high energy-consuming IMDs. Moreover, the parameters of the simulated colonic environment, such as pH and ORP value, varied along with the time. Hence, a new MFC configuration was developed. In this novel model, pH transducers were placed in cathodic and anodic areas, so as to regulate the reactor operation timely via external intervention. And two ORP transducers were inserted next to the pH transducers, for monitoring and adjusting the MFC operation efficiently. Besides, colonic haustra were designed in order to increase the difference between cathodic and anodic areas. Copyright © 2012 Elsevier B.V. All rights reserved.

Using hybrid implicit Monte Carlo diffusion to simulate gray radiation hydrodynamics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cleveland, Mathew A., E-mail: cleveland7@llnl.gov; Gentile, Nick

This work describes how to couple a hybrid Implicit Monte Carlo Diffusion (HIMCD) method with a Lagrangian hydrodynamics code to evaluate the coupled radiation hydrodynamics equations. This HIMCD method dynamically applies Implicit Monte Carlo Diffusion (IMD) [1] to regions of a problem that are opaque and diffusive while applying standard Implicit Monte Carlo (IMC) [2] to regions where the diffusion approximation is invalid. We show that this method significantly improves the computational efficiency as compared to a standard IMC/Hydrodynamics solver, when optically thick diffusive material is present, while maintaining accuracy. Two test cases are used to demonstrate the accuracy andmore » performance of HIMCD as compared to IMC and IMD. The first is the Lowrie semi-analytic diffusive shock [3]. The second is a simple test case where the source radiation streams through optically thin material and heats a thick diffusive region of material causing it to rapidly expand. We found that HIMCD proves to be accurate, robust, and computationally efficient for these test problems.« less

Characterization of atrial natriuretic peptide receptors in brain microvessel endothelial cells

NASA Technical Reports Server (NTRS)

Whitson, Peggy A.; Huls, M. H.; Sams, Clarence F.

1989-01-01

In view of the suggestions by Chabrier et al. (1987) and Steardo and Nathanson (1987) that atrial natriuretic peptide (ANP) may play a role in the fluid homeostasis of the brain, the ANP receptors in primary cultures of bovine brain microvessel endothelian cells were quantitated and characterized. Results of partition binding studies and the effect of cGMP additions indicated the presence of at least two types of ANP receptors, with the majority of the receptors being the nonguanylate cyclase coupled receptors. The presence of at least two ANP receptor types suggests an active role for ANP in regulating brain endothelial cell function.

[Oxygen diffusion through the venule walls in the rat cerebral cortex during breathing with pure oxygen].

PubMed

Vovenko, E P; Sokolova, I B; Loshchagin, O V

2002-03-01

Using oxygen microelectrodes, distribution of oxygen tension (pO2) has been studied in venules of the rat brain cortex at normobaric hyperoxia (spontaneous breathing with pure oxygen). It has been shown that inhalation of oxygen results in sharp increase of pO2 in majority of the venules under study. The pO2 distribution along the length of venous microvessels of 7-280 microns in diameter is best approximated by equation: pO2 = 76.44 e-0.0008D, n = 407. The pO2 distribution was characterised by extremely high pO2 values (180-240 mm Hg) in some minute venules. Heterogeneity of pO2 distribution in venous microvessels at hyperoxia was shown to be significantly increased. Profiles of pO2 between neighbouring arterioles and venules were for the first time measured. The data clearly evidenced that O2 diffusional shunting took place between cortical arterioles and venules, provided they were distanced from each other for not over 80-100 microns. Distribution of pO2 in venules has been shown to be dependent on the blood flow in the brain cortical microvessels.

Lymphangiogenesis assessed using three methods is related to tumour grade, breast cancer subtype and expression of basal marker.

PubMed

Niemiec, Joanna; Adamczyk, Agnieszka; Ambicka, Aleksandra; Mucha-Małecka, Anna; Wysocki, Wojciech; Mituś, Jerzy; Ryś, Janusz

2012-11-01

Lymphangiogenesis is a potential indicator of cancer patients' survival. However, there is no standardisation of methodologies applied to the assessment of lymphatic vessel density. In 156 invasive ductal breast cancers (T  1/N+/M0), lymphatic and blood vessels were visualised using podoplanin and CD34, respectively. Based on these markers expression, four parameters were assessed: (i) distribution of podoplanin-stained vessels (DPV) - the percentage of fields with at least one lymphatic vessel (a simple method proposed by us), (ii) lymphatic vessel density (LVD), (iii) LVD to microvessel density ratio (LVD/MVD) and (iv) the expression of podoplanin in cancer-associated fibroblasts. Next, we estimated relations between the above-mentioned parameters and: (i) breast cancer subtype, (ii) tumour grade, and (iii) basal markers expression. We found that intensive lymphangiogenesis, assessed using all studied methods, is positively related to high tumour grade, triple negative or HER2 subtype and expression of basal markers. Whereas, the absence of podoplanin expression in fibroblasts of cancer stroma is related to luminal A subtype, low tumour grade or lack of basal markers expression. Distribution of podoplanin-stained vessels, assessed by a simple method proposed by us (indicating the percentage of fields with at least one lymphatic vessel), might be used instead of the "hot-spot" method.

The transcription factor relish controls anaplasma marginale infection in the bovine tick rhipicephalus microplus

USDA-ARS?s Scientific Manuscript database

Rhipicephalus microplus is an important biological vector of Anaplasma marginale, the etiological agent of bovine anaplasmosis. The knowledge of tick immune responses to control bacterial infections remains limited. In this study, we demonstrate that transcription factor Relish from the Imd signalin...

Vitamin D binding protein-macrophage activating factor (DBP-maf) inhibits angiogenesis and tumor growth in mice.

PubMed

Kisker, Oliver; Onizuka, Shinya; Becker, Christian M; Fannon, Michael; Flynn, Evelyn; D'Amato, Robert; Zetter, Bruce; Folkman, Judah; Ray, Rahul; Swamy, Narasimha; Pirie-Shepherd, Steven

2003-01-01

We have isolated a selectively deglycosylated form of vitamin D binding protein (DBP-maf) generated from systemically available DBP by a human pancreatic cancer cell line. DBP-maf is antiproliferative for endothelial cells and antiangiogenic in the chorioallantoic membrane assay. DBP-maf administered daily was able to potently inhibit the growth of human pancreatic cancer in immune compromised mice (T/C=0.09). At higher doses, DBP-maf caused tumor regression. Histological examination revealed that treated tumors had a higher number of infiltrating macrophages as well as reduced microvessel density, and increased levels of apoptosis relative to untreated tumors. Taken together, these data suggest that DBP-maf is an antiangiogenic molecule that can act directly on endothelium as well as stimulate macrophages to attack both the endothelial and tumor cell compartment of a growing malignancy.

Angiogenesis Markers in Gynecological Tumors and Patents for Anti-Angiogenic Approach: Review.

PubMed

Abdalla, Douglas R; Simoens, Cindy; Bogers, John-Paul; Murta, Eddie F C; Michelin, Marcia A

2015-01-01

The formation of a tumor-associated vascular network is an important step in understanding the stages of tumor progression. This review aims to highlight the main markers of induction, proliferation and inhibition of angiogenesis, as well as the quantification of microvessel density, correlated with preclinical and clinical research in gynecologic cancers and also discussed related patents. Studies show that in the most advanced cases of gynecological cancers, biomarkers such as VEGF (Vascular Endothelial Growth Factor), MMP (Matrix Metalloproteinase), CD105 (Endoglin), TIMP (tissue inhibitors of metalloproteinases) and VASH (Vasohibin) are more expressed compared to healthy individuals. Continuous evaluation of these biomarkers in cancer cases could serve in the future as a basis for development of new therapeutic approaches, leading to a good response to cancer treatment, and thus increase survival of cancer patients.

Contrast-Enhanced Sonography Depicts Spontaneous Ovarian Cancer at Early Stages in a Preclinical Animal Model

PubMed Central

Barua, Animesh; Bitterman, Pincas; Bahr, Janice M.; Basu, Sanjib; Sheiner, Eyal; Bradaric, Michael J.; Hales, Dale B.; Luborsky, Judith L.; Abramowicz, Jacques S.

2011-01-01

Objective Our goal was to examine the feasibility of using laying hens, a preclinical model of human spontaneous ovarian cancer, in determining the kinetics of an ultrasound contrast agent indicative of ovarian tumor-associated neoangiogenesis in early-stage ovarian cancer. Methods Three-year-old White Leghorn laying hens with decreased ovarian function were scanned before and after intravenous injection of a human serum albumin–perflutren contrast agent at a dose of 5 µL/kg body weight. Gray scale morphologic characteristics, Doppler indices, the arrival time, peak intensity, and wash-out of the contrast agent were recorded and archived on still images and video clips. Hens were euthanized thereafter; sonographic predictions were compared at gross examination; and ovarian tissues were collected. Archived clips were analyzed to determine contrast parameters and Doppler intensities of vessels. A time-intensity curve per hen was drawn, and the area under the curve was derived. Tumor types and the density of ovarian microvessels were determined by histologic examination and immunohistochemistry and compared to sonographic predictions. Results The contrast agent significantly (P < .05) enhanced the visualization of microvessels, which was confirmed by immunohistochemistry. Contrast parameters, including the time of wash-out and area under the curve, were significantly different (P < .05) between ovaries of normal hens and hens with ovarian cancer and correctly detected cancer at earlier stages than the time of peak intensity. Conclusions The laying hen may be a useful animal model for determining ovarian tumor-associated vascular kinetics diagnostic of early-stage ovarian cancer using a contrast agent. This model may also be useful for testing the efficacy of different contrast agents in a preclinical setting. PMID:21357555

Luteolin Inhibits Human Prostate Tumor Growth by Suppressing Vascular Endothelial Growth Factor Receptor 2-Mediated Angiogenesis

PubMed Central

Pratheeshkumar, Poyil; Son, Young-Ok; Budhraja, Amit; Wang, Xin; Ding, Songze; Wang, Lei; Hitron, Andrew; Lee, Jeong-Chae; Kim, Donghern; Divya, Sasidharan Padmaja; Chen, Gang; Zhang, Zhuo; Luo, Jia; Shi, Xianglin

2012-01-01

Angiogenesis, the formation of new blood vessels from pre-existing vascular beds, is essential for tumor growth, invasion, and metastasis. Luteolin is a common dietary flavonoid found in fruits and vegetables. We studied the antiangiogenic activity of luteolin using in vitro, ex vivo, and in vivo models. In vitro studies using rat aortic ring assay showed that luteolin at non-toxic concentrations significantly inhibited microvessel sprouting and proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Luteolin also inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM) and matrigel plug assay. Gelatin zymographic analysis demonstrated the inhibitory effect of luteolin on the activation of matrix metalloproteinases MMP-2 and MMP-9. Western blot analysis showed that luteolin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT, ERK, mTOR, P70S6K, MMP-2, and MMP-9 in HUVECs. Proinflammatory cytokines such as IL-1β, IL-6, IL-8, and TNF-α level were significantly reduced by the treatment of luteolin in PC-3 cells. Luteolin (10 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that luteolin inhibited tumorigenesis by targeting angiogenesis. CD31 and CD34 immunohistochemical staining further revealed that the microvessel density could be remarkably suppressed by luteolin. Moreover, luteolin reduced cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, ERK, mTOR, P70S6K, MMP-2, and MMP-9 expressions. Taken together, our findings demonstrate that luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis. PMID:23300633

Combined Gene Therapy Using AdsVEGFR2 and AdsTie2 With Chemotherapy Reduces the Growth of Human Ovarian Cancer and Formation of Ascites in Mice.

PubMed

Tuppurainen, Laura; Sallinen, Hanna; Karvonen, Anni; Valkonen, Elina; Laakso, Hanne; Liimatainen, Timo; Hytönen, Elisa; Hämäläinen, Kirsi; Kosma, Veli-Matti; Anttila, Maarit; Ylä-Herttuala, Seppo

2017-06-01

Ovarian cancer is highly dependent on tumor microvessels and angiogenesis regulated by vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) and angiopoietins (Ang) and their Tie receptors. We studied the efficacy of adenoviral (Ad) gene therapy with soluble VEGFR2 and Tie2 combined with paclitaxel and carboplatin for the treatment of ovarian cancer. An intraperitoneal human ovarian cancer xenograft model in nude mice (n = 44) was used in this study. Gene therapy was given intravenously when the presence of sizable tumors was confirmed in magnetic resonance imaging. The study groups were as follows: AdCMV as a control (group I), AdCMV with chemotherapy (group II), AdsVEGFR2 and AdsTie2 (group III), and AdsVEGFR2 and AdsTie2 with chemotherapy (group IV). Antitumor effectiveness was assessed by overall tumor growth, ascites, immunohistochemistry, microvessel density, and sequential magnetic resonance imaging analyses. AdsVEGFR2 and AdsTie2 gene therapy (group III) significantly reduced tumor weights as compared with group II (P = 0.007). Accumulation of ascites was significantly reduced when the mice were treated with AdsVEGFR2 and AdsTie2 gene therapy or with combined gene therapy and chemotherapy as compared with controls (P = 0.029 and P = 0.010, respectively). Vascular endothelial growth factor and Ang2 levels in ascites fluid were elevated after the gene therapy. Combined inhibition of VEGF/VEGFR2 and Ang/Tie2 pathways provided efficient therapy for ovarian cancer in mice. In addition, antiangiogenic gene therapy has potential as a treatment for the accumulation of ascites.

Life and death in the microcirculation: a role for angiotensin II

NASA Technical Reports Server (NTRS)

Greene, A. S.; Cowley, A. W. (Principal Investigator)

1998-01-01

OBJECTIVE: Angiotensin II (ANGII) plays a critical role in the maintenance of the microcirculation and in the anatomical loss of microvessels (rarefaction) that occurs in low renin forms of hypertension and in animals fed a high-salt diet. Elevations in sodium intake can trigger a series of hemodynamic and hormonal responses culminating in a substantial rarefaction of small arterioles and capillaries in both normal and reduced renal mass hypertensive rats. METHODS: Immunohistochemistry, Northern blot, and reverse transcription-polymerase chain reaction (RT-PCR) analysis of microdissected blood vessels were used to localize ANGII receptors in the microcirculation. Chronic infusion of ANGII and other physiologic and pharmacologic manipulations of the reninangiotensin system in rats was combined with morphologic and mathematical analysis of the network architecture. RESULTS: We have shown that rarefaction of the microcirculation can cause an increase in total peripheral resistance, reduced tissue perfusion, decreased oxygen delivery, and impaired organ function. Although the mechanisms by which this occurs are not well understood, a number of key observations point to a role for the renin-angiotensin system in this effect. First, ANGII infused systemically at subpressor levels, or locally into the skeletal muscle interstitium, can induce significant microvessel growth. Second, localization of ANGII receptor proteins by immunohistochemistry and Western blotting and RNA localization by RT-PCR confirm the presence of AT1 receptors, which are growth-stimulatory, and AT2 receptors, which are growth-inhibitory in the microcirculation. Third, maintenance of ANGII at normal levels during periods of hypertension or high-salt diet completely eliminates rarefaction. CONCLUSIONS: Taken together, these results support the hypothesis that ANGII acting through AT1- and AT2-receptor mechanisms modulate vessel density during high-salt diet and hypertension.

ABT-510, a modified type 1 repeat peptide of thrombospondin, inhibits malignant glioma growth in vivo by inhibiting angiogenesis.

PubMed

Anderson, Joshua C; Grammer, J Robert; Wang, Wenquan; Nabors, L Burton; Henkin, Jack; Stewart, Jerry E; Gladson, Candece L

2007-03-01

Anti-angiogenic therapies would be particularly beneficial in the treatment of malignant gliomas. Peptides derived from the second type 1 repeat (TSR) of thrombospondin-1 (TSP-1) have been shown to inhibit angiogenesis in non-glioma tumor models and a modified TSR peptide, ABT-510, has now entered into Phase II clinical trials of its efficacy in non-glioma tumors. As microvascular endothelial cells (MvEC) exhibit heterogeneity, we evaluated the ability of the modified TSR peptide (NAcSarGlyValDallolleThrNvalleArgProNHE, ABT-510) to inhibit malignant glioma growth in vivo and to induce apoptosis of brain microvessel endothelial cells (MvEC) propagated in vitro. We found that daily administration of ABT-510 until euthanasia (days 7 to 19), significantly inhibited the growth of human malignant astrocytoma tumors established in the brain of athymic nude mice. The microvessel density was significantly lower and the number of apoptotic MvEC was significantly higher (3-fold) in the tumors of the ABT-510-treated animals. Similar results were found using a model in which the established tumor is an intracerebral malignant glioma propagated in a syngeneic mouse model. ABT-510 treatment of primary human brain MvEC propagated as a monolayer resulted in induction of apoptosis in a dose- and time-dependent manner through a caspase-8-dependent mechanism. It also inhibited tubular morphogenesis of MvEC propagated in collagen gels in a dose- and caspase-8 dependent manner through a mechanism that requires the TSP-1 receptor (CD36) on the MvEC. These findings indicate that ABT-510 should be evaluated as a therapeutic option for patients with malignant glioma.

Effects and mechanism of recombinant human erythropoietin on the growth of human breast cancer MDA-MB-231 cells in nude mice.

PubMed

Jin, Wen; Lin, Zhiwu; Zhang, Xiaorong; Kong, Lingying; Yang, Li

2015-08-01

This study aimed to explore the effects of recombinant human erythropoietin (rhEPO) on the growth of human breast cancer MDA-MB-231 cells in nude mice, and investigate its functions in regulating tumor growth, angiogenesis and apoptosis. A tumor-bearing nude mice model was established by subcutaneous injection of human breast cancer MDA-MB-231 cells. Two weeks later, the mice were randomly divided into four groups (n=6 for each group): negative control group, rhEPO group, EPO antibody group and EPO+EPO antibody group. Drugs were administered to the corresponding mice once every 3 days for five times. The size and weight of tumors were measured after the mice were sacrificed by cervical dislocation. The expression levels of EPO/EPOR, TNF-α, IL-10, and Bcl-2 in the tumor tissues were determined using RT-PCR and Western blot. The microvessel density (MVD) and expression of VEGF in the tumors were detected using immunohistochemistry. TUNEL assay was used to determine apoptosis in tumors. Results show that rhEPO significantly promoted the growth of MDA-MB-231 cells in nude mice (P<0.05). Compared with the negative control group, the expression levels of EPO, EPOR, TNF-α, IL-10, and VEGF, as well as the MVD values, were significantly elevated in the rhEPO group. However, the apoptotic index was significantly reduced (P<0.05). The ability of rhEPO to promote tumor growth may be associated with its functions in promoting microvessel formation and inhibiting tumor cell apoptosis. Copyright © 2015 Elsevier GmbH. All rights reserved.

Pannus inflammation in sacroiliitis following immune pathological injury and radiological structural damage: a study of 193 patients with spondyloarthritis.

PubMed

Wang, Dan Min; Lin, Ling; Peng, Jian Hua; Gong, Yao; Hou, Zhi Duo; Chen, Su Biao; Xiao, Zheng Yu

2018-06-08

The pathogenesis of sacroiliitis is unclear; therefore, we aimed to systematically study the immunopathology of sacroiliitis in patients with axial spondyloarthritis (axSpA), and explore the relationship between pannus formation, inflammation, and the structural damage caused by sacroiliitis. Fine needle aspiration biopsy of the sacroiliac joint (SIJ) was performed in 193 patients with axSpA. Clinical, laboratory, and imaging data were collected at baseline and during the follow up. Immunohistochemistry analysis was performed to detect CD34+ microvessels, CD68+ osteoclasts/macrophages, vascular endothelial growth factor (VEGF), metalloproteinase-3 (MMP-3), tumor necrosis factor-α (TNF-α), and caspase-3. Autopsy subjects were used as controls. In early sacroiliitis (grade 0-1) all pathological features could be observed, with the most common being subchondral pannus formation. Among the 193 patients, 98 were followed up for 1-13 years (mean 3.6 years); 63.3% had radiological progression at the endpoint. Multiple regression analysis showed that cartilage pannus invasion (OR 2.99, P = 0.010) and endochondral ossification (OR 3.97, P = 0.049) at baseline were risk factors for radiological structural damage. Compared to SIJ controls, the subchondral microvessel density, number of CD68+ multinuclear osteoclasts, and the levels of VEGF, caspase-3, MMP-3, and TNF-α expressed at the interface of the bone and cartilage were significantly higher in patients with sacroiliitis. Subchondral fibrovascular tissue formation is the most important pathological feature in early sacroiliitis. The existence of cartilage pannus invasion or endochondral ossification at baseline can predict radiological structural damage during the follow up.

Anti-sphingosine-1-phosphate monoclonal antibodies inhibit angiogenesis and sub-retinal fibrosis in a murine model of laser-induced choroidal neovascularization

PubMed Central

Caballero, Sergio; Swaney, James; Moreno, Kelli; Afzal, Aqeela; Kielczewski, Jennifer; Stoller, Glenn; Cavalli, Amy; Garland, William; Hansen, Geneviève; Sabbadini, Roger; Grant, Maria B.

2013-01-01

The efficacy of novel monoclonal antibodies that neutralize the pro-angiogenic mediator, sphingosine-1-phosphate (S1P), were tested using in vitro and in vivo angiogenesis models, including choroidal neovascularization (CNV) induced by laser disruption of Bruch’s membrane. S1P receptor levels in human brain choroid plexus endothelial cells (CPEC), human lung microvascular endothelial cells, human retinal vascular endothelial cells, and circulating endothelial progenitor cells were examined by semi-quantitative PCR. The ability of murine or humanized anti-S1P monoclonal antibodies (mAbs) to inhibit S1P-mediated microvessel tube formation by CPEC on Matrigel was evaluated and capillary density in subcutaneous growth factor-loaded Matrigel plugs was determined following anti-S1P treatment. S1P promoted in vitro capillary tube formation in CPEC consistent with the presence of cognate S1P1–5 receptor expression by these cells and the S1P antibody induced a dose-dependent reduction in microvessel tube formation. In a murine model of laser-induced rupture of Bruch’s membrane, S1P was detected in posterior cups of mice receiving laser injury, but not in uninjured controls. Intravitreous injection of anti-S1P mAbs dramatically inhibited CNV formation and sub-retinal collagen deposition in all treatment groups (p < 0.05 compared to controls), thereby identifying S1P as a previously unrecognized mediator of angiogenesis and subretinal fibrosis in this model. These findings suggest that neutralizing S1P with anti-S1P mAbs may be a novel method of treating patients with exudative age-related macular degeneration by reducing angiogenesis and sub-retinal fibrosis, which are responsible for visual acuity loss in this disease. PMID:18723015

Correlation between spontaneous apoptosis and the expression of angiogenic factors in advanced gastric adenocarcinoma.

PubMed

Ikeguchi, M; Cai, J; Fukuda, K; Oka, S; Katano, K; Tsujitani, S; Maeta, M; Kaibara, N

2001-06-01

The aim of this study was to investigate whether angiogenic factors influence the occurrence of spontaneous apoptosis in advanced gastric cancer. The apoptotic indices (AIs) of 97 tumors from 97 patients with advanced gastric cancer (pT3, pN0, pM0, Stage II) were analyzed by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end labeling (TUNEL) method. Intratumoral microvessel densities (IMVDs) of tumors stained with anti-CD34 monoclonal antibody were quantified under x 200 magnification using computer-assisted image analysis. The expressions of angiogenic factors, such as vascular endothelial growth factor (VEGF), thymidine phosphorylase (dThdPase), transforming growth factor-alpha (TGF-alpha), and p53 were analyzed immunohistochemically and compared with IMVDs and AIs. The mean IMVD of the 97 tumors was 365/mm2 (range 147-990/mm2). The mean AI of tumors was 2.1% (range 0-11.3%). A significant inverse correlation between the AIs and the IMVDs was shown (p = -0.278, P = 0.0064). The mean IMVDs of tumors with high expressions of dThdPase, TGF-alpha, or p53 were significantly higher than those of tumors with low expressions of these factors. The mean AI of tumors with high expressions of dThdPase was significantly lower than that of tumors with low expressions of dThdPase (P = 0.023). However, no significant correlations were detected between AIs and the expression levels of VEGF, TGF-alpha, or p53. In gastric cancer, dThdPase may play an important role in tumor progression by increasing microvessels and by suppressing apoptosis of cancer cells.

Numerical simulation of heat transfer in blood flow altered by electroosmosis through tapered micro-vessels.

PubMed

Prakash, J; Ramesh, K; Tripathi, D; Kumar, R

2018-07-01

A numerical simulation is presented to study the heat and flow characteristics of blood flow altered by electroosmosis through the tapered micro-vessels. Blood is assumed as non-Newtonian (micropolar) nanofluids. The flow regime is considered as asymmetric diverging (tapered) microchannel for more realistic micro-vessels which is produced by choosing the peristaltic wave train on the walls to have different amplitudes and phase. The Rosseland approximation is employed to model the radiation heat transfer and temperatures of the walls are presumed constants. The mathematical formulation of the present problem is simplified under the long-wavelength, low-Reynolds number and Debye-Hückel linearization approximations. The influence of various dominant physical parameters are discussed for axial velocity, microrotation distribution, thermal temperature distribution and nanoparticle volume fraction field. However, our foremost emphasis is to determine the effects of thermal radiation and coupling number on the axial velocity and microrotation distribution beneath electroosmotic environment. This analysis places a significant observation on the thermal radiation and coupling number which plays an influential role in hearten fluid velocity. This study is encouraged by exploring the nanofluid-dynamics in peristaltic transport as symbolized by heat transport in biological flows and also in novel pharmacodynamics pumps and gastro-intestinal motility enhancement. Copyright © 2018 Elsevier Inc. All rights reserved.

Microvascular fractal dimension predicts prognosis and response to chemotherapy in glioblastoma: an automatic image analysis study.

PubMed

Chen, Cong; He, Zhi-Cheng; Shi, Yu; Zhou, Wenchao; Zhang, Xia; Xiao, Hua-Liang; Wu, Hai-Bo; Yao, Xiao-Hong; Luo, Wan-Chun; Cui, You-Hong; Bao, Shideng; Kung, Hsiang-Fu; Bian, Xiu-Wu; Ping, Yi-Fang

2018-05-15

The microvascular profile has been included in the WHO glioma grading criteria. Nevertheless, microvessels in gliomas of the same WHO grade, e.g., WHO IV glioblastoma (GBM), exhibit heterogeneous and polymorphic morphology, whose possible clinical significance remains to be determined. In this study, we employed a fractal geometry-derived parameter, microvascular fractal dimension (mvFD), to quantify microvessel complexity and developed a home-made macro in Image J software to automatically determine mvFD from the microvessel-stained immunohistochemical images of GBM. We found that mvFD effectively quantified the morphological complexity of GBM microvasculature. Furthermore, high mvFD favored the survival of GBM patients as an independent prognostic indicator and predicted a better response to chemotherapy of GBM patients. When investigating the underlying relations between mvFD and tumor growth by deploying Ki67/mvFD as an index for microvasculature-normalized tumor proliferation, we discovered an inverse correlation between mvFD and Ki67/mvFD. Furthermore, mvFD inversely correlated with the expressions of a glycolytic marker, LDHA, which indicated poor prognosis of GBM patients. Conclusively, we developed an automatic approach for mvFD measurement, and demonstrated that mvFD could predict the prognosis and response to chemotherapy of GBM patients.

Photo-mediated ultrasound therapy (PUT): a novel method of selectively treating neovascularization (Conference Presentation)

NASA Astrophysics Data System (ADS)

Zhang, Haonan; Hu, Zi Zhong; Li, Jia; Mordovanakis, Aghapi G.; Yang, Xinmai; Paulus, Yannis M.; Wang, Xueding

2017-02-01

Retinal and choroidal neovascularization play a pivotal role in the leading causes of blindness including macular degeneration and diabetic retinopathy (DR). Current therapy by focal laser photocoagulation can damage the normal surrounding cells, such as the photoreceptor inner and outer segments which are adjacent to the retinal pigment epithelium (RPE), due to the use of high laser energy and millisecond pulse duration. Therapies with pharmaceutical agents involve systemic administration of drugs, which can cause adverse effects and patients may become drug-resistant. We have developed a noninvasive photo-mediated ultrasound therapy (PUT) technique as a localized antivascular method, and applied it to remove micro blood vessels in the retina. PUT takes advantage of the high native optical contrast among biological tissues, and has the unique capability to self-target microvessels without causing unwanted damages to the surrounding tissues. This technique promotes cavitation activity in blood vessels by synergistically applying nanosecond laser pulses and ultrasound bursts. Through the interaction between cavitation and blood vessel wall, blood clots in microvessels and vasoconstriction can be induced. As a result, microvessels can be occluded. In comparison with other techniques that involves cavitation, both laser and ultrasound energy needed in PUT is significantly lower, and hence improves the safety in therapy.

Numerical investigation of oxygen transport by hemoglobin-based carriers through microvessels.

PubMed

Hyakutake, Toru; Kishimoto, Takumi

2017-12-01

The small size of hemoglobin-based oxygen carriers (HBOCs) may expand the realm of new treatment possibilities for various circulatory diseases. The parametric evaluation of HBOC performance for oxygen transport within tissue is essential for effectively characterizing its performance for each circulatory disease assessed. Thus, the overarching objective of this present study was to numerically investigate the reaction-diffusion phenomenon of oxygenated HBOCs and oxygen on tissues through microvessels. We considered dissociation rate coefficients, oxygen affinity, and diffusion coefficients due to Brownian motion as the biophysical parameters for estimating HBOC performance for oxygen transport. A two-dimensional computational domain, including vessel and tissue regions, was, therefore, accordingly assumed. It was observed that HBOC flows in a microvessel with a diameter of 25 μm and a length of 1 mm, and that the dissociated oxygen diffuses to the tissue region. The results indicated that oxyhemoglobin saturation and partial oxygen tension in a downstream region changed according to each biophysical parameter of HBOC. Moreover, the change in oxygen consumption rate in the tissue region had considerable influence on the oxyhemoglobin saturation level within the vessel. Comparison between simulation results and existing in vitro experimental data of actual HBOCs and RBC showed qualitatively good agreement. These results provide important information for the effective design of robust HBOCs in future.

Pig but not Human Interferon-γ Initiates Human Cell-Mediated Rejection of Pig Tissue in vivo

NASA Astrophysics Data System (ADS)

Sultan, Parvez; Murray, Allan G.; McNiff, Jennifer M.; Lorber, Marc I.; Askenase, Philip W.; Bothwell, Alfred L. M.; Pober, Jordan S.

1997-08-01

Split-thickness pig skin was transplanted on severe combined immunodeficient mice so that pig dermal microvessels spontaneously inosculated with mouse microvessels and functioned to perfuse the grafts. Pig endothelial cells in the healed grafts constitutively expressed class I and class II major histocompatibility complex molecules. Major histocompatibility complex molecule expression could be further increased by intradermal injection of pig interferon-γ (IFN-γ ) but not human IFN-γ or tumor necrosis factor. Grafts injected with pig IFN-γ also developed a sparse infiltrate of mouse neutrophils and eosinophils without evidence of injury. Introduction of human peripheral blood mononuclear cells into the animals by intraperitoneal inoculation resulted in sparse perivascular mononuclear cell infiltrates in the grafts confined to the pig dermis. Injection of pig skin grafts on mice that received human peripheral blood mononuclear cells with pig IFN-γ (but not human IFN-γ or heat-inactivated pig IFN-γ ) induced human CD4+ and CD8+ T cells and macrophages to more extensively infiltrate the pig skin grafts and injure pig dermal microvessels. These findings suggest that human T cell-mediated rejection of xenotransplanted pig organs may be prevented if cellular sources of pig interferon (e.g., passenger lymphocytes) are eliminated from the graft.

Engineering of functional, perfusable 3D microvascular networks on a chip.

PubMed

Kim, Sudong; Lee, Hyunjae; Chung, Minhwan; Jeon, Noo Li

2013-04-21

Generating perfusable 3D microvessels in vitro is an important goal for tissue engineering, as well as for reliable modelling of blood vessel function. To date, in vitro blood vessel models have not been able to accurately reproduce the dynamics and responses of endothelial cells to grow perfusable and functional 3D vascular networks. Here we describe a microfluidic-based platform whereby we model natural cellular programs found during normal development and angiogenesis to form perfusable networks of intact 3D microvessels as well as tumor vasculatures based on the spatially controlled co-culture of endothelial cells with stromal fibroblasts, pericytes or cancer cells. The microvessels possess the characteristic morphological and biochemical markers of in vivo blood vessels, and exhibit strong barrier function and long-term stability. An open, unobstructed microvasculature allows the delivery of nutrients, chemical compounds, biomolecules and cell suspensions, as well as flow-induced mechanical stimuli into the luminal space of the endothelium, and exhibits faithful responses to physiological shear stress as demonstrated by cytoskeleton rearrangement and increased nitric oxide synthesis. This simple and versatile platform provides a wide range of applications in vascular physiology studies as well as in developing vascularized organ-on-a-chip and human disease models for pharmaceutical screening.

Pathological significance and prognostic roles of densities of CD57+ cells, CD68+ cells, and mast cells, and their ratios in clear cell renal cell carcinoma.

PubMed

Nakanishi, Hiromi; Miyata, Yasuyoshi; Mochizuki, Yasushi; Yasuda, Takuji; Nakamura, Yuichiro; Araki, Kyohei; Sagara, Yuji; Matsuo, Tomohiro; Ohba, Kojiro; Sakai, Hideki

2018-05-19

The immune system is closely associated with malignant behavior in renal cell carcinoma (RCC). Therefore, understanding the pathological roles of immune cells in tumor stroma is essential to discuss the pathological characteristics of RCC. In this study, the clinical significance of densities of CD57+ cells, CD68+ cells, and mast cells, and their ratios were investigated in patients with clear cell RCC. The densities of CD57+, CD68+, and mast cells were evaluated by immunohistochemical techniques in 179 patients. Proliferation index (PI), apoptotic index (AI), and microvessel density (MVD) were evaluated by using anti-Ki-67, anti-cleaved caspase-3, and anti-CD31 antibodies, respectively. The density of CD57+ cell was negatively correlated with grade, pT stage, and metastasis, although densities of CD68+ cell and mast cell were positively correlated. Ratios of CD68+ cell/CD57+ cell and mast cell/CD57+ cell were significantly correlated with grade, pT stage, and metastasis. Survival analyses showed that the CD68+ cell/CD57+ cell ratio was a significant predictor for cause-specific survival by multi-variate analyses (hazard ratio=1.41, 95% confidential interval=1.03-1.93, P=.031), and was significantly correlated with PI, AI, and MVD (r=.47; P <. 001, r=-.31, P<.001, and r=.40, P<.001, respectively). In conclusion, CD57+ cell, CD68+ cell, and mast cell played important roles in malignancy in clear cell RCC. The CD68+ cell/CD57+ cell ratio was strongly correlated with pathological features and prognosis in these patients because this ratio reflected the status of cancer cell proliferation, apoptosis, and angiogenesis. Copyright © 2018. Published by Elsevier Inc.

Functional acetylcholine muscarinic receptor subtypes in human brain microcirculation: identification and cellular localization.

PubMed

Elhusseiny, A; Cohen, Z; Olivier, A; Stanimirović, D B; Hamel, E

1999-07-01

Acetylcholine is an important regulator of local cerebral blood flow. There is, however, limited information available on the possible sites of action of this neurotransmitter on brain intraparenchymal microvessels. In this study, a combination of molecular and functional approaches was used to identify which of the five muscarinic acetylcholine receptors (mAChR) are present in human brain microvessels and their intimately associated astroglial cells. Microvessel and capillary fractions isolated from human cerebral cortex were found by reverse transcriptase-polymerase chain reaction to express m2, m3, and, occasionally, m1 and m5 receptor subtypes. To localize these receptors to a specific cellular compartment of the vessel wall, cultures of human brain microvascular endothelial and smooth muscle cells were used, together with cultured human brain astrocytes. Endothelial cells invariably expressed m2 and m5 receptors, and occasionally the m1 receptor; smooth muscle cells exhibited messages for all except the m4 mAChR subtypes, whereas messages for all five muscarinic receptors were identified in astrocytes. In all three cell types studied, acetylcholine induced a pirenzepine-sensitive increase (62% to 176%, P<0.05 to 0.01) in inositol trisphosphate, suggesting functional coupling of m1, m3, or m5 mAChR to a phospholipase C signaling cascade. Similarly, coupling of m2 or m4 mAChR to adenylate cyclase inhibition in endothelial cells and astrocytes, but not in smooth muscle cells, was demonstrated by the ability of carbachol to significantly reduce (44% to 50%, P<0.05 to 0.01) the forskolin-stimulated increase in cAMP levels. This effect was reversed by the mAChR antagonist AFDX 384. The results indicate that microvessels are able to respond to neurally released acetylcholine and that mAChR, distributed in different vascular and astroglial compartments, could regulate cortical perfusion and, possibly, blood-brain barrier permeability, functions that could become jeopardized in neurodegenerative disorders such as Alzheimer's disease.

Enhancement of P2X(7)-induced pore formation and apoptosis: an early effect of diabetes on the retinal microvasculature.

PubMed

Sugiyama, Tetsuya; Kobayashi, Masato; Kawamura, Hajime; Li, Qing; Puro, Donald G; Kobayshi, Masato

2004-03-01

A sight-threatening complication of diabetes is cell death in retinal capillaries. Currently, the mechanisms responsible for this classic manifestation of diabetic retinopathy remain uncertain. The hypothesis for the current study is that diabetes increases the vulnerability of retinal microvessels to the potentially lethal consequences of having their P2X(7) purinoceptors activated. A pathophysiological role is suspected for these receptor-operated channels because, in addition to transducing retinovascular responses to extracellular adenosine triphosphate (ATP), the sustained opening of these channels can induce the formation of large transmembrane pores. In pericyte-containing retinal microvessels that were freshly isolated from nondiabetic and streptozotocin-injected rats, cells with pores were identified by the uptake of YO-PRO-1. Cell viability was assayed by trypan blue dye exclusion, and cleaved caspase-3 immunoreactivity, TUNEL positivity, and nuclear morphology were used to detect apoptotic cells. Patch-clamp recordings assessed electrophysiological parameters. Activation of P2X(7) receptors caused large pores to form and apoptosis to occur in retinal capillaries of nondiabetic and diabetic rats. Of importance to diabetes, the agonist concentration needed to open pores and trigger apoptosis decreased markedly soon after the onset of streptozotocin-induced hyperglycemia. However, despite this increased sensitivity, diabetes minimally affected the P2X(7)-induced ionic currents. Thus, rather than upregulate the number of functional P2X(7) receptor/channels, diabetes appears to facilitate the channel-to-pore transition that occurs during activation of these purinoceptors. In this way, normally nonlethal concentrations of P2X(7) ligands may trigger apoptosis in microvessels of the diabetic retina. A diabetes-induced increase in the vulnerability of retinal microvessels to the lethal effect of P2X(7) receptor activation may be a previously unrecognized mechanism by which diabetic retinopathy progresses.

Increased pulmonary vascular contraction to serotonin after cardiopulmonary bypass: role of cyclooxygenase.

PubMed

Sato, K; Li, J; Metais, C; Bianchi, C; Sellke, F

2000-05-15

Pulmonary vascular resistance is frequently elevated after cardiopulmonary bypass (CPB). We examined if altered pulmonary microvascular reactivity to serotonin (5-HT) is due to altered expression of isoforms of nitric oxide synthase (NOS) or cyclooxygenase (COX). Pigs (n = 8) were heparinized and placed on total CPB for 90 min and then perfused off CPB for 90 min. Noninstrumented pigs (n = 6) served as controls for vascular studies. Relaxation responses (% of precontraction) of microvessels (60-150 microm in diameter) were examined in vitro in a pressurized (20 mm Hg) no-flow state with video microscopic imaging. Expression of eNOS, iNOS, and inducible (COX-2) and constitutive (COX-1) cyclooxygenase was examined with Western blotting and reverse transcription polymerase chain reaction. Pulmonary vascular resistance (PVR) increased from 316 +/- 39 mm Hg x s/cm(5) at baseline to 495 +/- 53 at 60 min and 565 +/- 62 at 90 min after termination of CPB. 5-HT elicited a relaxation response (46.8 +/- 11. 8%) in precontracted control microvessels. This response was not affected by the NOS inhibitor N(G)-nitro-l-arginine. After CPB, pulmonary microvessels contracted significantly to 5-HT (-29 +/- 27%, P < 0.05 vs control). This response was partially inhibited (7 +/- 20%, P = 0.06) in the presence of the COX-2 inhibitor NS398, but was unaffected by the thromboxane synthase inhibitor U63557A (-20 +/- 19%). Expression of iNOS or COX-1 was not changed after CPB. Protein and mRNA expressions of COX-2 both increased significantly after CPB, while that of eNOS decreased by approximately 50%. PVR increased after CPB. This was associated with a hypercontractile response of isolated pulmonary microvessels to 5-HT that was in part mediated by the release of prostaglandins (but not thromboxane) and associated with increased expression of COX-2 and with decreased expression of eNOS. Copyright 2000 Academic Press.

Association of high microvessel αvβ3 and low PTEN with poor outcome in stage 3 neuroblastoma: rationale for using first in class dual PI3K/BRD4 inhibitor, SF1126

PubMed Central

Singh, Alok R.; Joshi, Shweta; Vega, Francisco M.; Guo, Pinzheng; Xu, Jingying; Groshen, Susan; Ye, Wei; Millard, Melissa; Campan, Mihaela; Morales, Guillermo; Garlich, Joseph R.; Laird, Peter W.; Seeger, Robert C.; Shimada, Hiroyuki

2017-01-01

Neuroblastoma (NB) is the most common extracranial solid tumor in children. Our previous studies showed that the angiogenic integrin αvβ3 was increased in high-risk metastatic (stage 4) NB compared with localized neuroblastomas. Herein, we show that integrin αvβ3 was expressed on 68% of microvessels in MYCN-amplified stage 3 neuroblastomas, but only on 34% (means) in MYCN-non-amplified tumors (p < 0.001; n = 54). PTEN, a tumor suppressor involved in αvβ3 signaling, was expressed in neuroblastomas either diffusely, focally or not at all (immunohistochemistry). Integrin αvβ3 was expressed on 60% of tumor microvessels when PTEN was negative or focal, as compared to 32% of microvessels in tumors with diffuse PTEN expression (p < 0.001). In a MYCN transgenic mouse model, loss of one allele of PTEN promoted tumor growth, illustrating the potential role of PTEN in neuroblastoma pathogenesis. Interestingly, we report the novel dual PI-3K/BRD4 activity of SF1126 (originally developed as an RGD-conjugated pan PI3K inhibitor). SF1126 inhibits BRD4 bromodomain binding to acetylated lysine residues with histone H3 as well as PI3K activity in the MYCN amplified neuroblastoma cell line IMR-32. Moreover, SF1126 suppressed MYCN expression and MYCN associated transcriptional activity in IMR-32 and CHLA136, resulting in overall decrease in neuroblastoma cell viability. Finally, treatment of neuroblastoma tumors with SF1126 inhibited neuroblastoma growth in vivo. These data suggest integrin αvβ3, MYCN/BRD4 and PTEN/PI3K/AKT signaling as biomarkers and hence therapeutic targets in neuroblastoma and support testing of the RGD integrin αvβ3-targeted PI-3K/BRD4 inhibitor, SF1126 as a therapeutic strategy in this specific subgroup of high risk neuroblastoma. PMID:28881723

Quantitative targeted absolute proteomic analysis of transporters, receptors and junction proteins for validation of human cerebral microvascular endothelial cell line hCMEC/D3 as a human blood-brain barrier model.

PubMed

Ohtsuki, Sumio; Ikeda, Chiemi; Uchida, Yasuo; Sakamoto, Yumi; Miller, Florence; Glacial, Fabienne; Decleves, Xavier; Scherrmann, Jean-Michel; Couraud, Pierre-Olivier; Kubo, Yoshiyuki; Tachikawa, Masanori; Terasaki, Tetsuya

2013-01-07

Human cerebral microvascular endothelial cell line hCMEC/D3 is an established model of the human blood-brain barrier (BBB). The purpose of the present study was to determine, by means of quantitative targeted absolute proteomics, the protein expression levels in hCMEC/D3 cells of multiple transporters, receptors and junction proteins for comparison with our previously reported findings in isolated human brain microvessels. Among 91 target molecules, 12 transporters, 2 receptors, 1 junction protein and 1 membrane marker were present at quantifiable levels in plasma membrane fraction of hCMEC/D3 cells. ABCA2, MDR1, MRP4, BCRP, GLUT1, 4F2hc, MCT1, ENT1, transferrin and insulin receptors and claudin-5 were detected in both hCMEC/D3 cells and human brain microvessels. After normalization based on Na(+)/K(+) ATPase expression, the differences in protein expression levels between hCMEC/D3 cells and human brain microvessels were within 4-fold for these proteins, with the exceptions of ENT1, transferrin receptor and claudin-5. ABCA8, LAT1, LRP1 and γ-GTP were below the limit of quantification in the cells, but were found in human brain microvessels. ABCA3, ABCA6, MRP1 and ATA1 were found only in hCMEC/D3 cells. Furthermore, compared with human umbilical vein endothelial cells (HUVECs) as reference nonbrain endothelial cells, MDR1 was found only in hCMEC/D3 cells, and GLUT1 expression was 15-fold higher in hCMEC/D3 cells than in HUVECs. In conclusion, this is the first study to examine the suitability and limitations of the hCMEC/D3 cell line as a BBB functional model in terms of quantitative expression levels of transporters, receptors and tight junction proteins.

75 FR 21314 - Medicaid Program; Final FY 2008, Revised Preliminary FY 2009, and Preliminary FY 2010...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-23

... Federal share) IMD and other mental health facility DSH expenditures applicable to the State's FY 1995 DSH... State's total computable DSH expenditures attributable to the FY 1995 DSH allotment for mental health... DSH expenditures (mental health facility plus inpatient hospital) applicable to the FY 1995 DSH...

Electrostatic Radio Frequency (RF) Microelectromechanical Systems (MEMS) Switches With Metal Alloy Electric Contacts

DTIC Science & Technology

2004-09-01

Serway , Raymond A. Physics for Scientists and Engineers . New York: Saunders College Publishing, 1986. 141. Sharvin, Y.V. Sov. Phys. JETP , 21 :655 (1965...III. Theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 3.1 Micro-Switch Physical Description . . . . . . . . . . . 17 3.2 MEMS...Insertion Loss . . . . . . . . . . . . . . . . . . . . . . . . 56 IMD Intermodulation Distortion . . . . . . . . . . . . . . . . 56 PVD Physical Vapor

Intra- to Multi-Decadal Temperature Variability over the Continental United States: 1896-2012

USDA-ARS?s Scientific Manuscript database

The Optimal Ranking Regime (ORR) method was used to identify intra- to multi-decadal (IMD) time windows containing significant ranking sequences in U.S. climate division temperature data. The simplicity of the ORR procedure’s output – a time series’ most significant non-overlapping periods of high o...

Optimal ranking regime analysis of intra- to multidecadal U.S. climate variability. Part I: Temperature

USDA-ARS?s Scientific Manuscript database

The Optimal Ranking Regime (ORR) method was used to identify intra- to multi-decadal (IMD) time windows containing significant ranking sequences in U.S. climate division temperature data. The simplicity of the ORR procedure’s output – a time series’ most significant non-overlapping periods of high o...

National Centers for Environmental Prediction

Science.gov Websites

available at IMD Click here to go to the Special Report page Aug 2016 - IITM started experimental real-time Experimental version of GFS 10.0.0 ported to IITM & NCMRWF - February 2012 EnKF Hybrid GSI update - Spring diagnostics *Experimental* Climate Prediction Center (CPC) links... African Desk: SWFDP GFS forecasts South

Linearization of microwave photonic link based on nonlinearity of distributed feedback laser

NASA Astrophysics Data System (ADS)

Kang, Zi-jian; Gu, Yi-ying; Zhu, Wen-wu; Fan, Feng; Hu, Jing-jing; Zhao, Ming-shan

2016-02-01

A microwave photonic link (MPL) with spurious-free dynamic range (SFDR) improvement utilizing the nonlinearity of a distributed feedback (DFB) laser is proposed and demonstrated. First, the relationship between the bias current and nonlinearity of a semiconductor DFB laser is experimentally studied. On this basis, the proposed linear optimization of MPL is realized by the combination of the external intensity Mach-Zehnder modulator (MZM) modulation MPL and the direct modulation MPL with the nonlinear operation of the DFB laser. In the external modulation MPL, the MZM is biased at the linear point to achieve the radio frequency (RF) signal transmission. In the direct modulation MPL, the third-order intermodulation (IMD3) components are generated for enhancing the SFDR of the external modulation MPL. When the center frequency of the input RF signal is 5 GHz and the two-tone signal interval is 10 kHz, the experimental results show that IMD3 of the system is effectively suppressed by 29.3 dB and the SFDR is increased by 7.7 dB.

Validation of Accelerometer Prediction Equations in Children with Chronic Disease.

PubMed

Stephens, Samantha; Takken, Tim; Esliger, Dale W; Pullenayegum, Eleanor; Beyene, Joseph; Tremblay, Mark; Schneiderman, Jane; Biggar, Doug; Longmuir, Pat; McCrindle, Brian; Abad, Audrey; Ignas, Dan; Van Der Net, Janjaap; Feldman, Brian

2016-02-01

The purpose of this study was to assess the criterion validity of existing accelerometer-based energy expenditure (EE) prediction equations among children with chronic conditions, and to develop new prediction equations. Children with congenital heart disease (CHD), cystic fibrosis (CF), dermatomyositis (JDM), juvenile arthritis (JA), inherited muscle disease (IMD), and hemophilia (HE) completed 7 tasks while EE was measured using indirect calorimetry with counts determined by accelerometer. Agreement between predicted EE and measured EE was assessed. Disease-specific equations and cut points were developed and cross-validated. In total, 196 subjects participated. One participant dropped out before testing due to time constraints, while 15 CHD, 32 CF, 31 JDM, 31 JA, 30 IMD, 28 HE, and 29 healthy controls completed the study. Agreement between predicted and measured EE varied across disease group and ranged from (ICC) .13-.46. Disease-specific prediction equations exhibited a range of results (ICC .62-.88) (SE 0.45-0.78). In conclusion, poor agreement was demonstrated using current prediction equations in children with chronic conditions. Disease-specific equations and cut points were developed.

Structural basis of filopodia formation induced by the IRSp53/MIM homology domain of human IRSp53

PubMed Central

Millard, Thomas H; Bompard, Guillaume; Heung, Man Yeung; Dafforn, Timothy R; Scott, David J; Machesky, Laura M; Fütterer, Klaus

2005-01-01

The scaffolding protein insulin receptor tyrosine kinase substrate p53 (IRSp53), a ubiquitous regulator of the actin cytoskeleton, mediates filopodia formation under the control of Rho-family GTPases. IRSp53 comprises a central SH3 domain, which binds to proline-rich regions of a wide range of actin regulators, and a conserved N-terminal IRSp53/MIM homology domain (IMD) that harbours F-actin-bundling activity. Here, we present the crystal structure of this novel actin-bundling domain revealing a coiled-coil domain that self-associates into a 180 Å-long zeppelin-shaped dimer. Sedimentation velocity experiments confirm the presence of a single molecular species of twice the molecular weight of the monomer in solution. Mutagenesis of conserved basic residues at the extreme ends of the dimer abrogated actin bundling in vitro and filopodia formation in vivo, demonstrating that IMD-mediated actin bundling is required for IRSp53-induced filopodia formation. This study promotes an expanded view of IRSp53 as an actin regulator that integrates scaffolding and effector functions. PMID:15635447

NF-κB Immunity in the Brain Determines Fly Lifespan in Healthy Aging and Age-Related Neurodegeneration.

PubMed

Kounatidis, Ilias; Chtarbanova, Stanislava; Cao, Yang; Hayne, Margaret; Jayanth, Dhruv; Ganetzky, Barry; Ligoxygakis, Petros

2017-04-25

During aging, innate immunity progresses to a chronically active state. However, what distinguishes those that "age well" from those developing age-related neurological conditions is unclear. We used Drosophila to explore the cost of immunity in the aging brain. We show that mutations in intracellular negative regulators of the IMD/NF-κB pathway predisposed flies to toxic levels of antimicrobial peptides, resulting in early locomotor defects, extensive neurodegeneration, and reduced lifespan. These phenotypes were rescued when immunity was suppressed in glia. In healthy flies, suppressing immunity in glial cells resulted in increased adipokinetic hormonal signaling with high nutrient levels in later life and an extension of active lifespan. Thus, when levels of IMD/NF-κB deviate from normal, two mechanisms are at play: lower levels derepress an immune-endocrine axis, which mobilizes nutrients, leading to lifespan extension, whereas higher levels increase antimicrobial peptides, causing neurodegeneration. Immunity in the fly brain is therefore a key lifespan determinant. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Vitamin D Binding Protein-Macrophage Activating Factor (DBP-maf) Inhibits Angiogenesis and Tumor Growth in Mice1

PubMed Central

Kisker, Oliver; Onizuka, Shinya; Becker, Christian M; Fannon, Michael; Flynn, Evelyn; D'Amato, Robert; Zetter, Bruce; Folkman, Judah; Ray, Rahul; Swamy, Narasimha; Pirie-Shepherd, Steven

2003-01-01

Abstract We have isolated a selectively deglycosylated form of vitamin D binding protein (DBP-maf) generated from systemically available DBP by a human pancreatic cancer cell line. DBP-maf is antiproliferative for endothelial cells and antiangiogenic in the chorioallantoic membrane assay. DBP-maf administered daily was able to potently inhibit the growth of human pancreatic cancer in immune compromised mice (T/C=0.09). At higher doses, DBP-maf caused tumor regression. Histological examination revealed that treated tumors had a higher number of infiltrating macrophages as well as reduced microvessel density, and increased levels of apoptosis relative to untreated tumors. Taken together, these data suggest that DBP-maf is an antiangiogenic molecule that can act directly on endothelium as well as stimulate macrophages to attack both the endothelial and tumor cell compartment of a growing malignancy. PMID:12659668

The Characteristics of Incidental Pituitary Microadenomas in 120 Korean Forensic Autopsy Cases

PubMed Central

Kim, Jang-Hee; Seo, Jung-Seok; Lee, Bong-Woo; Lee, Sang-Young; Jeon, Seok-Hoon

2007-01-01

To investigate the characteristics of incidental pituitary microadenomas, we examined 120 pituitary glands from Korean forensic autopsy cases, from which eight tumors were identified (incidence 6.7%). The average age of the affected subjects was 50 yr (range: 33-96 yr) with a female predominance. The maximum diameters of the tumors ranged from 0.4 to 5.4 mm (mean: 2.8 mm). Immunohistochemical analysis of pituitary hormones revealed three growth hormone-secreting adenomas, one prolactin-producing adenoma, one gonadotropin-producing adenoma, one plurihormonal adenoma, and two null cell adenomas. MIB-1 staining for Ki-67 antigen showed no positive expression. The microvessel density (MVD) of the pituitary microadenomas ranged from 2.3 to 11.6% (mean: 5.3%) and was significantly lower than that of nonneoplastic pituitary glands (11.9-20.1%, mean: 14.8%). Our study provides reference data on incidental pituitary microadenomas in the Korean population. PMID:17923757

Angiogenesis in the Progression of Breast Ductal Proliferations

PubMed Central

Carpenter, Philip M.; Chen, Wen-Pin; Mendez, Aaron; McLaren, Christine E.; Su, Min-Ying

2013-01-01

Angiogenesis, the formation of blood vessels, is necessary for a tumor to grow, but when angiogenesis first appears in the progression of breast ductal carcinomas is unknown. To determine when this occurs, the authors examined microvessel density (MVD) by CD31 and CD105 immunostaining in normal ducts, 32 cases of usual hyperplasia, 19 cases of atypical hyperplasia, and 29 cases of ductal carcinoma in situ (DCIS). Simple hyperplasia had a 22-fold greater MVD than normal ducts (P < .0001). An increase during the progression of ductal changes was highly significant (P < .0001). To determine a possible mechanism, immunohistochemistry for vascular endothelial growth factor (VEGF) was evaluated. VEGF staining intensity of ductal epithelium increased during the progression from normal to hyperplastic to DCIS. This study shows that the first significant increase in angiogenesis occurs very early in the evolution of ductal proliferations as ductal cells become hyperplastic. PMID:19403546

[Effects of cuttlefish bone-bone morphogenetic protein composite material on osteogenesis and revascularization of bone defect in rats].

PubMed

Liu, Yuan; Yu, Jiang; Bai, Jie; Gu, Jin-song; Cai, Bin; Zhou, Xia

2013-12-01

To study the effects of cuttlefish bone-bone morphogenetic protein (BMP) composite material on osteogenesis and revascularization of bone defect in rats. The cuttlefish bone was formed into cylinder with the diameter of about 5 mm and height of about 2 mm after the shell was removed, and then it was soaked in the recombinant human BMP 2 to make a cuttlefish bone-BMP (CBB) composite material. Thirty SD rats, with a defect of skull in every rat, were divided into the CBB and pure cuttlefish bone (PCB) groups according to the random number table, with 15 rats in each group. The rats in the group CBB and group PCB were transplanted with the corresponding material to repair the skull defect. At post transplantation week (PTW) 4, 6, and 8, 5 rats from every group were sacrificed by exsanguination, and ink perfusion was performed. One day later, all the transplants and part of the skull surrounding the defect were harvested, and general observation was conducted at the same time. The specimens were paraffin sectioned for HE staining and Masson staining. The area of microvessel and the area of newborn bone were observed and analyzed through histopathological techniques and image collection system. Data were processed with the analysis of variance of factorial design and LSD test. The correlation between the area of microvessel and the area of newborn bone of the group CBB was analyzed with Pearson correlation analysis. (1) The general observation of the transplant region showed that the transplants were encapsulated by a capsule of fibrous connective tissue. The texture of capsule was soft and relatively thick at PTW 4. The texture was tenacious and thin, but rather compact at PTW 6 and 8. The transplants became gelatinous at PTW 4, and similar to the cartilage tissue at PTW 6 and 8. (2) Histological observation showed that the structure of the transplants in two groups was damaged at PTW 4. A moderate quantity of inflammatory cell infiltration could be observed. The amounts of the primary bone trabeculae and microvessels in group CBB were more abundant than those of group PCB, while the number of osteoclasts was less than those of group PCB. At PTW 6, the inflammatory cell infiltration in the transplants in both groups decreased obviously, the cuttlefish bone was found to be further degraded, and the number of newborn microvessels was increased. There were mature bone trabeculae around the transplants in both groups. And there were also mature bone trabeculae in the degraded CBB in group CBB. At PTW 8, the inflammatory reaction in the transplants in both groups disappeared; there were more mature bone trabeculae; the structure of the cuttlefish bone was found to be damaged basically. Bone trabeculae in group PCB were found around the transplant, while the bone trabeculae could be observed not only around the transplant but also in the degraded CBB in group CBB. The amount of the microvessels in group CBB was still larger than that of group PCB. (3) From PTW 4 to 8, the area of microvessel in group CBB [(63 ± 4), ( 136 ± 36), ( 347 ± 31) µm(2)] was larger than that in group PCB [(44 ± 7), (73 ± 4), (268 ± 42) µm(2), P < 0.05 or P < 0.01]. From PTW 4 to 8, the area of newborn bone in group CBB [(236 ± 26), (339 ± 42), (553 ± 40) µm(2)] was larger than that in group PCB [(137 ± 15), (243 ± 21), (445 ± 29) µm(2), with P values all below 0.01]. (4) The relation between the area of microvessel and the area of newborn bone was significantly positive (r = 0.948, P = 0.001). The CBB may exert good effect on osteogenesis and vascularization of rats with bone defect. It is a good three dimensional scaffold in bone tissue engineering.

Patients with inflammatory bowel disease have increased risk of autoimmune and inflammatory diseases

PubMed Central

Halling, Morten L; Kjeldsen, Jens; Knudsen, Torben; Nielsen, Jan; Hansen, Lars Koch

2017-01-01

AIM To investigate whether immune mediated diseases (IMD) are more frequent in patients with inflammatory bowel disease (IBD). METHODS In this population based registry study, a total of 47325 patients with IBD were alive and registered in the Danish National Patient Registry on December 16, 2013. Controls were randomly selected from the Danish Civil Registration System (CRS) and matched for sex, age, and municipality. We used ICD 10 codes to identify the diagnoses of the included patients. The IBD population was divided into three subgroups: Ulcerative colitis (UC), Crohn’s disease (CD) and Both the latter referring to those registered with both diagnoses. Subsequently, odds-ratios (OR) and 95%CI were obtained separately for each group and their respective controls. The use of Bonferoni post-test correction adjusted the significance level to P < 0.00125. P-values were estimated using Fisher’s exact test. RESULTS There were significantly more women than men in the registry, and a greater percentage of comorbidity in the IBD groups (P < 0.05). Twenty different IMDs were all significantly more frequent in the IBD group. Sixteen were associated with UC versus twelve with CD. In both UC and CD ORs were significantly increased (P < 0.00125) for primary sclerosing cholangitis (PSC), celiac disease, type 1 diabetes (T1D), sarcoidosis, asthma, iridocyclitis, psoriasis, pyoderma gangrenosum, rheumatoid arthritis, and ankylosing spondylitis. Restricted to UC (P < 0.00125) were autoimmune hepatitis, primary biliary cholangitis, Grave’s disease, polymyalgia rheumatica, temporal arteritis , and atrophic gastritis. Restricted to CD (P < 0.00125) were psoriatic arthritis and episcleritis. Restricted to women with UC (P < 0.00125) were atrophic gastritis, rheumatoid arthritis, temporal arteritis, and polymyalgia rheumatica. Restricted to women with CD were episcleritis, rheumatoid arthritis, and psoriatic arthritis. The only disease restricted to men (P < 0.00125) was sarcoidosis. CONCLUSION Immune mediated diseases were significantly more frequent in patients with IBD. Our results strengthen the hypothesis that some IMDs and IBD may have overlapping pathogenic pathways. PMID:28970729

Characteristics of recent dust storms over the Indian region using real time multi-satellite observations from the direct broadcast receiving system at IMD

NASA Astrophysics Data System (ADS)

Mitra, A. K.; Sharma, A. K.; Soni, V. K.; Kundu, P. K.

2013-04-01

In this study, observations from microwave satellites, visible and infrared instruments have been analyzed to detect dust storm over north and north-west part of India during 18-23 March 2012. This study investigated the approach to utilize the multi satellite data of Moderate Resolution Imaging Spectroradiometer (MODIS) on-board the Terra and Aqua satellite and the Advanced Microwave Sounding Unit (AMSU) on-board NOAA satellite to study the characteristics of dust storms from real time direct broadcast (DB) receiving system installed at three places of India Meteorological Department (IMD). The dust storm detection is based on the infrared brightness temperature (BT) difference between channels at 11 and 12 μm and polarized BT difference between two channels of 89 and 23.8 GHz. It is found that the significant differences between the BT of channel 89 and 23.8 can be used as a discriminator of identifying dust storm. The Total Ozone Mapping Spectroradiometer (TOMS) Aerosol Index (AI) and AMSU-A 23 GHz channel BT from NOAA satellite over the north and north-west part of India have also been analyzed. The result indicated the characteristic behavior between BT and AI during the different phases of the dust storm. Finally, the occurrence of dust outbreaks has also been validated with sky radiometer of IMD, which confirms the presence of a dust storm over the Indian region. Further, the findings of the study and its approaches apply to the other dust storm cases which occurred during the months of April and June 2012. The integrated approach suggested the potential to use high resolution data of microwave as well as thermal-infrared using multi-satellite observations from real time direct broadcast system for the detection of severe, moderate or weak dust storms very well. The approach is found to be promising for operational application.

Patients with inflammatory bowel disease have increased risk of autoimmune and inflammatory diseases.

PubMed

Halling, Morten L; Kjeldsen, Jens; Knudsen, Torben; Nielsen, Jan; Hansen, Lars Koch

2017-09-07

To investigate whether immune mediated diseases (IMD) are more frequent in patients with inflammatory bowel disease (IBD). In this population based registry study, a total of 47325 patients with IBD were alive and registered in the Danish National Patient Registry on December 16, 2013. Controls were randomly selected from the Danish Civil Registration System (CRS) and matched for sex, age, and municipality. We used ICD 10 codes to identify the diagnoses of the included patients. The IBD population was divided into three subgroups: Ulcerative colitis (UC), Crohn's disease (CD) and Both the latter referring to those registered with both diagnoses. Subsequently, odds-ratios (OR) and 95%CI were obtained separately for each group and their respective controls. The use of Bonferoni post-test correction adjusted the significance level to P < 0.00125. P -values were estimated using Fisher's exact test. There were significantly more women than men in the registry, and a greater percentage of comorbidity in the IBD groups ( P < 0.05). Twenty different IMDs were all significantly more frequent in the IBD group. Sixteen were associated with UC versus twelve with CD. In both UC and CD ORs were significantly increased ( P < 0.00125) for primary sclerosing cholangitis (PSC), celiac disease, type 1 diabetes (T1D), sarcoidosis, asthma, iridocyclitis, psoriasis, pyoderma gangrenosum, rheumatoid arthritis, and ankylosing spondylitis. Restricted to UC ( P < 0.00125) were autoimmune hepatitis, primary biliary cholangitis, Grave's disease, polymyalgia rheumatica, temporal arteritis , and atrophic gastritis. Restricted to CD ( P < 0.00125) were psoriatic arthritis and episcleritis. Restricted to women with UC ( P < 0.00125) were atrophic gastritis, rheumatoid arthritis, temporal arteritis, and polymyalgia rheumatica. Restricted to women with CD were episcleritis, rheumatoid arthritis, and psoriatic arthritis. The only disease restricted to men ( P < 0.00125) was sarcoidosis. Immune mediated diseases were significantly more frequent in patients with IBD. Our results strengthen the hypothesis that some IMDs and IBD may have overlapping pathogenic pathways.

Climate Change Studies over Bangalore using Multi-source Remote Sensing Data and GIS

NASA Astrophysics Data System (ADS)

B, S.; Gouda, K. C.; Laxmikantha, B. P.; Bhat, N.

2014-12-01

Urbanization is a form of metropolitan growth that is a response to often bewildering sets of economic, social, and political forces and to the physical geography of an area. Some of the causes of the sprawl include - population growth, economy, patterns of infrastructure initiatives like the construction of roads and the provision of infrastructure using public money encouraging development. The direct implication of such urban sprawl is the change in land use and land cover of the region. In this study the long term climate data from multiple sources like NCEP reanalysis, IMD observations and various satellite derived products from MAIRS, IMD, ERSL and TRMM are considered and analyzed using the developed algorithms for the better understanding of the variability in the climate parameters over Bangalore. These products are further mathematically analyzed to arrive at desired results by extracting land surface temperature (LST), Potential evapo-transmission (PET), Rainfall, Humidity etc. Various satellites products are derived from NASA (National Aeronautics Space Agency), Indian meteorological satellites and global satellites are helpful in massive study of urban issues at global and regional scale. Climate change analysis is well studied by using either single source data such as Temperature or Rainfall from IMD (Indian Meteorological Department) or combined data products available as in case of MAIRS (Monsoon Asia Integrated Regional Scale) program to get rainfall at regional scale. Finally all the above said parameters are normalized and analyzed with the help of various open source available software's for pre and post processing our requirements to obtain desired results. A sample of analysis i.e. the Inter annual variability of annual averaged Temperature over Bangalore is presented in figure 1, which clearly shows the rising trend of the temperature (0.06oC/year). Also the Land use and land cover (LULC) analysis over Bangalore, Day light hours from satellite derived products are analyzed and the correlation of climate parameters with LULC are presented.

Platelet size and density affect shear-induced thrombus formation in tortuous arterioles

NASA Astrophysics Data System (ADS)

Chesnutt, Jennifer K. W.; Han, Hai-Chao

2013-10-01

Thrombosis accounts for 80% of deaths in patients with diabetes mellitus. Diabetic patients demonstrate tortuous microvessels and larger than normal platelets. Large platelets are associated with increased platelet activation and thrombosis, but the physical effects of large platelets in the microscale processes of thrombus formation are not clear. Therefore, the objective of this study was to determine the physical effects of mean platelet volume (MPV), mean platelet density (MPD) and vessel tortuosity on platelet activation and thrombus formation in tortuous arterioles. A computational model of the transport, shear-induced activation, collision, adhesion and aggregation of individual platelets was used to simulate platelet interactions and thrombus formation in tortuous arterioles. Our results showed that an increase in MPV resulted in a larger number of activated platelets, though MPD and level of tortuosity made little difference on platelet activation. Platelets with normal MPD yielded the lowest amount of mural thrombus. With platelets of normal MPD, the amount of mural thrombus decreased with increasing level of tortuosity but did not have a simple monotonic relationship with MPV. The physical mechanisms associated with MPV, MPD and arteriole tortuosity play important roles in platelet activation and thrombus formation.

A Reproducible Computerized Method for Quantitation of Capillary Density using Nailfold Capillaroscopy.

PubMed

Cheng, Cynthia; Lee, Chadd W; Daskalakis, Constantine

2015-10-27

Capillaroscopy is a non-invasive, efficient, relatively inexpensive and easy to learn methodology for directly visualizing the microcirculation. The capillaroscopy technique can provide insight into a patient's microvascular health, leading to a variety of potentially valuable dermatologic, ophthalmologic, rheumatologic and cardiovascular clinical applications. In addition, tumor growth may be dependent on angiogenesis, which can be quantitated by measuring microvessel density within the tumor. However, there is currently little to no standardization of techniques, and only one publication to date reports the reliability of a currently available, complex computer based algorithms for quantitating capillaroscopy data.(1) This paper describes a new, simpler, reliable, standardized capillary counting algorithm for quantitating nailfold capillaroscopy data. A simple, reproducible computerized capillaroscopy algorithm such as this would facilitate more widespread use of the technique among researchers and clinicians. Many researchers currently analyze capillaroscopy images by hand, promoting user fatigue and subjectivity of the results. This paper describes a novel, easy-to-use automated image processing algorithm in addition to a reproducible, semi-automated counting algorithm. This algorithm enables analysis of images in minutes while reducing subjectivity; only a minimal amount of training time (in our experience, less than 1 hr) is needed to learn the technique.

A Reproducible Computerized Method for Quantitation of Capillary Density using Nailfold Capillaroscopy

PubMed Central

Daskalakis, Constantine

2015-01-01

Capillaroscopy is a non-invasive, efficient, relatively inexpensive and easy to learn methodology for directly visualizing the microcirculation. The capillaroscopy technique can provide insight into a patient’s microvascular health, leading to a variety of potentially valuable dermatologic, ophthalmologic, rheumatologic and cardiovascular clinical applications. In addition, tumor growth may be dependent on angiogenesis, which can be quantitated by measuring microvessel density within the tumor. However, there is currently little to no standardization of techniques, and only one publication to date reports the reliability of a currently available, complex computer based algorithms for quantitating capillaroscopy data.1 This paper describes a new, simpler, reliable, standardized capillary counting algorithm for quantitating nailfold capillaroscopy data. A simple, reproducible computerized capillaroscopy algorithm such as this would facilitate more widespread use of the technique among researchers and clinicians. Many researchers currently analyze capillaroscopy images by hand, promoting user fatigue and subjectivity of the results. This paper describes a novel, easy-to-use automated image processing algorithm in addition to a reproducible, semi-automated counting algorithm. This algorithm enables analysis of images in minutes while reducing subjectivity; only a minimal amount of training time (in our experience, less than 1 hr) is needed to learn the technique. PMID:26554744

Participation of blood vessel cells in human adaptive immune responses.

PubMed

Pober, Jordan S; Tellides, George

2012-01-01

Circulating T cells contact blood vessels either when they extravasate across the walls of microvessels into inflamed tissues or when they enter into the walls of larger vessels in inflammatory diseases such as atherosclerosis. The blood vessel wall is largely composed of three cell types: endothelial cells lining the entire vascular tree; pericytes supporting the endothelium of microvessels; and smooth muscle cells forming the bulk of large vessel walls. Each of these cell types interacts with and alters the behavior of infiltrating T cells in different ways, making these cells active participants in the processes of immune-mediated inflammation. In this review, we compare and contrast what is known about the nature of these interactions in humans. Copyright © 2011 Elsevier Ltd. All rights reserved.

Complexity of tumor vasculature in clear cell renal cell carcinoma.

PubMed

Qian, Chao-Nan; Huang, Dan; Wondergem, Bill; Teh, Bin Tean

2009-05-15

Clear cell renal cell carcinoma (CCRCC) is a highly vascularized cancer resistant to conventional chemotherapy and radiotherapy. Antiangiogenic therapy has achieved some effectiveness against this unique malignancy. The complexity of the tumor vasculature in CCRCC has led to differences in correlating tumor microvessel density with patient prognosis. The authors' recent findings demonstrated that there were at least 2 major categories of tumor vessels in CCRCC-namely, undifferentiated and differentiated-correlating with patient prognosis in contrasting ways, with higher undifferentiated vessel density indicating poorer prognosis, and higher differentiated vessel density correlating with better prognosis. Furthermore, the presence of pericytes supporting the differentiated vessels varied in CCRCC. The distributions of pericyte coverage and differentiated vessels in CCRCC were uneven. The tumor margin had a higher pericyte coverage rate for differentiated vessels than did the inner tumor area. The uneven distributions of pericyte coverage and differentiated vessels in CCRCC prompted the authors to revisit the mechanism of tumor central necrosis, which was also known to be a prognostic indicator for CCRCC. The discrepancy of prognostic correlation between protein and messenger RNA levels of vascular endothelial growth factor in CCRCC was discussed. The complexity of the tumor vasculature in CCRCC also led the authors to begin to re-evaluate the therapeutic effects of antiangiogenic agents for each type of tumor vessel, which will in turn significantly broaden understanding of tumor angiogenesis and improve therapeutic effect. (c) 2009 American Cancer Society.

Vascular pericyte density and angiogenesis associated with adenocarcinoma of the prostate.

PubMed

Killingsworth, Murray C; Wu, Xiaojuan

2011-01-01

Angiogenesis facilitates metabolism, proliferation and metastasis of adenocarcinoma cells in the prostate, as without the development of new vasculature tumor growth cannot be sustained. However, angiogenesis is variable with the well-known phenomenon of vascular 'hotspots' seen associated with viable tumor cell mass. With the recent recognition of pericytes as molecular regulators of angiogenesis, we have examined the interaction of these cells in actively growing new vessels. Pericyte interactions with developing new vessels were examined using transmission electron microscopy. Pericyte distribution was mapped from α-SMA+ immunostained histological sections and quantified using image analysis. Data was obtained from peripheral and more central regions of 27 cases with Gleason scores of 4-9. Pericyte numbers were increased around developing new vessel sprouts at sites of luminal maturation. Numbers were reduced around the actively growing tips of migrating endothelial cells and functional new vessels. Tumor regions internal to a 500-μm peripheral band showed higher microvessel pericyte density than the peripheral region. Pericytes were found to be key cellular components of developing new vessels in adenocarcinoma of the prostate. Their numbers increased at sites of luminal maturation with these cells displaying an activated phenotype different to quiescent pericytes. Increased pericyte density was found internal to the peripheral region, suggesting more mature vessels lie more centrally. Copyright © 2011 S. Karger AG, Basel.

[Recombinant adeno-associated virus mediated RNA interference of angiogenin expression inhibits cell growth of human lung adenocarcinoma].

PubMed

Li, Bai-Ling; Zhang, Guan-Xin; Hou, Xiao-Lei; Tan, Meng-Wei; Yuan, Yang; Liu, Xiao-Hong; Gong, De-Jun; Huang, Sheng-Dong

2009-03-01

To study the inhibition of angiogenin (ANG) expression in human lung squamous cancer cell strain-A549 through adeno-associated virus (AAV)-mediated RNA-interference, and therefore to observe its effect on the growth of cancer cells and tumor formation. Recombinant AAV expressing H1-promoter-induced small-interference- RNA (siRNA) targeting ANG (AAV-shANG) was constructed, and then transfected into A549 cells. A549 cells and cells transfected with AAV-Null were used as the control groups. The effects of the reduced expression of ANG by RNAi from AAV-shANG on the growth, formation, reproduction, apoptosis, and microvessel-density of the carcinoma were observed. In vitro experiment showed that AAV-shANG was constructed successfully, There was an significant decrease in the expression of ANG protein 72 h after transfection, compared with the normal A459 cells and AAV-Null cells (P < 0.01). Cell cycle analysis showed that the proliferation index (PI) of normal A549 cells, AAV-Null cells and AAVshANG cells were 0.32 +/- 0.29, 0.35 +/- 0.38 and 0.31 +/- 0.43, respectively. There was no statistic difference in the PIs among the 3 groups (P > 0.05). In vivo experiment using thymus-defect mice showed that, there was an remarkable reduction in the mass and volume of tumors in AAV-shANG transfected group, compared to the control groups. Microvessel-density was 9.4 +/- 1.5, 9.8 +/- 2.1 and 5.7 +/- 1.9, respectively in the 3 groups, a statistic difference among the AAV-shANG-transfected group, the normal A549 group and the AAV-Null transfected group. The percentages of apoptotic cells in each group were (7.7 +/- 3.1)%, (8.5 +/- 5.4)%, (17.1 +/- 8.6)%, respectively, the experimental group being higher than those of the control groups. Positive rates of PCNA were (84.8 +/- 9.7)%, (85.8 +/- 9.8)%, and (70.4 +/- 10.1)%, respectively, the AAV-shANG transfected cancer cells showing a lower PCNA index than the control groups. AAV-mediated expression of siRNA could reduce the expression of ANG in cancer cells, significantly enough to inhibit cell proliferation, promote cell apoptosis and inhibit tumor growth.

Anti-cancer effects of baicalein in non-small cell lung cancer in-vitro and in-vivo.

PubMed

Cathcart, Mary-Clare; Useckaite, Zivile; Drakeford, Clive; Semik, Vikki; Lysaght, Joanne; Gately, Kathy; O'Byrne, Kenneth J; Pidgeon, Graham P

2016-09-01

Baicalein is a widely used Chinese herbal medicine derived from Scutellaria baicalenesis, which has been traditionally used as anti-inflammatory and anti-cancer therapy. In this study we examined the anti-tumour pathways activated following baicalein treatment in non-small cell lung cancer (NSCLC), both in-vitro and in-vivo. The effect of baicalein treatment on H-460 cells in-vitro was assessed using both BrdU assay (cell proliferation) and High Content Screening (multi-parameter apoptosis assay). A xenograft nude mouse model was subsequently established using these cells and the effect of baicalein on tumour growth and survival assessed in-vivo. Tumours were harvested from these mice and histological tissue analysis carried out. VEGF, 12-lipoxygenase and microvessel density (CD-31) were assessed by immunohistochemistry (IHC), while H and E staining was carried out to assess mitotic index. Gene expression profiling was carried out on corresponding RNA samples using Human Cancer Pathway Finder Arrays and qRT-PCR, with further gene expression analysis carried out using qRT-PCR. Baicalein significantly decreased lung cancer proliferation in H-460 cells in a dose dependent manner. At the functional level, a dose-dependent induction in apoptosis associated with decreased cellular f-actin content, an increase in nuclear condensation and an increase in mitochondrial mass potential was observed. Orthotopic treatment of experimental H-460 tumours in athymic nude mice with baicalein significantly (p < 0.05) reduced tumour growth and prolonged survival. Histological analysis of resulting tumour xenografts demonstrated reduced expression of both 12-lipoxygenase and VEGF proteins in baicalein-treated tumours, relative to untreated. A significant (p < 0.01) reduction in both mitotic index and micro-vessel density was observed following baicalein treatment. Gene expression profiling revealed a reduction (p < 0.01) in both VEGF and FGFR-2 following baicalein treatment, with a corresponding increase (p < 0.001) in RB-1. This study is the first to demonstrate efficacy of baicalein both in-vitro and in-vivo in NSCLC. These effects may be mediated in part through a reduction in both cell cycle progression and angiogenesis. At the molecular level, alterations in expression of VEGF, FGFR-2, and RB-1 have been implicated, suggesting a molecular mechanism underlying this in-vivo effect.

76 FR 148 - Medicaid Program; Final FY 2009 and Preliminary FY 2011 Disproportionate Share Hospital...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-03

... Federal share) IMD and other mental health facility DSH expenditures applicable to the State's FY 1995 DSH... State's total computable DSH expenditures attributable to the FY 1995 DSH allotment for mental health... health DSH expenditures applicable to the State's FY 1995 DSH allotment by the total computable amount of...

Optimal ranking regime analysis of U.S. climate variablility. Part II: Precipitation and streamflow

USDA-ARS?s Scientific Manuscript database

In a preceding companion paper the Optimal Ranking Regime (ORR) method was used to identify intra- to multi-decadal (IMD) regimes in U.S. climate division temperature data during 1896-2012. Here, the method is used to test for annual and seasonal precipitation regimes during that same period. In add...

Implementation of ERDC HEP Geo-Material Model in CTH and Application

DTIC Science & Technology

2011-11-02

used TARDEC JWL inputs for C4 and Johnson- Cook Strength inputs   TARDEC JC fracture model inputs for 5083 plate changed due to problems seen in...fracture inputs from IMD tests -  LS-DYNA C4 JWL and Johnson-Cook strength inputs used in CTH runs -  Results indicate that TARDEC JC fracture model

The relationship between aortic stiffness and changes in retinal microvessels among Asian ischemic stroke patients.

PubMed

De Silva, D A; Woon, F-P; Manzano, J J F; Liu, E Y; Chang, H-M; Chen, C; Wang, J J; Mitchell, P; Kingwell, B A; Cameron, J D; Lindley, R I; Wong, T Y; Wong, M-C

2012-12-01

Large-artery stiffness is a risk factor for stroke, including cerebral small-vessel disease. Retinal microvascular changes are thought to mirror those in cerebral microvessels. We investigated the relationship between aortic stiffness and retinal microvascular changes in Asian ischemic stroke patients. We studied 145 acute ischemic stroke patients in Singapore who had aortic stiffness measurements using carotid-femoral pulse wave velocity (cPWV). Retinal photographs were assessed for retinal microvessel caliber and qualitative signs of focal arteriolar narrowing, arteriovenous nicking and enhanced arteriolar light reflex. Aortic stiffening was associated with retinal arteriolar changes. Retinal arteriolar caliber decreased with increasing cPWV (r=-0.207, P=0.014). After adjusting for age, gender, hypertension, diabetes, mean arterial pressure and small-vessel stroke subtype, patients within the highest cPWV quartile were more likely to have generalized retinal arteriolar narrowing defined as lowest caliber tertile (odds ratio (OR) 6.84, 95% confidence interval (CI) 1.45-32.30), focal arteriolar narrowing (OR 13.85, CI 1.82-105.67), arteriovenous nicking (OR 5.08, CI 1.12-23.00) and enhanced arteriolar light reflex (OR 3.83, CI 0.89-16.48), compared with those within the lowest quartile. In ischemic stroke patients, aortic stiffening is associated with retinal arteriolar luminal narrowing as well as features of retinal arteriolosclerosis.

Cerebral vessels segmentation for light-sheet microscopy image using convolutional neural networks

NASA Astrophysics Data System (ADS)

Hu, Chaoen; Hui, Hui; Wang, Shuo; Dong, Di; Liu, Xia; Yang, Xin; Tian, Jie

2017-03-01

Cerebral vessel segmentation is an important step in image analysis for brain function and brain disease studies. To extract all the cerebrovascular patterns, including arteries and capillaries, some filter-based methods are used to segment vessels. However, the design of accurate and robust vessel segmentation algorithms is still challenging, due to the variety and complexity of images, especially in cerebral blood vessel segmentation. In this work, we addressed a problem of automatic and robust segmentation of cerebral micro-vessels structures in cerebrovascular images acquired by light-sheet microscope for mouse. To segment micro-vessels in large-scale image data, we proposed a convolutional neural networks (CNNs) architecture trained by 1.58 million pixels with manual label. Three convolutional layers and one fully connected layer were used in the CNNs model. We extracted a patch of size 32x32 pixels in each acquired brain vessel image as training data set to feed into CNNs for classification. This network was trained to output the probability that the center pixel of input patch belongs to vessel structures. To build the CNNs architecture, a series of mouse brain vascular images acquired from a commercial light sheet fluorescence microscopy (LSFM) system were used for training the model. The experimental results demonstrated that our approach is a promising method for effectively segmenting micro-vessels structures in cerebrovascular images with vessel-dense, nonuniform gray-level and long-scale contrast regions.

Interleukin 16- (IL-16-) Targeted Ultrasound Imaging Agent Improves Detection of Ovarian Tumors in Laying Hens, a Preclinical Model of Spontaneous Ovarian Cancer.

PubMed

Barua, Animesh; Yellapa, Aparna; Bahr, Janice M; Adur, Malavika K; Utterback, Chet W; Bitterman, Pincas; Basu, Sanjib; Sharma, Sameer; Abramowicz, Jacques S

2015-01-01

Limited resolution of transvaginal ultrasound (TVUS) scanning is a significant barrier to early detection of ovarian cancer (OVCA). Contrast agents have been suggested to improve the resolution of TVUS scanning. Emerging evidence suggests that expression of interleukin 16 (IL-16) by the tumor epithelium and microvessels increases in association with OVCA development and offers a potential target for early OVCA detection. The goal of this study was to examine the feasibility of IL-16-targeted contrast agents in enhancing the intensity of ultrasound imaging from ovarian tumors in hens, a model of spontaneous OVCA. Contrast agents were developed by conjugating biotinylated anti-IL-16 antibodies with streptavidin coated microbubbles. Enhancement of ultrasound signal intensity was determined before and after injection of contrast agents. Following scanning, ovarian tissues were processed for the detection of IL-16 expressing cells and microvessels. Compared with precontrast, contrast imaging enhanced ultrasound signal intensity significantly in OVCA hens at early (P < 0.05) and late stages (P < 0.001). Higher intensities of ultrasound signals in OVCA hens were associated with increased frequencies of IL-16 expressing cells and microvessels. These results suggest that IL-16-targeted contrast agents improve the visualization of ovarian tumors. The laying hen may be a suitable model to test new imaging agents and develop targeted anti-OVCA therapeutics.

Angiostatin inhibits experimental liver fibrosis in mice.

PubMed

Vogten, J Mathys; Drixler, Tamas A; te Velde, Elisabeth A; Schipper, Marguerite E; van Vroonhoven, Theo J M V; Voest, Emile E; Borel Rinkes, Inne H M

2004-07-01

Liver fibrosis is a response to chronic hepatic damage, which ultimately leads to liver failure and necessitates liver transplantation. A characteristic of fibrosis is pathological vessel growth. This type of angiogenesis may contribute to the disturbance of hepatocyte perfusion dynamics and lead to aggravation of disease. We hypothesized that angiostatin can inhibit pathological vessel growth and, consequently, the development of hepatic fibrosis. Hepatic fibrosis was induced by injection of carbon tetrachloride for 5 weeks. Angiostatin mice received carbon tetrachloride for 5 weeks and angiostatin during weeks 4 and 5. After 5 weeks, immunohistochemistry for endothelial cell marker von Willebrand factor and for cell proliferation was performed. Angiogenesis was quantified by counting the number of immunopositive microvessels. Also, the relative fibrotic surface was determined using Sirius Red histostaining and computer image analysis. Immunohistochemistry revealed increased expression for von Willebrand factor in fibrotic livers. Immunopositive microvessels were localized in fibrotic areas surrounding larger vessels and in emerging fibrotic septa. Angiostatin reduced the number of immunopositive microvessels by 69% (p<0.001). In addition, angiostatin reduced the relative fibrotic area in the liver by 63+/-0.1% (p<0.001). Finally, angiostatin treatment was not associated with differences in cell proliferation. Angiostatin inhibits the development of pathological angiogenesis and liver fibrosis in mice. These results warrant further evaluation of angiostatin as an antifibrotic agent, potentially contributing to the deferment of liver transplantation and reduced recurrence of fibrotic disease in the transplanted liver.

Endothelin-A-receptor antagonism with atrasentan exhibits limited activity on the KU-19-19 bladder cancer cell line in a mouse model.

PubMed

Herrmann, Edwin; Tiemann, Arne; Eltze, Elke; Bolenz, Christian; Bremer, Christoph; Persigehl, Thorsten; Hertle, Lothar; Wülfing, Christian

2009-10-01

The endothelin axis consists of endothelin-1 (ET-1) and its two receptors, ET(A)- and ET(B)-receptor (ET(A)-R and ET(B)-R). In several tumor entities, the ET(A)-R plays a significant role as a drug target. In our study, we investigated whether inhibition of ET(A)-R with atrasentan leads to an antitumor effect in urinary bladder carcinoma as well. Twenty nude mice with thymic aplasia were subcutaneously administered 2 x 10(6) KU-19-19 bladder cancer cells in the right flank. Starting on the 22nd day after the injection, ten animals were treated with atrasentan (2.5 mg/kg BW intraperitoneally), and another ten animals were treated with placebo. During treatment, absolute tumor growth and relative growth rate over time were determined. After the end of treatment, the mitosis and necrosis rates, microvessel density, and receptor density in the tumor tissue were analyzed by immunohistochemistry. In addition, the expression intensities of ET-1, ET(A)-R, and ET(B)-R were evaluated semiquantitatively and compared between the groups. No significant differences between the active-treatment and placebo groups were detected, either with respect to absolute tumor growth (P = 0.333) or mitosis rate (P = 0.217). In the analysis of the necrosis rate and receptor density for ET(A)-R, a trend toward higher values in the active-treatment group (mean necrosis rate = 63.67%, receptor density: 1.417) than in the placebo group (mean necrosis rate = 46.25%, receptor density: 1.270) was found; however, neither difference was statistically significant (P = 0.08 and 0.219, respectively). ET(A)-R blockade with atrasentan in a bladder cancer xenograft model shows no significant antitumor effect.

Flight Regime Recognition Analysis for the Army UH-60A IMDS Usage

DTIC Science & Technology

2006-12-01

61 Figure 34. The Behavior of The Parameter Weight.On.Wheels........................... 65 Figure 35. The ... Behavior of a Take-off Regime in Subsetting Process ................ 68 xi Figure 36. Subsetting the Big Data into Smaller Sets (WOW, Flags...of components can be extended to their true lifetime (Bechhoefer, n.d.) This is directly related to the accurate representation of regime

Pickle Flavors Relish in Drosophila Immunity.

PubMed

Salminen, Tiina Susanna; Rämet, Mika

2016-09-14

Immune responses must be tightly controlled to avoid host damage. In Drosophila, two NF-κB signaling pathways, Toll and Imd, mediate host immune responses. In this issue of Cell Host & Microbe, Morris et al. (2016) introduce Pickle, a nuclear IκB that inhibits Drosophila immune signaling by modulating the NF-κB Relish. Copyright © 2016 Elsevier Inc. All rights reserved.

60-GHz Millimeter-wave Over Fiber with Directly Modulated Dual-mode Laser Diode

PubMed Central

Tsai, Cheng-Ting; Lin, Chi-Hsiang; Lin, Chun-Ting; Chi, Yu-Chieh; Lin, Gong-Ru

2016-01-01

A directly modulated dual-mode laser diode (DMLD) with third-order intermodulation distortion (IMD3) suppression is proposed for a 60-GHz millimeter-wave over fiber (MMWoF) architecture, enabling new fiber-wireless communication access to cover 4-km single-mode-fiber (SMF) and 3-m wireless 16-QAM OFDM transmissions. By dual-mode injection-locking, the throughput degradation of the DMLD is mitigated with saturation effect to reduce its threshold, IMD3 power and relative intensity noise to 7.7 mA, −85 dBm and −110.4 dBc/Hz, respectively, providing huge spurious-free dynamic range of 85.8 dB/Hz2/3. This operation suppresses the noise floor of the DMLD carried QPSK-OFDM spectrum by 5 dB. The optical receiving power is optimized to restrict the power fading effect for improving the bit error rate to 1.9 × 10−3 and the receiving power penalty to 1.1 dB. Such DMLD based hybrid architecture for 60-GHz MMW fiber-wireless access can directly cover the current optical and wireless networks for next-generation indoor and short-reach mobile communications. PMID:27297267

Differential immune responses of Monochamus alternatus against symbiotic and entomopathogenic fungi.

PubMed

Zhang, Wei; Meng, Jie; Ning, Jing; Qin, Peijun; Zhou, Jiao; Zou, Zhen; Wang, Yanhong; Jiang, Hong; Ahmad, Faheem; Zhao, Lilin; Sun, Jianghua

2017-08-01

Monochamus alternatus, the main vector beetles of invasive pinewood nematode, has established a symbiotic relationship with a native ectotrophic fungal symbiont, Sporothrix sp. 1, in China. The immune response of M. alternatus to S. sp. 1 in the coexistence of beetles and fungi is, however, unknown. Here, we report that immune responses of M. alternatus pupae to infection caused by ectotrophic symbiotic fungus S. sp. 1 and entomopathogenic fungus Beauveria bassiana differ significantly. The S. sp. 1 did not kill the beetles while B. bassiana killed all upon injection. The transcriptome results showed that the numbers of differentially expressed genes in M. alternatus infected with S. sp. 1 were 2-fold less than those infected with B. bassiana at 48 hours post infection. It was noticed that Toll and IMD pathways played a leading role in the beetle's immune system when infected by symbiotic fungus, but upon infection by entomopathogenic fungus, only the Toll pathway gets triggered actively. Furthermore, the beetles could tolerate the infection of symbiotic fungi by retracing their Toll and IMD pathways at 48 h. This study provided a comprehensive sequence resource of M. alternatus transcriptome for further study of the immune interactions between host and associated fungi.

NF-κB/Rel Proteins and the Humoral Immune Responses of Drosophila melanogaster

PubMed Central

Ganesan, Sandhya; Aggarwal, Kamna; Paquette, Nicholas; Silverman, Neal

2011-01-01

Nuclear Factor-κB (NF-κB)/Rel transcription factors form an integral part of innate immune defenses and are conserved throughout the animal kingdom. Studying the function, mechanism of activation and regulation of these factors is crucial for understanding host responses to microbial infections. The fruit fly Drosophila melanogaster has proved to be a valuable model system to study these evolutionarily conserved NF-κB mediated immune responses. Drosophila combats pathogens through humoral and cellular immune responses. These humoral responses are well characterized and are marked by the robust production of a battery of anti-microbial peptides. Two NF-κB signaling pathways, the Toll and the IMD pathways, are responsible for the induction of these antimicrobial peptides. Signal transduction in these pathways is strikingly similar to that in mammalian TLR pathways. In this chapter, we discuss in detail the molecular mechanisms of microbial recognition, signal transduction and NF-κB regulation, in both the Toll and the IMD pathways. Similarities and differences relative to their mammalian counterparts are discussed, and recent advances in our understanding of the intricate regulatory networks in these NF-κB signaling pathways are also highlighted. PMID:20852987

Mathematical modeling of atherosclerotic plaque destabilization: Role of neovascularization and intraplaque hemorrhage.

PubMed

Guo, Muyi; Cai, Yan; Yao, Xinke; Li, Zhiyong

2018-08-07

Observational studies have identified angiogenesis from the adventitial vasa vasorum and intraplaque hemorrhage (IPH) as critical factors in atherosclerotic plaque progression and destabilization. Here we propose a mathematical model incorporating intraplaque neovascularization and hemodynamic calculation with plaque destabilization for the quantitative evaluation of the role of neoangiogenesis and IPH in the vulnerable atherosclerotic plaque formation. An angiogenic microvasculature is generated by two-dimensional nine-point discretization of endothelial cell proliferation and migration from the vasa vasorum. Three key cells (endothelial cells, smooth muscle cells and macrophages) and three key chemicals (vascular endothelial growth factors, extracellular matrix and matrix metalloproteinase) are involved in the plaque progression model, and described by the reaction-diffusion partial differential equations. The hemodynamic calculation of the microcirculation on the generated microvessel network is carried out by coupling the intravascular, interstitial and transvascular flow. The plasma concentration in the interstitial domain is defined as the description of IPH area according to the diffusion and convection with the interstitial fluid flow, as well as the extravascular movement across the leaky vessel wall. The simulation results demonstrate a series of pathophysiological phenomena during the vulnerable progression of an atherosclerotic plaque, including the expanding necrotic core, the exacerbated inflammation, the high microvessel density (MVD) region at the shoulder areas, the transvascular flow through the capillary wall and the IPH. The important role of IPH in the plaque destabilization is evidenced by simulations with varied model parameters. It is found that the IPH can significantly speed up the plaque vulnerability by increasing necrotic core and thinning fibrous cap. In addition, the decreased MVD and vessel permeability may slow down the process of plaque destabilization by reducing the IPH dramatically. We envision that the present model and its future advances can serve as a valuable theoretical platform for studying the dynamic changes in the microenvironment during the plaque destabilization. Copyright © 2018 Elsevier Ltd. All rights reserved.

Dual-wavelength photothermal optical coherence tomography for blood oxygen saturation measurement

NASA Astrophysics Data System (ADS)

Yin, Biwei; Kuranov, Roman V.; McElroy, Austin B.; Milner, Thomas E.

2013-03-01

We report design and demonstration of a dual wavelength photothermal (DWP) optical coherence tomography (OCT) system for imaging of a phantom microvessel and measurement of hemoglobin oxygen saturation (SO2) level. The DWP-OCT system contains a swept-source (SS) two-beam phase-sensitive (PhS) OCT system (1060 nm) and two intensity modulated photothermal excitation lasers (770 nm and 800 nm). The PhS-OCT probe beam (1060 nm) and photothermal excitation beams are combined into one single-mode optical fiber. A galvanometer based two-dimensional achromatic scanning system is designed to provide 14 μm lateral resolution for the PhS-OCT probe beam (1060 nm) and 13 μm lateral resolution for photothermal excitation beams. DWP-OCT system's sensitivity is 102 dB, axial resolution is 13 μm in tissue and uses a real-time digital dispersion compensation algorithm. Noise floor for optical pathlength measurements is 300 pm in the signal frequency range (380-400 Hz) of photothermal modulation frequencies. Blood SO2 level is calculated from measured optical pathlength (op) signal in a 300 μm diameter microvessel phantom introduced by the two photothermal excitation beams. En-face and B-scan images of a phantom microvessel are recorded, and six blood samples' SO2 levels are measured using DWP-OCT and compared with values provided by a commercial blood oximeter. A mathematical model indicates thermal diffusion introduces a systematic artifact that over-estimates SO2 values and is consistent with measured data.

A standalone perfusion platform for drug testing and target validation in micro-vessel networks

PubMed Central

Zhang, Boyang; Peticone, Carlotta; Murthy, Shashi K.; Radisic, Milica

2013-01-01

Studying the effects of pharmacological agents on human endothelium includes the routine use of cell monolayers cultivated in multi-well plates. This configuration fails to recapitulate the complex architecture of vascular networks in vivo and does not capture the relationship between shear stress (i.e. flow) experienced by the cells and dose of the applied pharmacological agents. Microfluidic platforms have been applied extensively to create vascular systems in vitro; however, they rely on bulky external hardware to operate, which hinders the wide application of microfluidic chips by non-microfluidic experts. Here, we have developed a standalone perfusion platform where multiple devices were perfused at a time with a single miniaturized peristaltic pump. Using the platform, multiple micro-vessel networks, that contained three levels of branching structures, were created by culturing endothelial cells within circular micro-channel networks mimicking the geometrical configuration of natural blood vessels. To demonstrate the feasibility of our platform for drug testing and validation assays, a drug induced nitric oxide assay was performed on the engineered micro-vessel network using a panel of vaso-active drugs (acetylcholine, phenylephrine, atorvastatin, and sildenafil), showing both flow and drug dose dependent responses. The interactive effects between flow and drug dose for sildenafil could not be captured by a simple straight rectangular channel coated with endothelial cells, but it was captured in a more physiological branching circular network. A monocyte adhesion assay was also demonstrated with and without stimulation by an inflammatory cytokine, tumor necrosis factor-α. PMID:24404058

Blood Vessel Adaptation with Fluctuations in Capillary Flow Distribution

PubMed Central

Hu, Dan; Cai, David; Rangan, Aaditya V.

2012-01-01

Throughout the life of animals and human beings, blood vessel systems are continuously adapting their structures – the diameter of vessel lumina, the thickness of vessel walls, and the number of micro-vessels – to meet the changing metabolic demand of the tissue. The competition between an ever decreasing tendency of luminal diameters and an increasing stimulus from the wall shear stress plays a key role in the adaptation of luminal diameters. However, it has been shown in previous studies that the adaptation dynamics based only on these two effects is unstable. In this work, we propose a minimal adaptation model of vessel luminal diameters, in which we take into account the effects of metabolic flow regulation in addition to wall shear stresses and the decreasing tendency of luminal diameters. In particular, we study the role, in the adaptation process, of fluctuations in capillary flow distribution which is an important means of metabolic flow regulation. The fluctuation in the flow of a capillary group is idealized as a switch between two states, i.e., an open-state and a close-state. Using this model, we show that the adaptation of blood vessel system driven by wall shear stress can be efficiently stabilized when the open time ratio responds sensitively to capillary flows. As micro-vessel rarefaction is observed in our simulations with a uniformly decreased open time ratio of capillary flows, our results point to a possible origin of micro-vessel rarefaction, which is believed to induce hypertension. PMID:23029014

Anti-TNFα therapy transiently improves high density lipoprotein cholesterol levels and microvascular endothelial function in patients with rheumatoid arthritis: a Pilot Study

PubMed Central

2012-01-01

Background Rheumatoid arthritis (RA) is associated with increased morbidity and mortality from cardiovascular disease (CVD). This can be only partially attributed to traditional CVD risk factors such as dyslipidaemia and their downstream effects on endothelial function. The most common lipid abnormality in RA is reduced levels of high-density lipoprotein (HDL) cholesterol, probably due to active inflammation. In this longitudinal study we hypothesised that anti-tumor necrosis factor-α (anti-TNFα) therapy in patients with active RA improves HDL cholesterol, microvascular and macrovascular endothelial function. Methods Twenty-three RA patients starting on anti-TNFα treatment were assessed for HDL cholesterol level, and endothelial-dependent and -independent function of microvessels and macrovessels at baseline, 2-weeks and 3 months of treatment. Results Disease activity (CRP, fibrinogen, DAS28) significantly decreased during the follow-up period. There was an increase in HDL cholesterol levels at 2 weeks (p < 0.05) which was paralleled by a significant increase in microvascular endothelial-dependent function (p < 0.05). However, both parameters returned towards baseline at 12 weeks. Conclusion Anti-TNFα therapy in RA patients appears to be accompanied by transient but significant improvements in HDL cholesterol levels, which coexists with an improvement in microvascular endothelial-dependent function. PMID:22824166

Research on Shore-Ship Photonic Link Performance for Two- Frequency-Band Signals

NASA Astrophysics Data System (ADS)

Zuo, Yanqin; Cong, Bo

2016-02-01

Ka and Ku bands links for shore-ship communications suffer limited bandwidth and high loss. In this paper, photonics-based links are proposed and modeled. The principle of phase modulation (PM) is elaborated and analyzed. It is showed that PM can effectively suppress high-order inter-modulation distortion (IMD), reduce the insert loss and improve the reliability of the system.

Development of Generic Aircrew Measures of Performance for Distributed Mission Training

DTIC Science & Technology

2003-03-31

collecte de données utiles sur les performances humaines représente des défis considérables. De plus, on ne trouvera pas deux essais d’IMD exactement...weapons Countered bandits offensive Very sound energy management and aircraft manoeuvering Quickly capitalized on offensive position...Effectively countered bandits offensive to a neutral position Ideal Aircraft energy management and manoeuvering Expeditiously capitalized on

Temporal Changes in BEXSERO® Antigen Sequence Type Associated with Genetic Lineages of Neisseria meningitidis over a 15-Year Period in Western Australia

PubMed Central

Mowlaboccus, Shakeel; Perkins, Timothy T.; Smith, Helen; Sloots, Theo; Tozer, Sarah; Prempeh, Lydia-Jessica; Tay, Chin Yen; Peters, Fanny; Speers, David; Keil, Anthony D.; Kahler, Charlene M.

2016-01-01

Neisseria meningitidis is the causative agent of invasive meningococcal disease (IMD). The BEXSERO® vaccine which is used to prevent serogroup B disease is composed of four sub-capsular protein antigens supplemented with an outer membrane vesicle. Since the sub-capsular protein antigens are variably expressed and antigenically variable amongst meningococcal isolates, vaccine coverage can be estimated by the meningococcal antigen typing system (MATS) which measures the propensity of the strain to be killed by vaccinated sera. Whole genome sequencing (WGS) which identifies the alleles of the antigens that may be recognised by the antibody response could represent, in future, an alternative estimate of coverage. In this study, WGS of 278 meningococcal isolates responsible for 62% of IMD in Western Australia from 2000–2014 were analysed for association of genetic lineage (sequence type [ST], clonal complex [cc]) with BEXSERO® antigen sequence type (BAST) and MATS to predict the annual vaccine coverage. A hyper-endemic period of IMD between 2000–05 was caused by cc41/44 with the major sequence type of ST-146 which was not predicted by MATS or BAST to be covered by the vaccine. An increase in serogroup diversity was observed between 2010–14 with the emergence of cc11 serogroup W in the adolescent population and cc23 serogroup Y in the elderly. BASTs were statistically associated with clonal complex although individual antigens underwent antigenic drift from the major type. BAST and MATS predicted an annual range of 44–91% vaccine coverage. Periods of low vaccine coverage in years post-2005 were not a result of the resurgence of cc41/44:ST-146 but were characterised by increased diversity of clonal complexes expressing BASTs which were not predicted by MATS to be covered by the vaccine. The driving force behind the diversity of the clonal complex and BAST during these periods of low vaccine coverage is unknown, but could be due to immune selection and inter-strain competition with carriage of non-disease causing meningococci. PMID:27355628

Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1

PubMed Central

Morland, Cecilie; Andersson, Krister A.; Haugen, Øyvind P.; Hadzic, Alena; Kleppa, Liv; Gille, Andreas; Rinholm, Johanne E.; Palibrk, Vuk; Diget, Elisabeth H.; Kennedy, Lauritz H.; Stølen, Tomas; Hennestad, Eivind; Moldestad, Olve; Cai, Yiqing; Puchades, Maja; Offermanns, Stefan; Vervaeke, Koen; Bjørås, Magnar; Wisløff, Ulrik; Storm-Mathisen, Jon; Bergersen, Linda H.

2017-01-01

Physical exercise can improve brain function and delay neurodegeneration; however, the initial signal from muscle to brain is unknown. Here we show that the lactate receptor (HCAR1) is highly enriched in pial fibroblast-like cells that line the vessels supplying blood to the brain, and in pericyte-like cells along intracerebral microvessels. Activation of HCAR1 enhances cerebral vascular endothelial growth factor A (VEGFA) and cerebral angiogenesis. High-intensity interval exercise (5 days weekly for 7 weeks), as well as L-lactate subcutaneous injection that leads to an increase in blood lactate levels similar to exercise, increases brain VEGFA protein and capillary density in wild-type mice, but not in knockout mice lacking HCAR1. In contrast, skeletal muscle shows no vascular HCAR1 expression and no HCAR1-dependent change in vascularization induced by exercise or lactate. Thus, we demonstrate that a substance released by exercising skeletal muscle induces supportive effects in brain through an identified receptor. PMID:28534495

Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1.

PubMed

Morland, Cecilie; Andersson, Krister A; Haugen, Øyvind P; Hadzic, Alena; Kleppa, Liv; Gille, Andreas; Rinholm, Johanne E; Palibrk, Vuk; Diget, Elisabeth H; Kennedy, Lauritz H; Stølen, Tomas; Hennestad, Eivind; Moldestad, Olve; Cai, Yiqing; Puchades, Maja; Offermanns, Stefan; Vervaeke, Koen; Bjørås, Magnar; Wisløff, Ulrik; Storm-Mathisen, Jon; Bergersen, Linda H

2017-05-23

Physical exercise can improve brain function and delay neurodegeneration; however, the initial signal from muscle to brain is unknown. Here we show that the lactate receptor (HCAR1) is highly enriched in pial fibroblast-like cells that line the vessels supplying blood to the brain, and in pericyte-like cells along intracerebral microvessels. Activation of HCAR1 enhances cerebral vascular endothelial growth factor A (VEGFA) and cerebral angiogenesis. High-intensity interval exercise (5 days weekly for 7 weeks), as well as L-lactate subcutaneous injection that leads to an increase in blood lactate levels similar to exercise, increases brain VEGFA protein and capillary density in wild-type mice, but not in knockout mice lacking HCAR1. In contrast, skeletal muscle shows no vascular HCAR1 expression and no HCAR1-dependent change in vascularization induced by exercise or lactate. Thus, we demonstrate that a substance released by exercising skeletal muscle induces supportive effects in brain through an identified receptor.

Paracrine action of HO-1-modified mesenchymal stem cells mediates cardiac protection and functional improvement.

PubMed

Zeng, Bin; Ren, Xiaofeng; Lin, Guosheng; Zhu, Chengang; Chen, Honglei; Yin, Jiechao; Jiang, Hong; Yang, Bo; Ding, Danhua

2008-10-01

The aim has been to determine whether the supernatants of mesenchymal stem cells (MSCs) transfected with adenovirus carrying human heme oxygenase-1 (hHO-1) gene protect cardiomyocytes from ischemic injury. We have found that hHO-1 infected MSCs (hHO-1-MSCs) increased expression of hHO-1 protein. Apoptosis of cultured hHO-1-MSCs exposed to hypoxia was suppressed. Several cytokines, including HGF, bFGF, TGF-beta, VEGF and IL-1beta, were produced by hHO-1-MSCs, some being significantly enhanced under hypoxia stimulation. Meanwhile, those cytokines reduced caspase-3 level and activity in cultured adult rat ventricular cardiomyocytes (ARVCs) exposed to hypoxia. Supernatants obtained from hHO-1-MSCs improved left ventricular function, limited myocardial infarct size, increased microvessel density, and inhibited apoptosis of cardiomyocytes in rat myocardial infarction. It can be concluded hHO-1-modified MSCs prevent myocardial cell injury via secretion of paracrine-acting mediators.

The vascularization pattern of acellular nerve allografts after nerve repair in Sprague-Dawley rats.

PubMed

Zhu, Zhaowei; Huang, Yanyan; Zou, Xiaoyan; Zheng, Canbin; Liu, Jianghui; Qiu, Longhai; He, Bo; Zhu, Qingtang; Liu, Xiaolin

2017-11-01

We have demonstrated that angiogenesis in acellular nerve allografts (ANAs) can promote neuroregeneration. The present study aimed to investigate the microvascular regeneration pattern of ANAs in Sprague-Dawley (SD) rats. Sixty male SD rats were randomly divided into an autologous group and a rat acellular nerve allograft group (rANA), and 10-mm sciatic nerve defects were induced in these rats. On the 7th, 14th and 21st days after surgery, systemic perfusion with Evans Blue (EB) or lead oxide was performed on the rats through carotid intubation. Samples were then collected for gross observation, and the microvessels in the nerves were reconstructed through microscopic CT scans using MIMICS software. The vascular volume fraction (VF, %) and microvessel growth rate (V, mm/d) in both groups were then measured, and 1 month after surgery, NF-200 staining was performed to observe and compare the growth condition of the axons. Early post-operative perfusion with gelatin/EB showed EB permeation around the acellular nerve. Perfusion with gelatin/lead oxide showed that the blood vessels had grown into the allograft from both ends 7 days after the operation. Fourteen days after the operation, the microvessel growth rate of the autologous group was faster than that of the rANA group (0.39 ± 0.17 mm/d vs. 0.26 ± 0.14 mm/d, p < 0.05), and the vascular VF was also higher than that of the rANA group (8.92% ± 1.54% vs. 6.31% ± 1.21%, p < 0.05). Twenty-one days after the operation, the blood vessels at both ends of the allograft had connected to form a microvessel network. The growth rate was not significantly different between the two groups; however, the vascular VF of the autologous group was higher than that of the rANA group (12.18% ± 2.27% vs. 9.92% ± 0.84%, p < 0.05). One month after the operation, the NF-200 fluorescence (IOD) in the autologous group significantly increased compared with that of the rANA group (540,278 ± 17,424 vs. 473,310 ± 14,636, respectively, p < 0.05), suggesting that the results of the repair after nerve injury were significantly better in the autologous group than in the rANA group. Both the autologous nerve and ANAs rely on the permeation of tissue fluids to supply nutrients during the early stage, and microvessel growth mainly starts at both ends of the graft and enters the graft along the long axis. Compared to ANAs, the growth speed of revascularization in autologous nerve grafts was faster, leading to a better outcome in the autologous nerve group.

[Dynamic change in microcirculation of pancreas after experimental high-voltage electric burn].

PubMed

Zhang, Qing-fu; Bai, Yong-qiang

2009-10-01

To observe the changes in surface microcirculation of pancreas after high-voltage electric burn (HEB). Thirty rabbits were divided into electrical injury (E) group and control (C) group in a simple random method, with 15 rabbits in each group. Rabbit model of HEB was reproduced from E group with TC-30-20KVA type voltage regulator and YDJ-10KVA type experimental transformer. Rabbits in C group were shamly burned with the same equipment as in E group but not electrified. Intravenous blood of rabbits in both groups was drawn 15 mins before HEB and 0, 1, 2, 4, 8 h after to determine the levels of serum amylase and blood glucose. The morphology of the pancreas microvessels and its surrounding tissues, and the dynamic changes in microvascular blood flow were observed with WX-9 microscope and its image analytical system. The level of serum amylase of rabbits in E group increased gradually and peaked (849 +/- 39) U/L at 8 post HEB h (PHH), which decreased gradually reaching the nadir (153 +/- 21) U/L at 8 PHH in C group (P < 0.05). The blood glucose levels of rabbits in E group and C group increased gradually, with the former level obviously higher than the latter (P < 0.05). Arteriole, venule and capillary network on the surface of pancreatic lobules of rabbits in both groups were clearly seen and well-distributed in the natural way before HEB. In E group, arterioles of rabbits contracted at 0 PHH, and increased gradually in caliber size at 1 PHH; venules of rabbits were unevenly thickened at 2 PHH, and dilated at 8 PHH; the capillaries were contracted or with interrupted flow or completely obstructed at 0 PHH, and their thickness were uneven at 2 PHH, showing exudation at 8 PHH. There was no obvious change of microvessels in rabbits in C group at each time point. There was no exudation and bleeding around the microvessels on the pancreas surface of rabbits in both groups before HEB. In E group exudation was observed around microvessels at 1 PHH, bleeding was observed at 2 PHH and became obvious at 4 PHH; exudation and diffuse bleeding from capillaries were observed at 8 PHH. There was no exudation and bleeding in rabbits in C group as observed at each time point. Before HEB, blood flow speed in microvessels of rabbits in 2 groups was similar to each other (P > 0.05), and no erythrocyte aggregation or microthrombus was found in both groups. In E group, blood flow speed slowed down at 0 PHH as compared with that before HEB, it accelerated at 1 h and slowed down later; erythrocyte aggregation in venules and capillaries was found at 0 PHH, and it aggregated gradually. No above-mentioned change was found in C group. HEB produces microcirculation disturbance and functional disturbance of pancreas.

Deregulation of tumor angiogenesis and blockade of tumor growth in PPARbeta-deficient mice.

PubMed

Müller-Brüsselbach, Sabine; Kömhoff, Martin; Rieck, Markus; Meissner, Wolfgang; Kaddatz, Kerstin; Adamkiewicz, Jürgen; Keil, Boris; Klose, Klaus J; Moll, Roland; Burdick, Andrew D; Peters, Jeffrey M; Müller, Rolf

2007-08-08

The peroxisome proliferator-activated receptor-beta (PPARbeta) has been implicated in tumorigenesis, but its precise role remains unclear. Here, we show that the growth of syngeneic Pparb wild-type tumors is impaired in Pparb(-/-) mice, concomitant with a diminished blood flow and an abundance of hyperplastic microvascular structures. Matrigel plugs containing pro-angiogenic growth factors harbor increased numbers of morphologically immature, proliferating endothelial cells in Pparb(-/-) mice, and retroviral transduction of Pparb triggers microvessel maturation. We have identified the Cdkn1c gene encoding the cell cycle inhibitor p57(Kip2) as a PPARbeta target gene and a mediator of the PPARbeta-mediated inhibition of cell proliferation, which provides a possible mechanistic explanation for the observed tumor endothelial hyperplasia and deregulation of tumor angiogenesis in Pparb(-/-) mice. Our data point to an unexpected essential role for PPARbeta in constraining tumor endothelial cell proliferation to allow for the formation of functional tumor microvessels.

Live-cell imaging of invasion and intravasation in an artificial microvessel platform.

PubMed

Wong, Andrew D; Searson, Peter C

2014-09-01

Methods to visualize metastasis exist, but additional tools to better define the biologic and physical processes underlying invasion and intravasation are still needed. One difficulty in studying metastasis stems from the complexity of the interface between the tumor microenvironment and the vascular system. Here, we report the development of an investigational platform that positions tumor cells next to an artificial vessel embedded in an extracellular matrix. On this platform, we used live-cell fluorescence microscopy to analyze the complex interplay between metastatic cancer cells and a functional artificial microvessel that was lined with endothelial cells. The platform recapitulated known interactions, and its use demonstrated the capabilities for a systematic study of novel physical and biologic parameters involved in invasion and intravasation. In summary, our work offers an important new tool to advance knowledge about metastasis and candidate antimetastatic therapies. ©2014 American Association for Cancer Research.

Fluorescein isothiocyanate (FITC)-Dextran Extravasation as a Measure of Blood-Brain Barrier Permeability

PubMed Central

Natarajan, Reka; Northrop, Nicole

2017-01-01

The blood-brain barrier (BBB) is formed in part by vascular endothelial cells that constitute the capillaries and microvessels of the brain. The function of this barrier is to maintain homeostasis within the brain microenvironment and buffer the brain from changes in the periphery. A dysfunction of the BBB would permit circulating molecules and pathogens typically restricted to the periphery to enter the brain and interfere with normal brain function. As increased permeability of the BBB is associated with several neuropathologies, it is important to have a reliable and sensitive method that determines BBB permeability and the degree of BBB disruption. A detailed protocol is presented for assessing the integrity of the BBB by transcardial perfusion of a 10,000 Da FITC labeled dextran molecule and its visualization to determine the degree of extravasation from brain microvessels. PMID:28398646

Microcirculation of the pancreas. A quantitative study of physiology and changes in pancreatitis.

PubMed

Klar, E; Endrich, B; Messmer, K

1990-02-01

A rabbit model was designed to study the microcirculation of the pancreas with special reference to changes occurring during acute pancreatitis. Intravital microscopy was used in conjunction with video techniques allowing for continuous observation and off-line evaluation of microvessel diameters and blood cell velocities. Based on the microvessel geometry a functional microvascular unit could be defined at the level of the pancreatic lobule consisting of intralobular arteries and veins and an arcade-like preferential pathway framing the capillary network. Experimental acute pancreatitis resulted in immediate leakage of the macromolecular plasma marker (FITC-Dextran 70) from the microvasculature suggesting increased permeability. In contrast to control conditions, pancreatic capillaries were excluded from the circulation during acute pancreatitis starting 30 min after induction with only single capillaries remaining perfused after 3 hours. At the same time, there was constant blood flow through the preferential pathways representing shunt perfusion.

In-vivo visualization of melanoma tumor microvessels and blood flow velocity changes accompanying tumor growth

NASA Astrophysics Data System (ADS)

Ishida, Hiroki; Hachiga, Tadashi; Andoh, Tsugunobu; Akiguchi, Shunsuke

2012-11-01

We demonstrate that using micro multipoint laser Doppler velocimetry (μ-MLDV) for noninvasive in-vivo imaging of blood vessels is useful for diagnosing malignant melanomas by comparison with visual diagnosis by dermoscopy. The blood flow velocity in microvessels varied during growth of melanomas transplanted in mouse ears. Mouse ears were observed by μ-MLDV up to 16 days after transplantation. The blood flow velocity in the tumor increased with increasing time and reached maximum of 4.5 mm/s at 9 days, which is more than twice that prior to transplantation. After 12 days, when the lesion had grown to an area of 6.6 mm2, we observed the formation of new blood vessels in the tumor. Finally, when the lesion had an area of 18 mm2 after 16 days, the flow velocity in the tumor decreased to approximately 3.2 mm/s.

Hyperforin acts as an angiogenesis inhibitor.

PubMed

Schempp, Christoph M; Kiss, Judit; Kirkin, Vladimir; Averbeck, Marco; Simon-Haarhaus, Birgit; Kremer, Bernhard; Termeer, Christian C; Sleeman, Jonathan; Simon, Jan C

2005-11-01

Hyperforin is a plant compound from Hypericum perforatum that inhibits tumor cell proliferation in vitro by induction of apoptosis. Here, we report that hyperforin also acts as an angiogenesis inhibitor in vitro and in vivo. In vitro, hyperforin blocked microvessel formation of human dermal microvascular endothelial cells (HDMEC) on a complex extracellular matrix. Furthermore, hyperforin reduced proliferation of HDMEC in a dose-dependent manner, without displaying toxic effects or inducing apoptosis of the cells. To evaluate the antiangiogenic activity of hyperforin in vivo, Wistar rats were subcutaneously injected with MT-450 mammary carcinoma cells and were treated with peritumoral injections of hyperforin or solvent. Hyperforin significantly inhibited tumor growth, induced apoptosis of tumor cells and reduced tumor vascularization, as shown by in situ staining of CD31-positive microvessels in the tumor stroma. These data suggest that, in addition to the induction of tumor cell apoptosis, hyperforin can also suppress angiogenesis by a direct, non-toxic effect on endothelial cells.

[Morphological signs of mitochondrial cytopathy in skeletal muscles and micro-vessel walls in a patient with cerebral artery dissection associated with MELAS syndrome].

PubMed

Sakharova, A V; Kalashnikova, L A; Chaĭkovskaia, R P; Mir-Kasimov, M F; Nazarova, M A; Pykhtina, T N; Dobrynina, L A; Patrusheva, N L; Patrushev, L I; Protskiĭ, S V

2012-01-01

Skin and muscles biopsy specimens of a patient harboring A3243G mutation in mitochondrial DNA, with dissection of internal carotid and vertebral arteries, associated with MELAS were studied using histochemical and electron-microscopy techniques. Ragged red fibers, regional variability of SDH histochemical reaction, two types of morphologically atypical mitochondria and their aggregation were found in muscle. There was correlation between SDH histochemical staining and number of mitochondria revealed by electron microscopy in muscle tissue. Similar mitochondrial abnormality, their distribution and cell lesions followed by extra-cellular matrix mineralization were found in the blood vessel walls. In line with generalization of cytopathy process caused by gene mutation it can be supposed that changes found in skin and muscle microvessels also exist in large cerebral vessels causing the vessel wall "weakness", predisposing them to dissection.

Microvascular Guidance: A Challenge to Support the Development of Vascularised Tissue Engineering Construct

PubMed Central

Sukmana, Irza

2012-01-01

The guidance of endothelial cell organization into a capillary network has been a long-standing challenge in tissue engineering. Some research efforts have been made to develop methods to promote capillary networks inside engineered tissue constructs. Capillary and vascular networks that would mimic blood microvessel function can be used to subsequently facilitate oxygen and nutrient transfer as well as waste removal. Vascularization of engineering tissue construct is one of the most favorable strategies to overpass nutrient and oxygen supply limitation, which is often the major hurdle in developing thick and complex tissue and artificial organ. This paper addresses recent advances and future challenges in developing three-dimensional culture systems to promote tissue construct vascularization allowing mimicking blood microvessel development and function encountered in vivo. Bioreactors systems that have been used to create fully vascularized functional tissue constructs will also be outlined. PMID:22623881

Loss of Endothelial Barrier Antigen Immunoreactivity in Rat Retinal Microvessels is Correlated with Clostridium perfringens Type D Epsilon Toxin-induced Damage to the Blood-Retinal Barrier.

PubMed

Mander, K A; Finnie, J W

2018-01-01

Clostridium perfringens type D epsilon toxin (ETX) is a potent neurotoxin producing a severe, and often fatal, neurological disorder in ruminant livestock. Microvascular damage appears to be the fundamental action of ETX in the brain and, recently, similar vascular injury, with subsequent severe vasogenic oedema, has been reported in the retina of rats given ETX. Endothelial barrier antigen (EBA) is a useful marker of an intact blood-brain barrier in rats and it has been shown that loss of EBA immunoreactivity is correlated with ETX-induced cerebral microvascular damage in this species. This paper reports, for the first time, that loss of EBA immunoexpression also occurs in rat retinal microvessels exposed to ETX, the marked reduction in EBA immunopositivity acting as a useful marker for blood-retinal barrier breakdown produced by this neurotoxin. Copyright © 2017 Elsevier Ltd. All rights reserved.

Microvasculature remodeling in the mouse lower gut during inflammaging

PubMed Central

Jeong, Jae-Ho; Kim, KwangSoo; Lim, Daejin; Kim, Kun-Hee; Kim, Hyung-Seok; Lee, Sungsu; Song, Joo-Hye; Moon, Byoung-Gon; Choy, Hyon E.; Park, Sang Chul

2017-01-01

Inflammaging is defined as low-grade, chronic, systemic inflammation in aging, in the absence of overt infection. Age-associated deterioration of gastrointestinal function could be ascribed to the inflammaging, although evidence is yet to emerge. Here we show that microvessels in aging mouse intestine were progressively deprived of supportive structures, microvessel-associated pericytes and adherens junction protein vascular endothelial (VE)-cadherin, and became leaky. This alteration was ascribed to up-regulation of angiopoetin-2 in microvascular endothelial cells. Up-regulation of the angiopoietin-2 was by TNF-α, originated from M2-like residential CD206+ macrophages, proportion of which increases as animal ages. It was concluded that antigenic burdens encountered in intestine throughout life create the condition of chronic stage of inflammation, which accumulates M2-like macrophages expressing TNF-α. The TNF-α induces vascular leakage to facilitate recruitment of immune cells into intestine under the chronic inflammatory setting. PMID:28045067

Meningococcal B vaccination: real-world experience and future perspectives

PubMed Central

Kuhdari, Parvanè; Valente, Nicoletta; Gabutti, Giovanni

2016-01-01

Invasive meningococcal disease (IMD) represents a severe risk for health. It can be considered the most dangerous vaccine-preventable disease due to the high probability of related permanent sequelae and death. The introduction in many countries of the conjugate vaccines against A, C, W135, and Y meningococcal serogroups influenced significantly the impact of the disease. Recently, the difficulties in obtaining an effective vaccine against meningococcal serogroup B (MenB) have been get over through the reverse vaccinology, enabling the recognition of some antigens providing a response against most of circulating MenB strains worldwide. The new 4cMenB vaccine is recommended in Europe, Canada, Australia, the USA, and some Latin American countries. Even if sound data on efficacy and safety profile are available, the results in terms of effectiveness are still limited. The management of the MenB outbreaks in two US universities demonstrated the ability to quickly achieve high vaccination coverage rates and no new cases among immunized subjects were assessed. It is desirable that the opportunity to complete preventive intervention against IMD offered by the new 4cMenB vaccine should be recognized and that this vaccine is included in the vaccination schedule to complete the panel of immunization against Neisseria meningitidis. PMID:27309042

Exploring the immune signalling pathway-related genes of the cattle tick Rhipicephalus microplus: From molecular characterization to transcriptional profile upon microbial challenge.

PubMed

Rosa, Rafael D; Capelli-Peixoto, Janaína; Mesquita, Rafael D; Kalil, Sandra P; Pohl, Paula C; Braz, Glória R; Fogaça, Andrea C; Daffre, Sirlei

2016-06-01

In dipteran insects, invading pathogens are selectively recognized by four major pathways, namely Toll, IMD, JNK, and JAK/STAT, and trigger the activation of several immune effectors. Although substantial advances have been made in understanding the immunity of model insects such as Drosophila melanogaster, knowledge on the activation of immune responses in other arthropods such as ticks remains limited. Herein, we have deepened our understanding of the intracellular signalling pathways likely to be involved in tick immunity by combining a large-scale in silico approach with high-throughput gene expression analysis. Data from in silico analysis revealed that although both the Toll and JAK/STAT signalling pathways are evolutionarily conserved across arthropods, ticks lack central components of the D. melanogaster IMD pathway. Moreover, we show that tick immune signalling-associated genes are constitutively transcribed in BME26 cells (a cell lineage derived from embryos of the cattle tick Rhipicephalus microplus) and exhibit different transcriptional patterns in response to microbial challenge. Interestingly, Anaplasma marginale, a pathogen that is naturally transmitted by R. microplus, causes downregulation of immune-related genes, suggesting that this pathogen may manipulate the tick immune system, favouring its survival and vector colonization. Copyright © 2015 Elsevier Ltd. All rights reserved.

Annotation of the Asian Citrus Psyllid Genome Reveals a Reduced Innate Immune System

PubMed Central

Arp, Alex P.; Hunter, Wayne B.; Pelz-Stelinski, Kirsten S.

2016-01-01

Citrus production worldwide is currently facing significant losses due to citrus greening disease, also known as Huanglongbing. The citrus greening bacteria, Candidatus Liberibacter asiaticus (CLas), is a persistent propagative pathogen transmitted by the Asian citrus psyllid, Diaphorina citri Kuwayama (Hemiptera: Liviidae). Hemipterans characterized to date lack a number of insect immune genes, including those associated with the Imd pathway targeting Gram-negative bacteria. The D. citri draft genome was used to characterize the immune defense genes present in D. citri. Predicted mRNAs identified by screening the published D. citri annotated draft genome were manually searched using a custom database of immune genes from previously annotated insect genomes. Toll and JAK/STAT pathways, general defense genes Dual oxidase, Nitric oxide synthase, prophenoloxidase, and cellular immune defense genes were present in D. citri. In contrast, D. citri lacked genes for the Imd pathway, most antimicrobial peptides, 1,3-β-glucan recognition proteins (GNBPs), and complete peptidoglycan recognition proteins. These data suggest that D. citri has a reduced immune capability similar to that observed in A. pisum, P. humanus, and R. prolixus. The absence of immune system genes from the D. citri genome may facilitate CLas infections, and is possibly compensated for by their relationship with their microbial endosymbionts. PMID:27965582

Innate immune system capabilities of the Asian citrus psyllid, Diaphorina citri.

PubMed

Arp, Alex P; Martini, Xavier; Pelz-Stelinski, Kirsten S

2017-09-01

Citrus production worldwide is currently threatened by Huanglongbing, or citrus greening disease. The associated pathogen, Candidatus Liberibacter asiaticus (CLas), is transmitted by the Asian citrus psyllid, Diaphorina citri. Annotation of the D. citri genome revealed a reduced innate immune system lacking a number of antimicrobial peptides and the Imd pathway associated with defense against Gram-negative bacteria. We characterized this apparent immune reduction in survival assays in which D. citri were exposed to Gram-negative or Gram-positive bacteria. D. citri experienced significant mortality when exposed to Serratia marcescens (Gram-negative) through oral ingestion or by septic injury. Escherichia coli (Gram-negative) also caused significant D. citri mortality, but only when inoculated at high concentrations through oral ingestion or by septic injury. Neither Micrococcus luteus (Gram-positive) or Bacillus subtilis (Gram-positive) caused significant mortality as compared to controls in any experiment. E. coli titers increased rapidly following exposure, while M. luteus titer remained stable for 72 h. We demonstrate that D. citri is capable of defending against E. coli, a Gram-negative bacterium, despite lacking the Imd defense pathway. The tolerance of D. citri to M. luteus infection, yet inability to effectively clear infections, presents questions to efficacy of D. citri immune response to effectively clear Gram-positive infections. Copyright © 2017. Published by Elsevier Inc.

Genome-wide characterization and expression profiling of immune genes in the diamondback moth, Plutella xylostella (L.)

PubMed Central

Xia, Xiaofeng; Yu, Liying; Xue, Minqian; Yu, Xiaoqiang; Vasseur, Liette; Gurr, Geoff M.; Baxter, Simon W.; Lin, Hailan; Lin, Junhan; You, Minsheng

2015-01-01

The diamondback moth, Plutella xylostella (L.), is a destructive pest that attacks cruciferous crops worldwide. Immune responses are important for interactions between insects and pathogens and information on these underpins the development of strategies for biocontrol-based pest management. Little, however, is known about immune genes and their regulation patterns in P. xylostella. A total of 149 immune-related genes in 20 gene families were identified through comparison of P. xylostella genome with the genomes of other insects. Complete and conserved Toll, IMD and JAK-STAT signaling pathways were found in P. xylostella. Genes involved in pathogen recognition were expanded and more diversified than genes associated with intracellular signal transduction. Gene expression profiles showed that the IMD pathway may regulate expression of antimicrobial peptide (AMP) genes in the midgut, and be related to an observed down-regulation of AMPs in experimental lines of insecticide-resistant P. xylostella. A bacterial feeding study demonstrated that P. xylostella could activate different AMPs in response to bacterial infection. This study has established a framework of comprehensive expression profiles that highlight cues for immune regulation in a major pest. Our work provides a foundation for further studies on the functions of P. xylostella immune genes and mechanisms of innate immunity. PMID:25943446

Third order intermodulation distortion in HTS Josephson Junction downconverter at 12GHz

DOE Office of Scientific and Technical Information (OSTI.GOV)

Suzuki, Katsumi; Hayashi, Kunihiko; Fujimoto, Manabu

1994-12-31

Here the authors first report on the microwave characteristics of the third order intermodulation distortion(IMD3) in High-Tc Superconductor (HTS) Josephson Junction (JJ) Downconverter at 12GHz. They have successfully developed high quality nonlinear YBCO microbridge Josephson junctions for such an active MMIC as a mixer with RF, LO, IF and bias filters, which have been fabricated on (100) MgO substrates with 20mm x 20mm x 0.5mm dimensions. The minimum conversion loss of the JJ mixer is 11 dB at very small local microwave input power LO= {minus}20dBm which is two order less than Schottky diode mixer. Consequently, this small optimum LOmore » power gives the small RF input power at which the output IF power of the YBCO mixer saturates. Two-tone third-order intercept point(IP3) performance is a significantly important figure of merit typically used to define linearity of devices and circuits. The RF input power = {minus}15dBm at the IP3 point is obtained for the YBCO mixer at 15K and LO = 10.935GHz with {minus}22dBm. The have successfully measured the dependence of IMD3 on temperature, bias current and LO power.« less

Genome-wide characterization and expression profiling of immune genes in the diamondback moth, Plutella xylostella (L.).

PubMed

Xia, Xiaofeng; Yu, Liying; Xue, Minqian; Yu, Xiaoqiang; Vasseur, Liette; Gurr, Geoff M; Baxter, Simon W; Lin, Hailan; Lin, Junhan; You, Minsheng

2015-05-06

The diamondback moth, Plutella xylostella (L.), is a destructive pest that attacks cruciferous crops worldwide. Immune responses are important for interactions between insects and pathogens and information on these underpins the development of strategies for biocontrol-based pest management. Little, however, is known about immune genes and their regulation patterns in P. xylostella. A total of 149 immune-related genes in 20 gene families were identified through comparison of P. xylostella genome with the genomes of other insects. Complete and conserved Toll, IMD and JAK-STAT signaling pathways were found in P. xylostella. Genes involved in pathogen recognition were expanded and more diversified than genes associated with intracellular signal transduction. Gene expression profiles showed that the IMD pathway may regulate expression of antimicrobial peptide (AMP) genes in the midgut, and be related to an observed down-regulation of AMPs in experimental lines of insecticide-resistant P. xylostella. A bacterial feeding study demonstrated that P. xylostella could activate different AMPs in response to bacterial infection. This study has established a framework of comprehensive expression profiles that highlight cues for immune regulation in a major pest. Our work provides a foundation for further studies on the functions of P. xylostella immune genes and mechanisms of innate immunity.

Predictors of coverage of the national maternal pertussis and infant rotavirus vaccination programmes in England.

PubMed

Byrne, L; Ward, C; White, J M; Amirthalingam, G; Edelstein, M

2018-01-01

This study assessed variation in coverage of maternal pertussis vaccination, introduced in England in October 2012 in response to a national outbreak, and a new infant rotavirus vaccination programme, implemented in July 2013. Vaccine eligible patients were included from national vaccine coverage datasets and covered April 2014 to March 2015 for pertussis and January 2014 to June 2016 for rotavirus. Vaccine coverage (%) was calculated overall and by NHS England Local Team (LT), ethnicity and Index of Multiple Deprivation (IMD) quintile, and compared using binomial regression. Compared with white-British infants, the largest differences in rotavirus coverage were in 'other', white-Irish and black-Caribbean infants (-13·9%, -12·1% and -10·7%, respectively), after adjusting for IMD and LT. The largest differences in maternal pertussis coverage were in black-other and black-Caribbean women (-16·3% and -15·4%, respectively). Coverage was lowest in London LT for both programmes. Coverage decreased with increasing deprivation and was 14·0% lower in the most deprived quintile compared with the least deprived for the pertussis programme and 4·4% lower for rotavirus. Patients' ethnicity and deprivation were therefore predictors of coverage which contributed to, but did not wholly account for, geographical variation in coverage in England.

Invasive meningococcal disease in children in Jerusalem

PubMed Central

STEIN-ZAMIR, C.; ABRAMSON, N.; ZENTNER, G.; SHOOB, H.; VALINSKY, L.; BLOCK, C.

2008-01-01

SUMMARY Neisseria meningitidis is an important cause of childhood meningitis and septicaemia. Between 1999 and 2005, 133 invasive meningococcal disease (IMD) cases occurred in Jerusalem, 112 (84·2%) of them in children aged 0–14 years. The annual incidence rate in Jerusalem was higher than the national average (2·45±0·6 vs. 1·13±0·16/100 000 population, P=0·002). Most of the children (82·1%) were from low socio-economic Arab and Jewish ultra-orthodox communities; mortality was higher among Arab than Jewish children (1·3 vs. 0·22/100 000 person-years, P=0·004). A cluster of 10 children with severe meningococcal sepsis (three fatalities) emerged in the winter of 2003–2004. Compared to the other 102 cases in 1999–2005 both meningococcaemia (100% vs. 51%, P=0·003) and mortality (30% vs. 6·9%, P=0·014) rates were higher. Serogroup B comprised 77·6% of the bacterial isolates. Pulsed-field gel electrophoresis showed considerable variability among cluster isolates, but significant resemblance in Arab cases throughout 1999–2005. The increased susceptibility of specific sub-populations to IMD necessitates further evaluation. PMID:17662169

Blood-filled cerebrospinal fluid-enhanced pericyte microvasculature contraction in rat retina: A novel in vitro study of subarachnoid hemorrhage

PubMed Central

Liu, Zhi; Li, Qiang; Cui, Gaoyu; Zhu, Gang; Tang, Weihua; Zhao, Hengli; Zhang, John H.; Chen, Yujie; Feng, Hua

2016-01-01

Previously, it was widely accepted that the delayed ischemic injury and poor clinical outcome following subarachnoid hemorrhage (SAH) was caused by cerebral vasospasm. This classical theory was challenged by a clazosentan clinical trial, which failed to improve patient outcome, despite reversing angiographic vasospasm. One possible explanation for the results of this trial is the changes in microcirculation following SAH, particularly in pericytes, which are the primary cell type controlling microcirculation in the brain parenchyma. However, as a result of technical limitations and the lack of suitable models, there was no direct evidence of microvessel dysfunction following SAH. In the present study, whole-mount retinal microvasculature has been introduced to study microcirculation in the brain following experimental SAH in vitro. Artificial blood-filled cerebrospinal fluid (BSCF) was applied to the retinal microvasculature to test the hypothesis that the presence of subarachnoid blood affects the contractile properties of the pericytes containing cerebral microcirculation during the early phase of SAH. It was observed that BCSF induced retina microvessel contraction and that this contraction could be resolved by BCSF wash-out. Furthermore, BCSF application accelerated pericyte-populated collagen gel contraction and increased the expression of α-smooth muscle actin. In addition, BCSF induced an influx of calcium in cultured retinal pericytes. In conclusion, the present study demonstrates increased contractility of retinal microvessels and pericytes in the presence of BCSF in vitro. These findings suggest that pericyte contraction and microvascular dysfunction is induced following SAH, which could lead to greater susceptibility to SAH-induced ischemia. PMID:27698742

Oxygen gradients in the microcirculation.

PubMed

Pittman, R N

2011-07-01

Early in the last century August Krogh embarked on a series of seminal studies to understand the connection between tissue metabolism and mechanisms by which the cardiovascular system supplied oxygen to meet those needs. Krogh recognized that oxygen was supplied from blood to the tissues by passive diffusion and that the most likely site for oxygen exchange was the capillary network. Studies of tissue oxygen consumption and diffusion coefficient, coupled with anatomical studies of capillarity in various tissues, led him to formulate a model of oxygen diffusion from a single capillary. Fifty years after the publication of this work, new methods were developed which allowed the direct measurement of oxygen in and around microvessels. These direct measurements have confirmed the predictions by Krogh and have led to extensions of his ideas resulting in our current understanding of oxygenation within the microcirculation. Developments during the last 40 years are reviewed, including studies of oxygen gradients in arterioles, capillaries, venules, microvessel wall and surrounding tissue. These measurements were made possible by the development and use of new methods to investigate oxygen in the microcirculation, so mention is made of oxygen microelectrodes, microspectrophotometry of haemoglobin and phosphorescence quenching microscopy. Our understanding of oxygen transport from the perspective of the microcirculation has gone from a consideration of oxygen gradients in capillaries and tissue to the realization that oxygen has the ability to diffuse from any microvessel to another location under the conditions that there exists a large enough PO(2) gradient and that the permeability for oxygen along the intervening pathway is sufficient. © 2011 The Author. Acta Physiologica © 2011 Scandinavian Physiological Society.

Protein-bounded uremic toxin p-cresylsulfate induces vascular permeability alternations.

PubMed

Tang, Wei-Hua; Wang, Chao-Ping; Yu, Teng-Hung; Tai, Pei-Yang; Liang, Shih-Shin; Hung, Wei-Chin; Wu, Cheng-Ching; Huang, Sung-Hao; Lee, Yau-Jiunn; Chen, Shih-Chieh

2018-06-01

The goal of the present studies is to investigate that the impact of p-cresylsulfate (PCS) on the endothelial barrier integrity via in situ exposure and systemic exposure. Vascular permeability changes induced by local injection of PCS were evaluated by the techniques of both Evans blue (EB) and India ink tracer. Rats were intravenously injected with EB or India ink followed by intradermal injections of various doses of PCS (0, 0.4, 2, 10 and 50 µmol/site) on rat back skins. At different time points, skin EB was extracted and quantified. The administration of India ink was used to demonstrate leaky microvessels. Skin PCS levels were also determined by liquid chromatography-mass spectrometry. We also investigated whether the increased endothelial leakage occurred in the aortic endothelium in rats treated with 5/6 nephrectomy and intraperitoneal injection of PCS 50 mg/kg/day for 4 weeks. The aortic endothelial integrity was evaluated by increased immunoglobulin G (IgG) leakage. High doses of PCS, but not lower doses, significantly induced vascular leakage as compared to saline injection and EB leakage exhibited in time-dependent manner. A time-correlated increase in leaky microvessels was detected in the tissues examined. The injected PCS declined with time and displayed an inverse relationship with vascular leakage. Chronic kidney disease (CKD) rats administered with PCS, compared to control rats, had significantly higher serum levels of PCS and apparent IgG deposition in the aortic intima. Increased endothelial leakage induced by PCS in skin microvessels and the aorta of CKD rats suggests that the PCS-induced endothelial barrier dysfunction.

Effect of intraplaque angiogenesis to atherosclerotic rupture-prone plaque induced by high shear stress in rabbit model

PubMed Central

Qiu, Juhui; Lei, Daoxi; Hu, Jianjun; Yin, Tieying; Zhang, Kang; Yu, Donghong

2017-01-01

Abstract Atherosclerotic prone-rupture plaque is mainly localized in the region of the entrance to the stenosis with high shear stress and the reasons are largely unknown. Our hypothesis is that such a distribution of cells in atherosclerotic plaque may depend on the angiogenesis. Silastic collars induced regions of high shear stress (20.68 ± 5.27 dynes/cm2) in the upstream flow and low shear stress (12.25 ± 1.28 dynes/cm2) in the downstream flow in carotid arteries. Compared with the low shear stress region, plaques in the high shear stress region showed more intraplaque haemorrhaging, less collagen and higher apoptotic rates of vascular smooth muscle cells; endothelial cells (ECs) in the high shear stress region were characterized with integrity and high endothelial nitric oxide synthase (eNOS) expression (1570.3 ± 345.5% vs 172.9 ± 49.9%). The number of intraplaque microvessels is very high in the high shear stress region (15 ± 1.8 n/mm2 vs 3.5 ± 0.4 n/mm2), and the microvessels in the plaque show ECs were abnormal, with membrane blebs, intracytoplasmic vacuoles and leukocyte infiltration. Our current study reveals that the integrity of the endothelium and the vulnerability of atherosclerotic plaques are simultaneously localized in high shear stress regions, and we provide evidence for the first time that microvessels in the intraplaque maybe responsible for rupture-prone plaque formation in the high shear stress region. PMID:28798867

Interactive effects of acupuncture on pain and distress in major burns: An experiment with rats.

PubMed

Abali, Ayse Ebru; Cabioglu, Tugrul; Ozdemir, Handan; Haberal, Mehmet

2015-06-01

This study sought to investigate the interactive effects of acupuncture on pain and distress and the local progress in the burn wound in an experimental major burn model. Forty-eight male Sprague-Dawley rats were divided into six groups: S group (sham/observation during 7 days after injury); SA group (sham/acupuncture/observation during 7 days after injury); B1 group (burns/observation during 1h after injury); BA1 group (burns/acupuncture/observation during 1 h after injury); B7 group (burns/observation during 7 days after injury); and BA7 group (burns/acupuncture/observation during 7 days after injury). Pain and distress scores were evaluated throughout the study. The amounts of neutrophils and mononuclear cells were evaluated semiquantitatively, and the number of microvessels was evaluated quantitatively. Our data indicated that the average pain score of BA7 group was significantly lower than the other study groups. Histopathologic investigations indicate that the amounts of neutrophil and mononuclear cell and numbers of microvessels in the unburned skin were higher in acupuncture-applied groups. The number of microvessels in burn wounds of BA7 group was significantly higher than that of the other groups. Our data suggest that acupuncture provides low pain and distress scores in experimental rat model, and it contributes to wound healing with an enhanced angiogenesis during the acute phase of burns. Future clinical and experimental studies should be conducted to discern the benefits from acupuncture in pain management of burn patients. Copyright © 2014 Elsevier Ltd and ISBI. All rights reserved.

Oxygen Gradients in the Microcirculation

PubMed Central

Pittman, Roland N.

2010-01-01

Early in the last century August Krogh embarked on a series of seminal studies to understand the connection between tissue metabolism and mechanisms by which the cardiovascular system supplied oxygen to meet those needs. Krogh recognized that oxygen was supplied from blood to the tissues by passive diffusion and that the most likely site for oxygen exchange was the capillary network. Studies of tissue oxygen consumption and diffusion coefficient, coupled with anatomical studies of capillarity in various tissues, led him to formulate a model of oxygen diffusion from a single capillary. Fifty years after the publication of this work, new methods were developed which allowed the direct measurement of oxygen in and around microvessels. These direct measurements have confirmed the predictions by Krogh and have led to extensions of his ideas resulting in our current understanding of oxygenation within the microcirculation. Developments during the last 40 years are reviewed, including studies of oxygen gradients in arterioles, capillaries, venules, microvessel wall and surrounding tissue. These measurements were made possible by the development and use of new methods to investigate oxygen in the microcirculation, so mention is made of oxygen microelectrodes, microspectrophotometry of haemoglobin and phosphorescence quenching microscopy. Our understanding of oxygen transport from the perspective of the microcirculation has gone from a consideration of oxygen gradients in capillaries and tissue to the realization that oxygen has the ability to diffuse from any microvessel to another location under the conditions that there exists a large enough PO2 gradient and that the permeability for oxygen along the intervening pathway is sufficient. PMID:21281453

Mediastinal micro-vessels clipping during lymph node dissection may contribute to reduce postoperative pleural drainage

PubMed Central

Yan, Shi; Wang, Xing; Lv, Chao; Phan, Kevin; Wang, Yuzhao; Wang, Jia; Yang, Yue

2016-01-01

Background Postoperative pleural drainage markedly influences the length of postoperative stay and financial costs of medical care. The aim of this study is to retrospectively investigate potentially predisposing factors related to pleural drainage after curative thoracic surgery and to explore the impact of mediastinal micro-vessels clipping on pleural drainage control after lymph node dissection. Methods From February 2012 to November 2013, 322 consecutive cases of operable non-small cell lung cancers (NSCLC) undergoing lobectomy and mediastinal lymph node dissection with or without application of clipping were collected. Total and daily postoperative pleural drainage were recorded. Propensity score matching (1:2) was applied to balance variables potentially impacting pleural drainage between group clip and group control. Analyses were performed to compare drainage volume, duration of chest tube and postoperative hospital stay between the two groups. Variables linked with pleural drainage in whole cohort were assessed using multivariable logistic regression analysis. Results Propensity score matching resulted in 197 patients (matched cohort). Baseline patient characteristics were matched between two groups. Group clip showed less cumulative drainage volume (P=0.020), shorter duration of chest tube (P=0.031) and postoperative hospital stay (P=0.022) compared with group control. Risk factors significantly associated with high-output drainage in multivariable logistic regression analysis were being male, age >60 years, bilobectomy/sleeve lobectomy, pleural adhesion, the application of clip applier, duration of operation ≥220 minutes and chylothorax (P<0.05). Conclusions This study suggests that mediastinal micro-vessels clipping during lymph node dissection may reduce postoperative pleural drainage and thus shorten hospital stay. PMID:27076936

Peroxynitrite mediates testosterone-induced vasodilation of microvascular resistance vessels.

PubMed

Puttabyatappa, Yashoda; Stallone, John N; Ergul, Adviye; El-Remessy, Azza B; Kumar, Sanjiv; Black, Stephen; Johnson, Maribeth; Owen, Mary P; White, Richard E

2013-04-01

Our knowledge of how androgens influence the cardiovascular system is far from complete, and this lack of understanding is especially true of how androgens affect resistance vessels. Our aim was to identify the signaling mechanisms stimulated by testosterone (TES) in microvascular arteries and to understand how these mechanisms mediate TES-induced vasodilation. Mesenteric microvessels were isolated from male Sprague-Dawley rats. Tension studies demonstrated a rapid, concentration-dependent, vasodilatory response to TES that did not involve protein synthesis or aromatization to 17β-estradiol. Dichlorofluorescein fluorescence and nitrotyrosine immunoblot experiments indicated that TES stimulated peroxynitrite formation in microvessels, and functional studies demonstrated that TES-induced vasodilation was inhibited by scavenging peroxynitrite. As predicted, TES enhanced the production of both peroxynitrite precursors (i.e., superoxide and nitic oxide), and xanthine oxidase was identified as the likely source of TES-stimulated superoxide production. Functional and biochemical studies indicated that TES signaling involved activity of the phosphoinositide 3 (PI3) kinase-protein kinase B (Akt) cascade initiated by activation of the androgen receptor and culminated in enhanced production of cGMP and microvascular vasodilation. These findings, derived from a variety of analytical and functional approaches, provide evidence for a novel nongenomic signaling mechanism for androgen action in the microvasculature: TES-stimulated vasodilation mediated primarily by peroxynitrite formed from xanthine oxidase-generated superoxide and NO. This response was associated with activation of the PI3 kinase-Akt signaling cascade initiated by activation of the androgen receptor. We propose this mechanism could account for TES-stimulated cGMP production in microvessels and, ultimately, vasodilation.

Peroxynitrite Mediates Testosterone-Induced Vasodilation of Microvascular Resistance Vessels

PubMed Central

Puttabyatappa, Yashoda; Stallone, John N.; Ergul, Adviye; El-Remessy, Azza B.; Kumar, Sanjiv; Black, Stephen; Johnson, Maribeth; Owen, Mary P.

2013-01-01

Our knowledge of how androgens influence the cardiovascular system is far from complete, and this lack of understanding is especially true of how androgens affect resistance vessels. Our aim was to identify the signaling mechanisms stimulated by testosterone (TES) in microvascular arteries and to understand how these mechanisms mediate TES-induced vasodilation. Mesenteric microvessels were isolated from male Sprague-Dawley rats. Tension studies demonstrated a rapid, concentration-dependent, vasodilatory response to TES that did not involve protein synthesis or aromatization to 17β-estradiol. Dichlorofluorescein fluorescence and nitrotyrosine immunoblot experiments indicated that TES stimulated peroxynitrite formation in microvessels, and functional studies demonstrated that TES-induced vasodilation was inhibited by scavenging peroxynitrite. As predicted, TES enhanced the production of both peroxynitrite precursors (i.e., superoxide and nitic oxide), and xanthine oxidase was identified as the likely source of TES-stimulated superoxide production. Functional and biochemical studies indicated that TES signaling involved activity of the phosphoinositide 3 (PI3) kinase-protein kinase B (Akt) cascade initiated by activation of the androgen receptor and culminated in enhanced production of cGMP and microvascular vasodilation. These findings, derived from a variety of analytical and functional approaches, provide evidence for a novel nongenomic signaling mechanism for androgen action in the microvasculature: TES-stimulated vasodilation mediated primarily by peroxynitrite formed from xanthine oxidase-generated superoxide and NO. This response was associated with activation of the PI3 kinase-Akt signaling cascade initiated by activation of the androgen receptor. We propose this mechanism could account for TES-stimulated cGMP production in microvessels and, ultimately, vasodilation. PMID:23318471

Papillary Muscle Free Strain in Patients with Severe Degenerative and Functional Mitral Regurgitation.

PubMed

Kılıcgedik, Alev; Kahveci, Gokhan; Gurbuz, Ahmet Seyfeddin; Karabay, Can Yucel; Guler, Ahmet; Efe, Suleyman Cagan; Aung, Soe Moe; Arslantas, Ugur; Demir, Serdar; Izgi, Ibrahim Akin; Kirma, Cevat

2017-04-01

The role of papillary muscle function in severe mitral regurgitation with preserved and reduced left ventricular ejection fraction and the method of choice to evaluate PM have still been the subjects of controversy. To evaluate and compare papillary muscle function in and between patients with severe degenerative and functional mitral regurgitation by using the free strain method. 64 patients with severe mitral regurgitation - 39 patients with degenerative mitral regurgitation (DMR group) and 25 patients with severe functional mitral regurgitation (FMR group) - and 30 control subjects (control group) were included in the study. Papillary muscle function was evaluated through the free strain method from apical four chamber images of the anterolateral papillary muscle (APM) and from apical three chamber images of the posteromedial papillary muscle (PPM). Global left ventricular longitudinal and circumferential strains were evaluated by applying 2D speckle tracking imaging. Global left ventricular longitudinal strain (DMR group, -17 [-14.2/-20]; FMR group, -9 [-7/-10.7]; control group, -20 [-18/-21] p < 0.001), global left ventricular circumferential strain (DMR group, -20 [-14.5/-22.7]; FMR group, -10 [-7/-12]; control group, -23 [-21/-27.5] p < 0.001) and papillary musle strains (PPMS; DMR group, -30.5 [-24/-46.7]; FMR group, -18 [-12/-30]; control group; -43 [-34.5/-39.5] p < 0.001; APMS; DMR group, (-35 [-23.5/-43]; FMR group, -20 [-13.5/-26]; control group, -40 [-32.5/-48] p < 0.001) were significantly different among all groups. APMS and PPMS were highly correlated with LVEF (p < 0.001, p < 0.001; respectively), GLS (p < 0.001, p < 0.001; respectively) and GCS (p < 0.001, p < 0.00; respectively) of LV among all groups. No correlation was found between papillary muscle strains and effective orifice area (EOA) in both groups of severe mitral regurgitation. Measuring papillary muscle longitudinal strain by the free strain method is practical and applicable. Papillary muscle dysfunction plays a small role in severe MR due to degenerative or functional causes and papillary muscle functions in general seems to follow left ventricular function. PPM is the most affected PM in severe mitral regurgitation in both groups of DMR and FMR. O papel da função do músculo papilar na regurgitação mitral grave com fração de ejeção do ventrículo esquerdo preservada e reduzida e o método de escolha para avaliar PM ainda são objetos de controvérsia. Avaliar e comparar a função dos músculos papilares entre pacientes com insuficiência mitral funcional e degenerativa pelo método free strain. 64 pacientes com insuficiência mitral grave - 39 pacientes com insuficiência mitral degenerativa grave (grupo IMD) e 25 com insuficiência mitral funcional grave (grupo IMF) - e 30 indivíduos controle (grupo controle) foram incluídos no estudo. A função dos músculos papilares foi avaliada pelo método free strain a partir de imagens apicais quatro-câmaras do músculo papilar anterolateral (MPA) e imagens apicais três-câmaras do músculo papilar posteromedial (MPP). Strains circunferenciais e longitudinais globais do ventrículo esquerdo foram avaliados por meio de imagens bidimensionais a partir do rastreamento de conjunto de pontos de cinza (speckle tracking). O strain longitudinal global do ventrículo esquerdo (grupo IMD, -17 [-14,2/-20]; grupo IMF, -9 [-7/-10,7]; grupo controle, -20 [-18/-21] p < 0,001); strain circunferencial global do ventrículo esquerdo (grupo IMD, -20 [-14,5/-22,7]; grupo IMF, -10 [-7/-12]; grupo controle, -23 [-21/-27,5] p < 0,001) e strains de músculos papilares (MPP; grupo IMD, -30,5 [-24/-46,7]; grupo IMF, -18 [-12/-30]; grupo controle; -43 [-34,5/-39,5] p < 0,001; MPA; grupo IMD, (-35 [-23,5/-43]; grupo IMF, -20 [-13,5/-26]; grupo controle, -40 [-32,5/-48] p < 0,001) mostraram-se significativamente diferentes nos grupos. MPA e MPP mostraram-se altamente correlacionados com a FEVE (p < 0,001, p < 0,00; respectivamente), SLG (p < 0,001, p < 0,001; respectivamente) e SCG (p < 0,001, p < 0,001; respectivamente) do VE entre todos os grupos. Não foi encontrada correlação entre os strains de músculos papilares e área eficaz do orifício (AEO) nos grupos de insuficiência mitral grave. A medição do strain longitudinal de músculos papilares pelo método free strain é prática e aplicável. A disfunção dos músculos papilares tem um papel pequeno em IM grave devido a causas degenerativas e funcionais, e a função dos músculos papilares, em general, parece seguir a função ventricular esquerda. O MPP é o MP mais afetado na insuficiência mitral em ambos os grupos, IMD e IMF.

Simulation and Optimization of Soft Gamma-Ray Concentrator Using Thin Film Multilayer Structures

NASA Astrophysics Data System (ADS)

Shirazi, Farzane; Bloser, Peter F.; Aliotta, Paul H.; Echt, Olof; Krzanowski, James E.; Legere, Jason S.; McConnell, Mark L.; Tsavalas, John G.; Wong, Emily N.; Kippen, R. Marc

2016-04-01

We are reporting the investigation result of channeling and concentrating soft gamma rays (above 100 keV) using multilayer thin films of alternating low and high-density materials. This will enable future telescopes for higher energies with same mission parameters already proven by NuSTAR. Base on initial investigations at Los Alamos National Laboratory (LANL) we are investigating of producing these multilayers with the required thicknesses and smoothness using magnetron sputter (MS) and pulsed laser deposition (PLD) techniques. A suitable arrangement of bent multilayer structures of alternating low and high-density materials will channel soft gamma-ray photons via total external reflection and then concentrate the incident radiation to a point. The high-energy astrophysics group at the UNH Space Science Center (SSC) is testing these structures for their ability to channel 122 keV gamma rays in the laboratory. In addition of experimental works, we have been working on gamma ray tracing model of the concentrator by IDL, making use of optical properties calculated by the IMD software. This modeling allows us to calculate efficiency and focal length for different energy bands and materials and compare them with experimental result. Also we will combine concentrator modeling result and detector simulation by Geant4 to archive a complete package of gamma-ray telescope simulation. If successful, this technology will offer the potential for soft gamma-ray telescopes with focal lengths of less than 10 m, removing the need for formation flying spacecraft and opening the field up to balloon-borne instruments and providing greatly increased sensitivity for modest cost and complexity.

Stroke and the Cell Therapy Saga: Towards a Safe, Swift and Efficient Utilization of cells.

PubMed

Kubis, Nathalie

2017-01-01

The first clinical trials of cell therapy in stroke were first published in the 2000s and consisted of neural stems cells transplanted via the intracerebral pathway. Since mesenchymal stem cells showed similar capacities to differentiate into neural cells and allowed autologous cell transplantation, they were then preferentially studied, including diabetes and hypertension. More recently, bone marrow derived mononuclear cells were successfully transplanted in stroke with no need of culture processing, and simple collection by density gradient centrifugation rendering them immediately ready for use. They improve post-stroke neurological deficit in rodents and clinical trials have shown the feasibility of intra-arterial or intravenous administration. The underlying mechanisms are not yet understood. We investigated the therapeutic potential of peripheral blood derived mononuclear cells (PB-MNC) harvested from diabetic patients and stimulated by ephrin-B2 (PB-MNC+). We showed that intravenously injected PB-MNC+ after cerebral ischemia reduced infarct volume at day 3, increased cell proliferation in the peri-infarct area and the subventricular zone, decreased microglial cell density, and upregulated TGF-β expression. At D14, microvessel density was increased and functional recovery enhanced, whereas plasma levels of BDNF were increased in treated mice. Ephrin-B2 induced phenotype switching of PB-MNC by upregulating genes controlling cell proliferation, inflammation and angiogenesis, as confirmed by adhesion and Matrigel assays. PB-MNC+ transplantation in stroke is a promising approach and should be investigated for the development of rapid, non-invasive bedside cell therapy strategies in stroke.(Presented at the 1944th Meeting, July 19, 2017).

Development of photoacoustic imaging technology overlaid on ultrasound imaging and its clinical application

NASA Astrophysics Data System (ADS)

Ishihara, Miya; Tsujita, Kazuhiro; Horiguchi, Akio; Irisawa, Kaku; Komatsu, Tomohiro; Ayaori, Makoto; Hirasawa, Takeshi; Kasamatsu, Tadashi; Hirota, Kazuhiro; Tsuda, Hitoshi; Ikewaki, Katsunori; Asano, Tomohiko

2015-03-01

Purpose: Photoacoustic imaging (PAI) enables one to visualize the distribution of hemoglobin and acquire a map of microvessels without using contrast agents. The purpose of our study is to develop a clinically applicable PAI system integrated with a clinical ultrasound (US) array system with handheld PAI probes providing coregistered PAI and US images. Clinical research trials were performed to evaluate the performance and feasibility of clinical value. Materials and Methods: We developed two types of handheld PAI probes: a linear PAI probe combining a conventional linear-array US probe with optical illumination and a transrectal ultrasonography (TRUS)-type PAI probe. We performed experiments with Japanese white rabbits and conducted clinical research trials of urology and vascular medicine with the approval of the medical human ethics committee of the National Defense Medical College. Results: We successfully acquired high-dynamic-range images of the vascular network ranging from capillaries to landmark arteries and identified the femoral vein, deep femoral vein, and great saphenous vein of rabbits. These major vessels in the rabbits groin are surrounded with microvessels connected to each other. Periprostatic microvessels were monitored during radical prostatectomy for localized prostate cancer and they were colocalized with nerve fibers, and their distribution was consistent with the corresponding PAI. The TRUS-type PAI probe clearly demonstrated the location and extent of the neurovascular bundle (NVB) better than does TRUS alone. Conclusions: The system, which can obtain a PAI, a US image, and a merged image, was innovatively designed so that medical doctors can easily find the location without any prior knowledge or extended skills to analyze the obtained images. Our pilot feasibility study confirms that PAI could be an imaging modality useful in the screening study and diagnostic biopsy.

Critical role of TRPP2 and TRPC1 channels in stretch-induced injury of blood-brain barrier endothelial cells.

PubMed

Berrout, Jonathan; Jin, Min; O'Neil, Roger G

2012-02-03

The microvessels of the brain are very sensitive to mechanical stresses such as observed in traumatic brain injury (TBI). Such stresses can quickly lead to dysfunction of the microvessel endothelial cells, including disruption of blood-brain barrier (BBB). It is now evident that elevation of cytosolic calcium levels ([Ca2+]i) can compromise the BBB integrity, however the mechanism by which mechanical injury can produce a [Ca2+]i increase in brain endothelial cells is unclear. To assess the effects of mechanical/stretch injury on [Ca2+]i signaling, mouse brain microvessel endothelial cells (bEnd3) were grown to confluency on elasticized membranes and [Ca2+]i monitored using fura 2 fluorescence imaging. Application of an injury, using a pressure/stretch pulse of 50 ms, induced a rapid transient increase in [Ca2+]i. In the absence of extracellular Ca2+, the injury-induced [Ca2+]i transient was greatly reduced, but not fully eliminated, while unloading of Ca2+ stores by thapsigargin treatment in the absence of extracellular Ca2+ abolished the injury transient. Application of LOE-908 and amiloride, TRPC and TRPP2 channel blockers, respectively, both reduced the transient [Ca2+]i increase. Further, siRNA knockdown assays directed at TRPC1 and TRPP2 expression also resulted in a reduction of the injury-induced [Ca2+]i response. In addition, stretch injury induced increases of NO production and actin stress fiber formation, both of which were markedly reduced upon treatment with LOE908 and/or amiloride. We conclude that mechanical injury of brain endothelial cells induces a rapid influx of calcium, mediated by TRPC1 and TRPP2 channels, which leads to NO synthesis and actin cytoskeletal rearrangement. Copyright © 2011. Published by Elsevier B.V.

Increased lymphocyte trafficking to colonic microvessels is dependent on MAdCAM-1 and C-C chemokine mLARC/CCL20 in DSS-induced mice colitis.

PubMed

Teramoto, K; Miura, S; Tsuzuki, Y; Hokari, R; Watanabe, C; Inamura, T; Ogawa, T; Hosoe, N; Nagata, H; Ishii, H; Hibi, T

2005-03-01

Although enhanced lymphocyte trafficking is associated with colitis formation, little information about its regulation is available. The aim of this study was to examine how the murine liver and activation-regulated chemokine (mLARC/CCL20) contributes to lymphocyte recruitment in concert with vascular adhesion molecules in murine chronic experimental colitis. T and B lymphocytes isolated from the spleen were fluorescence-labelled and administered to recipient mice. Lymphocyte adhesion to microvessels of the colonic mucosa and submucosa was observed with an intravital microscope. To induce colitis, the mice received two cycles of treatment with 2% dextran sodium sulphate (DSS). In some of the experiments antibodies against the adhesion molecules or anti-mLARC/CCL20 were administered, or CC chemokine receptor 6 (CCR6) of the lymphocytes was desensitized with excess amounts of mLARC/CCL20. Significant increases in T and B cell adhesion to the microvessels of the DSS-treated mucosa and submucosa were observed. In chronic colitis, the accumulation of lymphocytes was significantly inhibited by anti-mucosal addressin cell adhesion molecule (MAdCAM)-1 mAb, but not by anti-vascular cell adhesion molecule-1. In DSS-treated colonic tissue, the expression of mLARC/CCL20 was significantly increased, the blocking of mLARC/CCL20 by monoclonal antibody or the desensitization of CCR6 with mLARC/CCL20 significantly attenuated the DSS-induced T and B cell accumulation. However, the combination of blocking CCR6 with MAdCAM-1 did not further inhibit these accumulations. These results suggest that in chronic DSS-induced colitis, both MAdCAM-1 and mLARC/CCL20 may play important roles in T and B lymphocyte adhesion in the inflamed colon under flow conditions.