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Sample records for peripheral vasculature implications

  1. Peripheral vasculature in essential hypertension.

    PubMed

    Mulvany, M J

    1996-08-01

    1. Haemodynamic evidence shows that in essential hypertension minimum vascular resistance and vascular pressor response are increased and that the vascular reserve is decreased. 2. The haemodynamic changes are most easily explained in terms of a generalized narrowing of the vasculature and an increase in the ratio between the thickness of the tunica media and the lumen diameter (media: lumen ratio), with no change in the functional properties of the smooth muscle itself. 3. Histological and in vitro studies of resistance vessels confirm these predictions. Moreover, the evidence indicates that these changes are associated mainly with remodelling (rearrangement of the same amount of material) of the vessels, rather than growth. 4. Although the alteration in small artery structure is usually appropriate to the actual blood pressure, the structure appears not only to be a secondary adaptation, but is also dependent on other factors, including neurohumoral factors. 5. The available evidence shows that normalization of the resistance vessel structure (by increasing lumen diameter and decreasing the media:lumen ratio) should be achieved not by inhibition of growth but by (reverse) remodelling. Recent evidence from clinical investigations shows that this can be achieved in essential hypertensive patients treated with the angiotensin-converting enzyme inhibitor perindopril. 6. The role of the resistance vasculature as a primary determinant of blood pressure remains unclear. It is suggested that the requirement for normalization of resistance vascular structure is due to a need to increase the vascular reserve.

  2. Optoacoustic angiography of peripheral vasculature

    NASA Astrophysics Data System (ADS)

    Ermilov, Sergey; Su, Richard; Zamora, Mario; Hernandez, Travis; Nadvoretsky, Vyacheslav; Oraevsky, Alexander

    2012-02-01

    We developed a new optoacoustic microangiography system (OmAS) intended for in-vivo vascular imaging of a human finger. The system employs an arc-shaped acoustic array that is rotated 360 degrees around the finger providing optoacoustic data necessary for tomographic reconstruction of the three-dimensional images of a finger. A near-infrared Q-switched laser is used to generate optoacoustic signals with increased contrast of blood vessels. The laser is coupled through two randomized fiberoptic bundles oriented in orthogonal optoacoustic mode. To demonstrate OmAS capabilities, we present a time-series of optoacoustic images of a human finger taken after the hypothermia stress test. The images show a detailed vascular anatomy of a finger down to the capillary level. A series of quick 30s scans allowed us to visualize the thermoregulatory response within the studied finger as it was manifested via vasomotor activity during the hypothermia recovery. We propose that the developed system can be used for diagnostics of various medical conditions that are manifested in change of the peripheral (finger) blood flow. Examples of the medical conditions that could be diagnosed and staged using the OmAS include the peripheral arterial disease (PAD), thrombosis, frostbite, and traumas.

  3. Real time imaging of peripheral nerve vasculature using optical coherence angiography

    NASA Astrophysics Data System (ADS)

    Vasudevan, Srikanth; Kumsa, Doe; Takmakov, Pavel; Welle, Cristin G.; Hammer, Daniel X.

    2016-03-01

    The peripheral nervous system (PNS) carries bidirectional information between the central nervous system and distal organs. PNS stimulation has been widely used in medical devices for therapeutic indications, such as bladder control and seizure cessation. Investigational uses of PNS stimulation include providing sensory feedback for improved control of prosthetic limbs. While nerve safety has been well documented for stimulation parameters used in marketed devices, novel PNS stimulation devices may require alternative stimulation paradigms to achieve maximum therapeutic benefit. Improved testing paradigms to assess the safety of stimulation will expedite the development process for novel PNS stimulation devices. The objective of this research is to assess peripheral nerve vascular changes in real-time with optical coherence angiography (OCA). A 1300-nm OCA system was used to image vasculature changes in the rat sciatic nerve in the region around a surface contacting single electrode. Nerves and vasculature were imaged without stimulation for 180 minutes to quantify resting blood vessel diameter. Walking track analysis was used to assess motor function before and 6 days following experiments. There was no significant change in vessel diameter between baseline and other time points in all animals. Motor function tests indicated the experiments did not impair functionality. We also evaluated the capabilities to image the nerve during electrical stimulation in a pilot study. Combining OCA with established nerve assessment methods can be used to study the effects of electrical stimulation safety on neural and vascular tissue in the periphery.

  4. FD-OCT and IVUS intravascular imaging modalities in peripheral vasculature.

    PubMed

    Spiliopoulos, S; Kitrou, P; Katsanos, K; Karnabatidis, D

    2017-02-01

    Intra-Vascular Ultra-Sound (IVUS) and Frequency Domain-Optical Coherence Tomography (FD-OCT), in vivo, intra-vascular, imaging modalities, widely used in the field of coronary disease, have been recently implemented in peripheral endovascular procedures, for procedural assessment, plaque characterization and determination of predictors of treatment outcomes. Their unique characteristics have also been used in order to provide additional features and improve the performance of re-entry devices and atherotomes. Areas covered: Present review focuses on available literature regarding these two promising imaging technologies in the peripheral vasculature, highlighting the added value produced by their use in endovascular therapy, their limitations and their utilization in new endovascular devices. Authors also provide their future perspective and the possible benefits in understanding vascular behavior and lesion characterization in peripheral endovascular interventions. Expert commentary: By providing both quantitative but also qualitative data on vessel and lesion morphology, intravascular imaging modalities offer a valid solution for endovascular treatment evaluation and outcome presentation homogeneity.

  5. Peripheral Vasculature: High-Temporal- and High-Spatial-Resolution Three-dimensional Contrast-enhanced MR Angiography1

    PubMed Central

    Haider, Clifton R.; Glockner, James F.; Stanson, Anthony W.; Riederer, Stephen J.

    2009-01-01

    Purpose: To prospectively evaluate the feasibility of performing high-spatial-resolution (1-mm isotropic) time-resolved three-dimensional (3D) contrast material–enhanced magnetic resonance (MR) angiography of the peripheral vasculature with Cartesian acquisition with projection-reconstruction–like sampling (CAPR) and eightfold accelerated two-dimensional (2D) sensitivity encoding (SENSE). Materials and Methods: All studies were approved by the institutional review board and were HIPAA compliant; written informed consent was obtained from all participants. There were 13 volunteers (mean age, 41.9; range, 27–53 years). The CAPR sequence was adapted to provide 1-mm isotropic spatial resolution and a 5-second frame time. Use of different receiver coil element sizes for those placed on the anterior-to-posterior versus left-to-right sides of the field of view reduced signal-to-noise ratio loss due to acceleration. Results from eight volunteers were rated independently by two radiologists according to prominence of artifact, arterial to venous separation, vessel sharpness, continuity of arterial signal intensity in major arteries (anterior and posterior tibial, peroneal), demarcation of origin of major arteries, and overall diagnostic image quality. MR angiographic results in two patients with peripheral vascular disease were compared with their results at computed tomographic angiography. Results: The sequence exhibited no image artifact adversely affecting diagnostic image quality. Temporal resolution was evaluated to be sufficient in all cases, even with known rapid arterial to venous transit. The vessels were graded to have excellent sharpness, continuity, and demarcation of the origins of the major arteries. Distal muscular branches and the communicating and perforating arteries were routinely seen. Excellent diagnostic quality rating was given for 15 (94%) of 16 evaluations. Conclusion: The feasibility of performing high-diagnostic-quality time-resolved 3D

  6. Intermittent hypoxia and arterial blood pressure control in humans: role of the peripheral vasculature and carotid baroreflex.

    PubMed

    Tremblay, Joshua C; Boulet, Lindsey M; Tymko, Michael M; Foster, Glen E

    2016-09-01

    Intermittent hypoxia (IH) occurs in association with obstructive sleep apnea and likely contributes to the pathogenesis of hypertension. The purpose of this study was to examine the putative early adaptations at the level of the peripheral vasculature and carotid baroreflex (CBR) that may promote the development of hypertension. Ten healthy male participants (26 ± 1 yr, BMI = 24 ± 1 kg/m(2)) were exposed to 6 h of IH (1-min cycles of normoxia and hypoxia) and SHAM in a single-blinded, counterbalanced crossover study design. Ambulatory blood pressure was measured during each condition and the following night. Vascular strain of the carotid and femoral artery, a measure of localized arterial stiffness, and hemodynamic shear patterns in the brachial and femoral arteries were measured during each condition. Brachial artery reactive hyperemia flow-mediated vasodilation was assessed before and after each condition as a measure of endothelial function. CBR function and its control over leg vascular conductance (LVC) were measured after each condition with a variable-pressure neck chamber. Intermittent hypoxia 1) increased nighttime pulse pressure by 3.2 ± 1.3 mmHg, 2) altered femoral but not brachial artery hemodynamics, 3) did not affect brachial artery endothelial function, 4) reduced vascular strain in the carotid and possibly femoral artery, and 5) shifted CBR mean arterial pressure (MAP) to higher MAP while blunting LVC responses to CBR loading. These results suggest limb-specific vascular impairments, reduced vascular strain, and CBR resetting combined with blunted LVC responses are factors in the early pathogenesis of IH-induced development of hypertension. Copyright © 2016 the American Physiological Society.

  7. Structure of solid tumors and their vasculature: Implications for therapy with monoclonal antibodies

    SciTech Connect

    Dvorak, H.F.; Nagy, J.A.; Dvorak, A.M. )

    1991-03-01

    Delivery of monoclonal antibodies to solid tumors is a vexing problem that must be solved if these antibodies are to realize their promise in therapy. Such success as has been achieved with monoclonal antibodies is attributable to the local hyperpermeability of the tumor vasculature, a property that favors antibody extravasation at tumor sites and that is mediated by a tumor-secreted vascular permeability factor. However, leaky tumor blood vessels are generally some distance removed from target tumor cells, separated by stroma and by other tumor cells that together represent significant barriers to penetration by extravasated monoclonal antibodies. For this reason, alternative approaches may be attractive. These include the use of antibody-linked cytotoxins, which are able to kill tumor cells without immediate contact, and direction of antibodies against nontumor cell targets, for example, antigens unique to the tumor vascular endothelium or to tumor stroma. 50 refs.

  8. Sex Steroids Modulate Uterine-Placental Vasculature: Implications for Obstetrics and Neonatal Outcomes

    PubMed Central

    Maliqueo, Manuel; Echiburú, Bárbara; Crisosto, Nicolás

    2016-01-01

    Adequate blood supply to the uterine-placental region is crucial to ensure the transport of oxygen and nutrients to the growing fetus. Multiple factors intervene to achieve appropriate uterine blood flow and the structuring of the placental vasculature during the early stages of pregnancy. Among these factors, oxygen concentrations, growth factors, cytokines, and steroid hormones are the most important. Sex steroids are present in extremely high concentrations in the maternal circulation and are important paracrine and autocrine regulators of a wide range of maternal and placental functions. In this regard, progesterone and estrogens act as modulators of uterine vessels and decrease the resistance of the spiral uterine arteries. On the other hand, androgens have the opposite effect, increasing the vascular resistance of the uterus. Moreover, progesterone and estrogens modulate the synthesis and release of angiogenic factors by placental cells, which regulates trophoblastic invasion and uterine artery remodeling. In this scenario, it is not surprising that women with pregnancy-related pathologies, such as early miscarriages, preterm delivery, preeclampsia, and fetal growth restriction, exhibit altered sex steroid concentrations. PMID:27199767

  9. Aortic stiffness and blood pressure variability in young people: a multimodality investigation of central and peripheral vasculature

    PubMed Central

    Boardman, Henry; Lewandowski, Adam J.; Lazdam, Merzaka; Kenworthy, Yvonne; Whitworth, Polly; Zwager, Charlotte L.; Francis, Jane M.; Aye, Christina Y.L.; Williamson, Wilby; Neubauer, Stefan; Leeson, Paul

    2017-01-01

    Introduction: Increased blood pressure (BP) variability is a cardiovascular risk marker for young individuals and may relate to the ability of their aorta to buffer cardiac output. We used a multimodality approach to determine relations between central and peripheral arterial stiffness and BP variability. Methods: We studied 152 adults (mean age of 31 years) who had BP variability measures based on SD of awake ambulatory BPs, 24-h weighted SD and average real variability (ARV). Global and regional aortic distensibility was measured by cardiovascular magnetic resonance, arterial stiffness by cardio-ankle vascular index (CAVI) and pulse wave velocity (PWV) by SphygmoCor (carotid–femoral) and Vicorder (brachial–femoral). Results: In young people, free from overt cardiovascular disease, all indices of SBP and DBP variability correlated with aortic distensibility (global aortic distensibility versus awake SBP SD: r = −0.39, P < 0.001; SBP ARV: r = −0.34, P < 0.001; weighted 24-h SBP SD: r = −0.42, P < 0.001). CAVI, which closely associated with aortic distensibility, also related to DBP variability, as well as awake SBP SD (r = 0.19, P < 0.05) and weighted 24-h SBP SD (r = 0.24, P < 0.01), with a trend for SBP ARV (r = 0.17, P = 0.06). In contrast, associations with PWV were only between carotid–femoral PWV and weighted SD of SBP (r = 0.20, P = 0.03) as well as weighted and ARV of DBP. Conclusion: Greater BP variability in young people relates to increases in central aortic stiffness, strategies to measure and protect aortic function from a young age may be important to reduce cardiovascular risk. PMID:27846043

  10. Non-enhanced, ECG-gated MR angiography of the pedal vasculature: comparison with contrast-enhanced MR angiography and digital subtraction angiography in peripheral arterial occlusive disease.

    PubMed

    Schubert, Tilman; Takes, Martin; Aschwanden, Markus; Klarhoefer, Markus; Haas, Tanja; Jacob, Augustinus L; Liu, David; Gutzeit, Andreas; Kos, Sebastian

    2016-08-01

    This study was conducted in order to compare a high resolution, non-contrast-enhanced MRA (NATIVE SPACE, NE-MRA) of the pedal vasculature with contrast-enhanced MRA (CE-MRA) and digital subtraction angiography (DSA) in patients with peripheral arterial occlusive disease (PAOD). The prospective study consists of 20 PAOD patients. All patients underwent percutaneous transluminal angioplasty or stenting and received MR angiographies the following day. With CE-MRA, 75.7 % of vessel segments showed good, 16.4 % suboptimal and 7.9 % not usable image quality. With NE-MRA, 64.6 % showed good, 18.6 % suboptimal and 16.8 % not usable image quality. CE-MRA showed a sensitivity and negative predictive value of 90 %/95 % regarding significant stenosis (greater than 50 %), and specificity and positive predictive value were 88 %/77 %. Accordingly, sensitivity and negative predictive value for the NE-MRA were 96 %/97 % and specificity and positive predictive value were 80 %/69 % for stenoses greater than 50 %. The applied NE-MRA technique achieves high diagnostic accuracy even in very small distal arteries of the foot. However, the rate of non-diagnostic vessel segments is considerably higher for NE-MRA than for CE-MRA. NE-MRA is a valuable alternative to CE-MRA in selected patients. • Comparison of non-enhanced MRA with contrast-enhanced MRA and DSA as gold standard. • High resolution MRA at 3 T for the depiction of small pedal vessels. • Evaluation of high resolution non-enhanced MRA in PAOD patients.

  11. The Role of the Tumor Vasculature in the Host Immune Response: Implications for Therapeutic Strategies Targeting the Tumor Microenvironment.

    PubMed

    Hendry, Shona A; Farnsworth, Rae H; Solomon, Benjamin; Achen, Marc G; Stacker, Steven A; Fox, Stephen B

    2016-01-01

    Recently developed cancer immunotherapy approaches including immune checkpoint inhibitors and chimeric antigen receptor T cell transfer are showing promising results both in trials and in clinical practice. These approaches reflect increasing recognition of the crucial role of the tumor microenvironment in cancer development and progression. Cancer cells do not act alone, but develop a complex relationship with the environment in which they reside. The host immune response to tumors is critical to the success of immunotherapy; however, the determinants of this response are incompletely understood. The immune cell infiltrate in tumors varies widely in density, composition, and clinical significance. The tumor vasculature is a key component of the microenvironment that can influence tumor behavior and treatment response and can be targeted through the use of antiangiogenic drugs. Blood vascular and lymphatic endothelial cells have important roles in the trafficking of immune cells, controlling the microenvironment, and modulating the immune response. Improving access to the tumor through vascular alteration with antiangiogenic drugs may prove an effective combinatorial strategy with immunotherapy approaches and might be applicable to many tumor types. In this review, we briefly discuss the host's immune response to cancer and the treatment strategies utilizing this response, before focusing on the pathological features of tumor blood and lymphatic vessels and the contribution these might make to tumor immune evasion.

  12. The Role of the Tumor Vasculature in the Host Immune Response: Implications for Therapeutic Strategies Targeting the Tumor Microenvironment

    PubMed Central

    Hendry, Shona A.; Farnsworth, Rae H.; Solomon, Benjamin; Achen, Marc G.; Stacker, Steven A.; Fox, Stephen B.

    2016-01-01

    Recently developed cancer immunotherapy approaches including immune checkpoint inhibitors and chimeric antigen receptor T cell transfer are showing promising results both in trials and in clinical practice. These approaches reflect increasing recognition of the crucial role of the tumor microenvironment in cancer development and progression. Cancer cells do not act alone, but develop a complex relationship with the environment in which they reside. The host immune response to tumors is critical to the success of immunotherapy; however, the determinants of this response are incompletely understood. The immune cell infiltrate in tumors varies widely in density, composition, and clinical significance. The tumor vasculature is a key component of the microenvironment that can influence tumor behavior and treatment response and can be targeted through the use of antiangiogenic drugs. Blood vascular and lymphatic endothelial cells have important roles in the trafficking of immune cells, controlling the microenvironment, and modulating the immune response. Improving access to the tumor through vascular alteration with antiangiogenic drugs may prove an effective combinatorial strategy with immunotherapy approaches and might be applicable to many tumor types. In this review, we briefly discuss the host’s immune response to cancer and the treatment strategies utilizing this response, before focusing on the pathological features of tumor blood and lymphatic vessels and the contribution these might make to tumor immune evasion. PMID:28066431

  13. Emerging Roles of Lymphatic Vasculature in Immunity

    PubMed Central

    2017-01-01

    The lymphatic vasculature has been regarded as a passive conduit for interstitial fluid and responsible for the absorption of macromolecules such as proteins or lipids and transport of nutrients from food. However, emerging data show that the lymphatic vasculature system plays an important role in immune modulation. One of its major roles is to coordinate antigen transport and immune-cell trafficking from peripheral tissues to secondary lymphoid organs, lymph nodes. This perspective was recently updated with the notion that the interaction between lymphatic endothelial cells and leukocytes controls the immune-cell migration and immune responses by regulating lymphatic flow and various secreted molecules such as chemokines and cytokines. In this review, we introduce the lymphatic vasculature networks and genetic transgenic models for research on the lymphatic vasculature system. Next, we discuss the contribution of lymphatic endothelial cells to the control of immune-cell trafficking and to maintenance of peripheral tolerance. Finally, the physiological roles and features of the lymphatic vasculature system are further discussed regarding inflammation-induced lymphangiogenesis in a pathological condition, especially in mucosal tissues such as the gastrointestinal tract and respiratory tract. PMID:28261022

  14. Ergot alkaloids induce vasoconstriction of bovine foregut vasculature

    USDA-ARS?s Scientific Manuscript database

    Alkaloids produced by the Neotyphodium coenophialum endophyte in association with tall fescue (Lolium arundinaceum) are imputed to cause peripheral symptoms of fescue toxicosis. We hypothesized that theses compounds could correspondingly affect foregut vasculature. The objective of this study was to...

  15. Peripheral muscle abnormalities in cystic fibrosis: Etiology, clinical implications and response to therapeutic interventions.

    PubMed

    Gruet, Mathieu; Troosters, Thierry; Verges, Samuel

    2017-09-01

    Peripheral muscle dysfunction is an important systemic consequence of cystic fibrosis (CF) with major clinical implications, such as exercise intolerance and reduced quality of life. Evidence is now accumulating that lack of physical activity is unlikely to be the sole explanation for peripheral muscle dysfunction of patients with CF. Particularly, the demonstration of CFTR expression in both murine and human skeletal muscle suggests the potential implication of intrinsic CF-related factors. By combining data from both human and animal models, this review describes CF peripheral muscle abnormalities and critically reviews the advances in understanding the impact of the underlying mechanisms. We also describe how peripheral muscles respond to intervention in this population. Methodological concerns and directions for future research are also considered. Peripheral muscle atrophy and weakness is prevalent in patients with CF and associated with reduced aerobic and anaerobic performances. Further investigations are however needed to confirm alterations in peripheral muscle endurance and fatigability. Physical inactivity is probably the major contributor of peripheral muscle abnormalities in patients with CF with mild-to-moderate phenotypes. However, the relative influence of additional factors (e.g. inflammation, metabolic abnormalities) probably increases with disease severity making specific and individualized interventions necessary in severe patients. Exercise training is the most effective intervention to address peripheral muscle dysfunction but other strategies, such as neuromuscular electrical stimulation and nutritional or hormonal supplementation may be of interest in some patients. Investigations are needed to determine whether pharmacological interventions such as CFTR modulators are effective to address this condition. To better elucidate the etiology of peripheral muscle dysfunction in CF, future studies should combine measurements at the cellular level

  16. Ghrelin: Central and Peripheral Implications in Anorexia Nervosa

    PubMed Central

    Méquinion, Mathieu; Langlet, Fanny; Zgheib, Sara; Dickson, Suzanne; Dehouck, Bénédicte; Chauveau, Christophe; Viltart, Odile

    2012-01-01

    Increasing clinical and therapeutic interest in the neurobiology of eating disorders reflects their dramatic impact on health. Chronic food restriction resulting in severe weight loss is a major symptom described in restrictive anorexia nervosa (AN) patients, and they also suffer from metabolic disturbances, infertility, osteopenia, and osteoporosis. Restrictive AN, mostly observed in young women, is the third largest cause of chronic illness in teenagers of industrialized countries. From a neurobiological perspective, AN-linked behaviors can be considered an adaptation that permits the endurance of reduced energy supply, involving central and/or peripheral reprograming. The severe weight loss observed in AN patients is accompanied by significant changes in hormones involved in energy balance, feeding behavior, and bone formation, all of which can be replicated in animals models. Increasing evidence suggests that AN could be an addictive behavior disorder, potentially linking defects in the reward mechanism with suppressed food intake, heightened physical activity, and mood disorder. Surprisingly, the plasma levels of ghrelin, an orexigenic hormone that drives food-motivated behavior, are increased. This increase in plasma ghrelin levels seems paradoxical in light of the restrained eating adopted by AN patients, and may rather result from an adaptation to the disease. The aim of this review is to describe the role played by ghrelin in AN focusing on its central vs. peripheral actions. In AN patients and in rodent AN models, chronic food restriction induces profound alterations in the « ghrelin » signaling that leads to the development of inappropriate behaviors like hyperactivity or addiction to food starvation and therefore a greater depletion in energy reserves. The question of a transient insensitivity to ghrelin and/or a potential metabolic reprograming is discussed in regard of new clinical treatments currently investigated. PMID:23549309

  17. Validation of Right Ruminal Vein and Artery as Models of Bovine Foregut Vasculature

    USDA-ARS?s Scientific Manuscript database

    Endophyte-infected (Neotyphodium coenophialum) tall fescue (Lolium arundinaceum) produces alkaloids that have been associated with peripheral vasoconstriction in grazing animals and ingestion of these alkaloids may effect splanchnic vasculature. Because of significant differences in morphological an...

  18. Sarcomas related to the heart and vasculature.

    PubMed

    Raaf, H N; Raaf, J H

    1994-01-01

    Soft tissue sarcoma is the most common malignant neoplasm of the heart, pericardium, and great vessels. Its presentation is infrequent, nonspecific, and subtle. For example, emboli from these tumors to the lungs or peripheral arteries may mimic thrombotic embolic disease. New noninvasive techniques such as echocardiography and magnetic resonance imaging (MRI) aid in diagnosis and preoperative assessment. Angiosarcoma, the most common cardiac sarcoma, is aggressive and usually arises in the right atrium. Kaposi's sarcoma of the heart has been found in patients with AIDS and in immunosuppressed organ transplant recipients. Most primary sarcomas of the aorta and pulmonary artery (the elastic arteries) show minimal differentiation and are classified as "intimal, sarcomas," whereas leiomyosarcomas predominate in the muscular arteries and great veins. Surgical resection of any sarcoma of the vasculature, when feasible, is technically challenging but may result in cure or palliation. Adjuvant chemotherapy and radiation therapy can also relieve symptoms and prolong survival.

  19. The perifoveal vasculature in albinism.

    PubMed Central

    Gregor, Z.

    1978-01-01

    The perifoveal vasculature was studied in a series of patients with oculocutaneous tyrosinase-positive albinism. Fluorescein angiographic studies show a normal distribution of the major retinal blood vessels and in some cases of the capillaries in the macular area of these patients. Images PMID:687555

  20. Nicotine stimulates expression of proteins implicated in peripheral and central sensitization.

    PubMed

    Hawkins, J L; Denson, J E; Miley, D R; Durham, P L

    2015-04-02

    Pain patients who are nicotine dependent report a significantly increased incidence and severity of pain intensity. The goal of this study was to determine the effects of prolonged nicotine administration on inflammatory proteins implicated in the development of peripheral and central sensitization of the trigeminal system. Behavioral, immunohistochemical, and microarray studies were utilized to investigate the effects of nicotine administered daily for 14 days via an Alzet® osmotic pump in Sprague Dawley rats. Systemic nicotine administration caused a significant increase in nocifensive withdrawals to mechanical stimulation of trigeminal neurons. Nicotine stimulated expression of the pro-inflammatory signal transduction proteins phosphorylated-extracellular signal-regulated kinase (p-ERK), phosphorylated-c-Jun N-terminal kinase (p-JNK), and protein kinase A (PKA) in the spinal trigeminal nucleus. Nicotine also promoted elevations in the expression of glial fibrillary acidic protein (GFAP), a biomarker of activated astrocytes, and the microglia biomarker ionized calcium-binding adapter molecule 1 (Iba1). Similarly, levels of eleven cytokines were significantly elevated with the largest increase in expression of TNF-α. Levels of PKA, p-ERK, and p-JNK in trigeminal ganglion neurons were increased by nicotine. Our findings demonstrate that prolonged systemic administration of nicotine promotes sustained behavioral and cellular changes in the expression of key proteins in the spinal trigeminal nucleus and trigeminal ganglion implicated in the development and maintenance of peripheral and central sensitization.

  1. Constriction of bovine vasculature caused by endophyte-infected tall fescue seed extract is similar to pure ergovaline

    USDA-ARS?s Scientific Manuscript database

    A mixture of ergot alkaloids does not increase the contractile response of peripheral bovine vasculature, but may increase the contractile response of foregut vasculature. Preliminary data indicated that an extract of tall fescue seed induced a greater contractile response in ruminal artery and vein...

  2. Complexity analysis of angiogenesis vasculature

    NASA Astrophysics Data System (ADS)

    Mahadevan, Vijay; Tyrell, James A.; Tong, Ricky T.; Brown, Edward B.; Jain, Rakesh K.; Roysam, Badrinath

    2005-04-01

    Tumor vasculature has a high degree of irregularity as compared to normal vasculature. The quantification of the morphometric complexity in tumor images can be useful in diagnosis. Also, it is desirable in several other medical applications to have an automated complexity analysis to aid in diagnosis and prognosis under treatment. e.g. in diabetic retinopathy and in arteriosclerosis. In addition, prior efforts at segmentation of the tumor vasculature using matched filtering, template matching and splines have been hampered by the irregularity of these vessels. We try to solve both problems by introducing a novel technique for vessel detection, followed by a tracing-independent complexity analysis based on a combination of ideas. First, the vessel cross-sectional profile is modeled using a continuous and everywhere differentiable family of super-Gaussian curves. This family generates rectangular profiles that can accurately localize the vessel boundaries in microvasculature images. Second, a robust non-linear regression algorithm based on M-estimators is used to estimate the parameters that optimally characterize the vessel"s shape. A framework for the quantitative analysis of the complexity of the vasculature based on the vessel detection is presented. A set of measures that quantify the complexity are proposed viz. Squared Error, Entropy-based and Minimum Description Length-based Shape Complexities. They are completely automatic and can deal with complexities of the entire vessel unlike existing tortuousity measures which deal only with vessel centerlines. The results are validated using carefully constructed phantom and real image data with ground truth information from an expert observer.

  3. The actions of hyperthermia on the autonomic nervous system: central and peripheral mechanisms and clinical implications.

    PubMed

    Burke, Shoshana; Hanani, Menachem

    2012-05-21

    Hyperthermia is defined as an elevated body temperature due to failed thermoregulation. It can occur under physiological conditions such as intense exercise or due to pathology such as malignant hyperthermia and heat stroke. It has also been implicated as a cause for sudden infant death syndrome. High temperatures are also used in medical interventions - hyperthermic chemotherapy or radiofrequency ablation, for example, which have serious side effects. The effect of hyperthermia on the central nervous system has not been fully researched, but even less is known on the effects of hyperthermia on the peripheral autonomic nervous system. In this review we discuss how conditions such as malignant or therapeutic hyperthermia affect the central and peripheral components of the autonomic nervous system, smooth muscle, skeletal muscle and cardiac muscle. We conclude that there is sufficient evidence for the detrimental effect of hyperthermia on central nerves, and that these effects are long lasting, although the major mechanism for this remains unknown. Similarly, the direct damage of hyperthermia to the enteric nerves also seems to be long lasting. In contrast, the reduced contractility of cardiac muscle and gastrointestinal smooth muscle when exposed to hyperthermia is short-lived. The consensus is that inadequate calcium handling is the mechanism of heat damage to cardiac and skeletal muscle. There is no such consensus when dealing with smooth muscle. The mechanism of hyperthermic damage to autonomic end organs such as the gastrointestinal tract has yet to be elucidated and further research into both central and peripheral hyperthermia is necessary. Copyright © 2012 Elsevier B.V. All rights reserved.

  4. “Galectin-1 Induces Central and Peripheral Cell Death: Implications in T-Cell Physiopathology”

    PubMed Central

    Rabinovich, G. A.

    2000-01-01

    The immune system has a remarkable capacity to maintain a state of equilibrium even as it responds to a diverse array of foreign proteins and despite its contact exposure to self-antigens. Apoptosis is one of the mechanisms aimed at preserving the homeostasis after the completion of an immune response, thus returning the immune system to a basal state and warranting the elimination of autoagressive cells in both central and peripheral lymphoid organs. Targeted deletions in critical genes involved in the apoptotic death machinery together with natural spontaneous mutations have clearly shown the importance of apoptosis in the regulation of the immune response. This complex scenario of stimulatory and inhibitory genes has been enriched with the finding that galectin-1, a 14.5 kDa β-galactoside-binding protein, is able to induce apoptosis of immature cortical thymocytes and mature T cells by cross-linking cell surface glycoconjugates. Galectin-1 is present not only in central and peripheral lymphoid organs, but also at sites of immune privilege. In the present article we will discuss the implications of galectin-1-induced apoptosis in T-cell physiopathology in an attempt to validate its therapeutic potential in autoimmune and inflammatory diseases. PMID:11097206

  5. Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance.

    PubMed

    Lotta, Luca A; Gulati, Pawan; Day, Felix R; Payne, Felicity; Ongen, Halit; van de Bunt, Martijn; Gaulton, Kyle J; Eicher, John D; Sharp, Stephen J; Luan, Jian'an; De Lucia Rolfe, Emanuella; Stewart, Isobel D; Wheeler, Eleanor; Willems, Sara M; Adams, Claire; Yaghootkar, Hanieh; Forouhi, Nita G; Khaw, Kay-Tee; Johnson, Andrew D; Semple, Robert K; Frayling, Timothy; Perry, John R B; Dermitzakis, Emmanouil; McCarthy, Mark I; Barroso, Inês; Wareham, Nicholas J; Savage, David B; Langenberg, Claudia; O'Rahilly, Stephen; Scott, Robert A

    2017-01-01

    Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms in common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.

  6. Unilateral persistent fetal vasculature coexisting with anterior segment dysgenesis.

    PubMed

    Khokhar, Sudarshan; Gupta, Shikha; Arora, Tarun; Gogia, Varun; Dada, Tanuj

    2013-08-01

    Persistent fetal vasculature (PFV) is a common congenital developmental anomaly of the eye which results from failure of the embryological primary vitreous and hyaloid vasculature to regress by the time of birth (Int Ophthalmol Clin 48: 53-62, 2008). Typically, it is divided into anterior, posterior or combined types and is characterized by the presence of a vascular stalk located between the optic disc and the posterior lens capsule (Int Ophthalmol Clin 48: 53-62, 2008). Although it has been reported to manifest itself differently, in our case it presented in a microphthalmic eye as anterior segment dysgenesis with broad-based mid-peripheral synechiae, posterior embryotoxon, iridoschisis, ectropion uveae, hypotony and subluxated cataractous lens with a taut anterior hyaloid face which are rare associations with PFV.

  7. The Vasculature in Chagas Disease

    PubMed Central

    Prado, Cibele M.; Jelicks, Linda A.; Weiss, Louis M.; Factor, Stephen M.; Tanowitz, Herbert B.; Rossi, Marcos A.

    2013-01-01

    The cardiovascular manifestations of Chagas disease are well known. However, the contribution of the vasculature and specifically the microvasculature has received little attention. This chapter reviews the evidence supporting the notion that alterations in the microvasculature especially in the heart contribute to the pathogenesis of chagasic cardiomyopathy. These data may also be important in understanding the contributions of the microvasculature in the aetiologies of other cardiomyopathies. The role of endothelin-1 and of thromboxane A2 vascular spasm and platelet aggregation is also discussed. Further, these observations may provide target(s) for intervention. PMID:21884888

  8. Cataract progression after prophylactic laser peripheral iridotomy: potential implications for the prevention of glaucoma blindness.

    PubMed

    Lim, Laurence S; Husain, Rahat; Gazzard, Gus; Seah, Steve K L; Aung, Tin

    2005-08-01

    To evaluate changes in lens opacity in the first year after prophylactic laser peripheral iridotomy (LPI) performed in fellow eyes of subjects with acute primary angle closure (APAC). Prospective observational case series. Sixty Asian subjects with unilateral APAC. All fellow eyes underwent prophylactic LPI within the first week of presentation, followed by 1 week of topical steroids. The degree of lens opacity was graded at the slit-lamp examination using the Lens Opacity Classification System III (LOCS III) with standard color photographs as the reference for grading of lens opacity. This was performed 2 weeks, 4 months, and 12 months after LPI. Progression in lens opacity was defined as an increase in LOCS III grade by 2 or more units in any lens region. Lens Opacity Classification Sytem III grades in nuclear, cortical, and posterior subcapsular (PSC) regions. Most patients were Chinese (85%) and female (63.3%), with an average age of 61.5 +/- 10.6 years. The mean baseline LOCS grades in the nuclear, cortical, and PSC regions were 3.58 +/- 0.74, 0.57 +/- 1.08, and 0.23 +/- 0.72, respectively. With 12 months of follow-up, 14 of the 60 eyes (23.3%; 95% confidence interval, 16.9-29.7%) showed significant progression in any lens region. Progression in the nuclear, cortical, and PSC regions was documented in 5%, 6.7%, and 16.7% of cases, respectively. By use of logistic regression, the following factors were not found to be significant for cataract progression in any lens region: age, race, gender, history of hypertension or diabetes, presence of peripheral anterior synechiae or angle width at baseline, and total laser energy delivered. In fellow eyes of APAC, prophylactic LPI is complicated by significant cataract progression, mainly in the posterior subcapsular region. These findings may have implications for the role of prophylactic LPI in the prevention of angle-closure blindness.

  9. Anthropometry of fetal vasculature in the chorionic plate.

    PubMed

    Gordon, Z; Elad, D; Almog, R; Hazan, Y; Jaffa, A J; Eytan, O

    2007-12-01

    Normal fetal development is dependent on adequate placental blood perfusion. The functional role of the placenta takes place mainly in the capillary system; however, ultrasound imaging of fetal blood flow is commonly performed on the umbilical artery, or on its first branches over the chorionic plate. The objective of this study was to evaluate the structural organization of the feto-placental vasculature of the chorionic plate. Casting of the placental vasculature was performed on 15 full-term placentas using a dental polymer mixed with colored ink. Observations of the cast models revealed that the branching architecture of the chorionic vessel is a combination of dichotomous and monopodial patterns, where the first two to three generations are always of a dichotomous nature. Analysis of the daughter-to-mother diameter ratios in the chorionic vessels provided a maximum in the range of 0.6-0.8 for the dichotomous branches, whereas in monopodial branches it was in the range of 0.1-0.3. Similar to previous studies, this study reveals that the vasculature architecture is mostly monopodial for the marginal cord insertion and mostly dichotomous for the central insertion. The more marginal the umbilical cord insertion is on the chorionic plate, the more monopodial branching patterns are created to compensate the dichotomous pattern deficiency to perfuse peripheral placental territories.

  10. The Pleiotropic Role of L1CAM in Tumor Vasculature

    PubMed Central

    Angiolini, Francesca; Cavallaro, Ugo

    2017-01-01

    Angiogenesis, the formation of new vessels, is a key step in the development, invasion, and dissemination of solid tumors and, therefore, represents a viable target in the context of antitumor therapy. Indeed, antiangiogenic approaches have given promising results in preclinical models and entered the clinical practice. However, in patients, the results obtained so far with antiangiogenic drugs have not completely fulfilled expectations, especially because their effect has been transient with tumors developing resistance and evasion mechanisms. A better understanding of the mechanisms that underlie tumor vascularization and the functional regulation of cancer vessels is a prerequisite for the development of novel and alternative antiangiogenic treatments. The L1 cell adhesion molecule (L1CAM), a cell surface glycoprotein previously implicated in the development and plasticity of the nervous system, is aberrantly expressed in the vasculature of various cancer types. L1CAM plays multiple pro-angiogenic roles in the endothelial cells of tumor-associated vessels, thus emerging as a potential therapeutic target. In addition, L1CAM prevents the maturation of cancer vasculature and its inhibition promotes vessel normalization, a process that is thought to improve the therapeutic response of tumors to cytotoxic drugs. We here provide an overview on tumor angiogenesis and antiangiogenic therapies and summarize the current knowledge on the biological role of L1CAM in cancer vasculature. Finally, we highlight the clinical implications of targeting L1CAM as a novel antiangiogenic and vessel-normalizing approach. PMID:28134764

  11. The Instructive Role of the Vasculature in Stem Cell Niches.

    PubMed

    Putnam, Andrew J

    2014-11-01

    An important hallmark of many adult stem cell niches is their proximity to the vasculature in vivo, a feature common to neural stem cells (NSCs), mesenchymal stem cells (MSCs) from bone marrow, adipose, and other tissues, hematopoietic stem cells (HSCs), and many tumor stem cells. This review summarizes key studies supporting the vasculature's instructive role in adult stem cell niches, and the putative underlying molecular mechanisms by which blood vessels in these niches exert control over progenitor cell fates. The importance of the perivascular niche for pathology, notably tumor metastasis and dormancy, is also highlighted. Finally, the implications of the perivascular regulation of stem and progenitor cells on biomaterial design and the impact on future research directions are discussed.

  12. Retinal vasculature classification using novel multifractal features

    NASA Astrophysics Data System (ADS)

    Ding, Y.; Ward, W. O. C.; Duan, Jinming; Auer, D. P.; Gowland, Penny; Bai, L.

    2015-11-01

    Retinal blood vessels have been implicated in a large number of diseases including diabetic retinopathy and cardiovascular diseases, which cause damages to retinal blood vessels. The availability of retinal vessel imaging provides an excellent opportunity for monitoring and diagnosis of retinal diseases, and automatic analysis of retinal vessels will help with the processes. However, state of the art vascular analysis methods such as counting the number of branches or measuring the curvature and diameter of individual vessels are unsuitable for the microvasculature. There has been published research using fractal analysis to calculate fractal dimensions of retinal blood vessels, but so far there has been no systematic research extracting discriminant features from retinal vessels for classifications. This paper introduces new methods for feature extraction from multifractal spectra of retinal vessels for classification. Two publicly available retinal vascular image databases are used for the experiments, and the proposed methods have produced accuracies of 85.5% and 77% for classification of healthy and diabetic retinal vasculatures. Experiments show that classification with multiple fractal features produces better rates compared with methods using a single fractal dimension value. In addition to this, experiments also show that classification accuracy can be affected by the accuracy of vessel segmentation algorithms.

  13. [Regeneration and repair of peripheral nerves: clinical implications in facial paralysis surgery].

    PubMed

    Hontanilla, B; Vidal, A

    2000-01-01

    Peripheral nerve lesions are one of the most frequent causes of chronic incapacity. Upper or lower limb palsies due to brachial or lumbar plexus injuries, facial paralysis and nerve lesions caused by systemic diseases are one of the major goals of plastic and reconstructive surgery. However, the poor results obtained in repaired peripheral nerves during the Second World War lead to a pessimist vision of peripheral nerve repair. Nevertheless, a well understanding of microsurgical principles in reconstruction and molecular biology of nerve regeneration have improved the clinical results. Thus, although the results obtained are quite far from perfect, these procedures give to patients a hope in the recuperation of their lesions and then on function. Technical aspects in nerve repair are well established; the next step is to manipulate the biology. In this article we will comment the biological processes which appear in peripheral nerve regeneration, we will establish the main concepts on peripheral nerve repair applied in facial paralysis cases and, finally, we will proportionate some ideas about how clinical practice could be affected by manipulation of the peripheral nerve biology.

  14. Chemotherapy-induced peripheral neuropathy: a review and implications for oncology nursing practice.

    PubMed

    Wickham, Rita

    2007-06-01

    Advances in supportive care have increased the likelihood that previously less common adverse effects of chemotherapy will be more evident. The incidence of chemotherapy-induced peripheral neuropathy (CIPN) is increasing because more neurotoxic drugs have been developed and because patients are living longer and receiving multiple chemotherapy regimens. This article reviews the anatomy of the peripheral nervous system, the proposed mechanisms of CIPN, and manifestations of CIPN from vinca alkaloids, taxanes, and platinum analogs. Major topics of this article are evidence-based data regarding symptom management, a review of medical management, and a synthesis of nursing care for patients at risk for or experiencing CIPN.

  15. Gpr177 regulates pulmonary vasculature development.

    PubMed

    Jiang, Ming; Ku, Wei-yao; Fu, Jiang; Offermanns, Stefan; Hsu, Wei; Que, Jianwen

    2013-09-01

    Establishment of the functional pulmonary vasculature requires intimate interaction between the epithelium and mesenchyme. Previous genetic studies have led to inconsistent conclusions about the contribution of epithelial Wnts to pulmonary vasculature development. This discrepancy is possibly due to the functional redundancy among different Wnts. Here, we use Shh-Cre to conditionally delete Gpr177 (the mouse ortholog of Drosophila Wntless, Wls), a chaperon protein important for the sorting and secretion of Wnt proteins. Deletion of epithelial Gpr177 reduces Wnt signaling activity in both the epithelium and mesenchyme, resulting in severe hemorrhage and abnormal vasculature, accompanied by branching defects and abnormal epithelial differentiation. We then used multiple mouse models to demonstrate that Wnt/β-catenin signaling is not only required for the proliferation and differentiation of mesenchyme, but also is important for the maintenance of smooth muscle cells through the regulation of the transcription factor Kruppel-like factor 2 (Klf2). Together, our studies define a novel mechanism by which epithelial Wnts regulate the normal development and maintenance of pulmonary vasculature. These findings provide insight into the pathobiology of congenital lung diseases, such as alveolar capillary dysplasia (ACD), that have abnormal alveolar development and dysmorphic pulmonary vasculature.

  16. Control of somatic membrane potential in nociceptive neurons and its implications for peripheral nociceptive transmission

    PubMed Central

    Du, Xiaona; Hao, Han; Gigout, Sylvain; Huang, Dongyang; Yang, Yuehui; Li, Li; Wang, Caixue; Sundt, Danielle; Jaffe, David B.; Zhang, Hailin; Gamper, Nikita

    2014-01-01

    Peripheral sensory ganglia contain somata of afferent fibres conveying somatosensory inputs to the central nervous system. Growing evidence suggests that the somatic/perisomatic region of sensory neurons can influence peripheral sensory transmission. Control of resting membrane potential (Erest) is an important mechanism regulating excitability, but surprisingly little is known about how Erest is regulated in sensory neuron somata or how changes in somatic/perisomatic Erest affect peripheral sensory transmission. We first evaluated the influence of several major ion channels on Erest in cultured small-diameter, mostly capsaicin-sensitive (presumed nociceptive) dorsal root ganglion (DRG) neurons. The strongest and most prevalent effect on Erest was achieved by modulating M channels, K2P and 4-aminopiridine-sensitive KV channels, while hyperpolarization-activated cyclic nucleotide-gated, voltage-gated Na+, and T-type Ca2+ channels to a lesser extent also contributed to Erest. Second, we investigated how varying somatic/perisomatic membrane potential, by manipulating ion channels of sensory neurons within the DRG, affected peripheral nociceptive transmission in vivo. Acute focal application of M or KATP channel enhancers or a hyperpolarization-activated cyclic nucleotide-gated channel blocker to L5 DRG in vivo significantly alleviated pain induced by hind paw injection of bradykinin. Finally, we show with computational modelling how somatic/perisomatic hyperpolarization, in concert with the low-pass filtering properties of the t-junction within the DRG, can interfere with action potential propagation. Our study deciphers a complement of ion channels that sets the somatic Erest of nociceptive neurons and provides strong evidence for a robust filtering role of the somatic and perisomatic compartments of peripheral nociceptive neuron. PMID:25168672

  17. Calcitonin gene-related peptide promotes cellular changes in trigeminal neurons and glia implicated in peripheral and central sensitization

    PubMed Central

    2011-01-01

    Background Calcitonin gene-related peptide (CGRP), a neuropeptide released from trigeminal nerves, is implicated in the underlying pathology of temporomandibular joint disorder (TMD). Elevated levels of CGRP in the joint capsule correlate with inflammation and pain. CGRP mediates neurogenic inflammation in peripheral tissues by increasing blood flow, recruiting immune cells, and activating sensory neurons. The goal of this study was to investigate the capability of CGRP to promote peripheral and central sensitization in a model of TMD. Results Temporal changes in protein expression in trigeminal ganglia and spinal trigeminal nucleus were determined by immunohistochemistry following injection of CGRP in the temporomandibular joint (TMJ) capsule of male Sprague-Dawley rats. CGRP stimulated expression of the active forms of the MAP kinases p38 and ERK, and PKA in trigeminal ganglia at 2 and 24 hours. CGRP also caused a sustained increase in the expression of c-Fos neurons in the spinal trigeminal nucleus. In contrast, levels of P2X3 in spinal neurons were only significantly elevated at 2 hours in response to CGRP. In addition, CGRP stimulated expression of GFAP in astrocytes and OX-42 in microglia at 2 and 24 hours post injection. Conclusions Our results demonstrate that an elevated level of CGRP in the joint, which is associated with TMD, stimulate neuronal and glial expression of proteins implicated in the development of peripheral and central sensitization. Based on our findings, we propose that inhibition of CGRP-mediated activation of trigeminal neurons and glial cells with selective non-peptide CGRP receptor antagonists would be beneficial in the treatment of TMD. PMID:22145886

  18. In Vitro Study of Directly Bioprinted Perfusable Vasculature Conduits

    PubMed Central

    Zhang, Yahui; Yu, Yin; Akkouch, Adil; Dababneh, Amer; Dolati, Farzaneh

    2014-01-01

    The ability to create three dimensional (3D) thick tissues is still a major tissue engineering challenge. It requires the development of a suitable vascular supply for an efficient media exchange. An integrated vasculature network is particularly needed when building thick functional tissues and/or organs with high metabolic activities, such as the heart, liver and pancreas. In this work, human umbilical vein smooth muscle cells (HUVSMCs) were encapsulated in sodium alginate and printed in the form of vasculature conduits using a coaxial deposition system. Detailed investigations were performed to understand the dehydration, swelling and degradation characteristics of printed conduits. In addition, because perfusional, permeable and mechanical properties are unique characteristics of natural blood vessels, for printed conduits these properties were also explored in this work. The results show that cells encapsulated in conduits had good proliferation activities and that their viability increased during prolonged in vitro culture. Deposition of smooth muscle matrix and collagen was observed around the peripheral and luminal surface in long-term cultured cellular vascular conduit through histology studies. PMID:25574378

  19. Nitric oxide in the pulmonary vasculature.

    PubMed

    Coggins, Matthew P; Bloch, Kenneth D

    2007-09-01

    Homeostasis in the pulmonary vasculature is maintained by the actions of vasoactive compounds, including nitric oxide (NO). NO is critical for normal development of the pulmonary vasculature and continues to mediate normal vasoregulation in adulthood. Loss of NO bioavailability is one component of the endothelial dysfunction and vascular pathology found in pulmonary hypertension (PH). A broad research effort continues to expand our understanding of the control of NO production and NO signaling and has generated novel theories on the importance of pulmonary NO production in the control of the systemic vasculature. This understanding has led to exciting developments in our ability to treat PH, including inhaled NO and phosphodiesterase inhibitors, and to several promising directions for future therapies using nitric oxide-donor compounds, stimulators of soluble guanylate cyclase, progenitor cells expressing NO synthase (NOS), and NOS gene manipulation.

  20. Nonclassical Patrolling Monocyte Function in the Vasculature

    PubMed Central

    Thomas, Graham; Tacke, Robert; Hedrick, Catherine C.

    2015-01-01

    Nonclassical patrolling monocytes are characterized by their unique ability to actively patrol the vascular endothelium under homeostatic and inflammatory conditions. Patrolling monocyte subsets (CX3CR1highLy6C− in mouse, and CX3CR1highCD14dimCD16+ in humans) are distinct from the classical monocyte subsets (CCR2highLy6C+ in mouse, and CCR2highCD14+CD16− in humans) and exhibit unique functions in the vasculature and inflammatory disease. Patrolling monocytes function in a number of disease settings to remove damaged cells and debris from the vasculature, and have been associated with wound healing and the resolution of inflammation in damaged tissues. This review highlights the unique functions of these patrolling monocytes in the vasculature and during inflammation. PMID:25838429

  1. A new animal model of spontaneous autoimmune peripheral polyneuropathy: implications for Guillain-Barré syndrome

    PubMed Central

    2014-01-01

    Background Spontaneous autoimmune peripheral neuropathy including Guillain-Barré Syndrome (GBS) represents as one of the serious emergencies in neurology. Although pathological changes have been well documented, molecular and cellular mechanisms of GBS are still under-explored, partially due to short of appropriate animal models. The field lacks of spontaneous and translatable models for mechanistic investigations. As GBS is preceded often by viral or bacterial infection, a condition can enhance co-stimulatory activity; we sought to investigate the critical role of T cell co-stimulation in this autoimmune disease. Results Our previous study reported that transgene-derived constitutive expression of co-stimulator B7.2 on antigen presenting cells of the nervous tissues drove spontaneous neurological disorders. Depletion of CD4+ T cells in L31 mice accelerated the onset and increased the prevalence of the disease. In the current study, we further demonstrated that L31/CD4-/- mice exhibited both motor and sensory deficits, including weakness and paresis of limbs, numbness to mechanical stimuli and hypersensitivity to thermal stimulation. Pathological changes were characterized by massive infiltration of macrophages and CD8+ T cells, demyelination and axonal damage in peripheral nerves, while changes in spinal cords could be secondary to the PNS damage. In symptomatic L31/CD4-/- mice, the disruption of the blood neural barriers was observed mainly in peripheral nerves. Interestingly, the infiltration of immune cells was initiated in pre-symptomatic L31/CD4-/- mice, prior to the disease onset, in the DRG and spinal roots where the blood nerve barrier is virtually absent. Conclusions L31/CD4-/- mice mimic most parts of clinical and pathological signatures of GBS in human; thus providing an unconventional opportunity to experimentally explore the critical events that lead to spontaneous, autoimmune demyelinating disease of the peripheral nervous system. PMID:24401681

  2. Residual function in peripheral nerve stumps of amputees: implications for neural control of artificial limbs.

    PubMed

    Dhillon, Gurpreet S; Lawrence, Stephen M; Hutchinson, Douglas T; Horch, Kenneth W

    2004-07-01

    It is not known whether motor and sensory pathways associated with a missing or denervated limb remain functionally intact over periods of many months or years after amputation or chronic peripheral nerve transection injury. We examined the extent to which activity on chronically severed motor nerve fibers could be controlled by human amputees and whether distally referred tactile and proprioceptive sensations could be induced by stimulation of sensory axons in the nerve stumps. Amputees undergoing elective stump procedures were invited to participate in this study. Longitudinal intrafascicular electrodes were threaded percutaneously and implanted in severed nerves of human amputees. The electrodes were interfaced to an amplifier and stimulator system controlled by a laptop computer. Electrophysiologic tests were conducted for 2 consecutive days after recovery from the surgery. It was possible to record volitional motor nerve activity uniquely associated with missing limb movements. Electrical stimulation through the implanted electrodes elicited discrete, unitary, graded sensations of touch, joint movement, and position, referring to the missing limb. These findings indicate that both central and peripheral motor and somatosensory pathways retain significant residual connectivity and function for many years after limb amputation. This implies that peripheral nerve interfaces could be used to provide amputees with prosthetic limbs that have more natural feel and control than is possible with current myoelectric and body-powered control systems.

  3. Implications of isolation and low genetic diversity in peripheral populations of an amphi-Atlantic coral.

    PubMed

    Nunes, F; Norris, R D; Knowlton, N

    2009-10-01

    Limited dispersal and connectivity in marine organisms can have negative fitness effects in populations that are small and isolated, but reduced genetic exchange may also promote the potential for local adaptation. Here, we compare the levels of genetic diversity and connectivity in the coral Montastraea cavernosa among both central and peripheral populations throughout its range in the Atlantic. Genetic data from one mitochondrial and two nuclear loci in 191 individuals show that M. cavernosa is subdivided into three genetically distinct regions in the Atlantic: Caribbean-North Atlantic, Western South Atlantic (Brazil) and Eastern Tropical Atlantic (West Africa). Within each region, populations have similar allele frequencies and levels of genetic diversity; indeed, no significant differentiation was found between populations separated by as much as 3000 km, suggesting that this coral species has the ability to disperse over large distances. Gene flow within regions does not, however, translate into connectivity across the entire Atlantic. Instead, substantial differences in allele frequencies across regions suggest that genetic exchange is infrequent between the Caribbean, Brazil and West Africa. Furthermore, markedly lower levels of genetic diversity are observed in the Brazilian and West African populations. Genetic diversity and connectivity may contribute to the resilience of a coral population to disturbance. Isolated peripheral populations may be more vulnerable to human impacts, disease or climate change relative to those in the genetically diverse Caribbean-North Atlantic region.

  4. Immune-mediated processes implicated in chemotherapy-induced peripheral neuropathy.

    PubMed

    Lees, Justin G; Makker, Preet G S; Tonkin, Ryan S; Abdulla, Munawwar; Park, Susanna B; Goldstein, David; Moalem-Taylor, Gila

    2017-03-01

    Chemotherapy-induced peripheral neuropathy (CIPN) and associated neuropathic pain are challenging complications of cancer treatment. Many of the major classes of chemotherapeutics can cause neurotoxicity and significantly modulate the immune system. There is ongoing investigation regarding whether reciprocal crosstalk between the nervous and immune systems occurs and, indeed, contributes to neuropathic pain during treatment with chemotherapeutics. An emerging concept is that neuroinflammation is one of the major mechanisms underlying CIPN. Here, we discuss recent findings, which provide insight into this complex process of neuroimmune interactions. Findings show limited infiltration of leukocytes into the nervous system of CIPN animals and varying degrees of peripheral and central glial activation depending on the chemotherapeutic drug, dose, schedule, and timing. Most evidence suggests an increase in pro-inflammatory cytokine expression and changes in immune signalling pathways. There is, however, limited evidence available from human studies and it remains unclear whether neuroinflammatory responses are the cause of neuropathy or a bystander effect of the chemotherapy treatment.

  5. Malignant peripheral nerve sheath tumour (MPNST): the clinical implications of cellular signalling pathways.

    PubMed

    Katz, Daniela; Lazar, Alexander; Lev, Dina

    2009-10-19

    Malignant peripheral nerve sheath tumour (MPNST) is a rare malignancy accounting for 3-10% of all soft tissue sarcomas. Most MPNSTs arise in association with peripheral nerves or deep neurofibromas and may originate from neural crest cells, although the specific cell of origin is uncertain. Approximately half of MPNSTs occur in the setting of neurofibromatosis type 1 (NF1), an autosomal dominant disorder with an incidence of approximately one in 3500 persons; the remainder of MPNSTs develop sporadically. In addition to a variety of clinical manifestations, approximately 8-13% of NF1 patients develop MPNSTs, which are the leading cause of NF1-related mortality. Surgical resection is the mainstay of MPNST clinical management. However, because of invasive growth, propensity to metastasise, and limited sensitivity to chemotherapy and radiation, MPNST has a guarded to poor prognosis. Five-year survival rates of only 20-50% indicate an urgent need for improved therapeutic approaches. Recent work in this field has identified several altered intracellular signal transduction cascades and deregulated tyrosine kinase receptors, posing the possibility of personalised, targeted therapeutics. However, expanded knowledge of MPNST molecular pathobiology will be needed to meaningfully apply such approaches for the benefit of afflicted patients.

  6. PSP activates monocytes in resting human peripheral blood mononuclear cells: immunomodulatory implications for cancer treatment.

    PubMed

    Sekhon, Bhagwant Kaur; Sze, Daniel Man-Yuen; Chan, Wing Keung; Fan, Kei; Li, George Qian; Moore, Douglas Edwin; Roubin, Rebecca Heidi

    2013-06-15

    Polysaccharopeptide (PSP), from Coriolus versicolor, has been used as an adjuvant to chemotherapy, and has demonstrated anti-tumor and immunomodulating effects. However its mechanism remains unknown. To elucidate how PSP affects immune populations, we compared PSP treatments both with and without prior incubation in phytohaemagglutinin (PHA) - a process commonly used in immune population experimentation. We first standardised a capillary electrophoresis fingerprinting technique for PSP identification and characterisation. We then established the proliferative capability of PSP on various immune populations in peripheral blood mononuclear cells, using flow cytometry, without prior PHA treatment. It was found that PSP significantly increased the number of monocytes (CD14(+)/CD16(-)) compared to controls without PHA. This increase in monocytes was confirmed using another antibody panel of CD14 and MHCII. In contrast, proliferations of T-cells, NK, and B-cells were not significantly changed by PSP. Thus, stimulating monocyte/macrophage function with PSP could be an effective therapeutic intervention in targeting tumors.

  7. Pharmacology of TRP channels in the vasculature.

    PubMed

    Jardín, Isaac; Dionisio, Natalia; Lopez, Jose J; Salido, Gines M; Rosado, Juan A

    2013-07-01

    The TRP family of cation-permeable channels owes its name to a Drosophila TRP mutant with impaired vision due to transient rather than sustained receptor potential. Mammalian TRP channels can be grouped into 6 subfamilies, including TRPC, TRPM, TRPV, TRPA, TRPP and TRPML and a number of TRP family members have been identified in the vasculature. TRP channels play an important functional role in the vasculature as mediators of cation influx across the plasma membrane, thus contributing to a large number of processes such as vascular smooth muscle contraction and vascular pressure or the responses to oxidative stress, mechanical stimuli, heat and hypoxia-induced vascular remodelling. TRP channelopaties are involved in the pathogenesis of different disorders including hypertension and cardiomyopathy. A number of identified natural compounds and synthetic agents have been reported to modulate TRP function, and are the base for therapeutical strategies.

  8. Prototyping of cerebral vasculature physical models.

    PubMed

    Khan, Imad S; Kelly, Patrick D; Singer, Robert J

    2014-01-01

    Prototyping of cerebral vasculature models through stereolithographic methods have the ability to accurately depict the 3D structures of complicated aneurysms with high accuracy. We describe the method to manufacture such a model and review some of its uses in the context of treatment planning, research, and surgical training. We prospectively used the data from the rotational angiography of a 40-year-old female who presented with an unruptured right paraclinoid aneurysm. The 3D virtual model was then converted to a physical life-sized model. The model constructed was shown to be a very accurate depiction of the aneurysm and its associated vasculature. It was found to be useful, among other things, for surgical training and as a patient education tool. With improving and more widespread printing options, these models have the potential to become an important part of research and training modalities.

  9. [Endometrial vasculature in women with hydrosalpinx].

    PubMed

    Kirichenko, A K; Khorzhevskiĭ, V A

    2014-01-01

    To study the endometrial vasculature in women with hydrosalpinx and to determine a possible correlation between its state and the morphometric parameters of other structural components of the uterine mucosa. The endometrium was studied in 20 patients with primary tubal infertility in hydrosalpinx. A control group included 20 women with established fertility and a regular menstrual cycle with a good obstetric and gynecological history. The spectrum of morphometric parameters included the relative volumes occupied by the endometrial glands and glandular epithelium; the height of the integumentary epithelium; and the number of stromal cells per mm2. Stereometric (glandular-stromal, epithelial-stromal) indices and epithelium/glandular lumen ratio were calculated. The endometrial vasculature was estimated by immunohistochemical assay of CD31- and CD34-expressing cells. There was a decrease in the specific volume occupied by positively stained vascular endotheliocytes and a predominance of the stromal component of the endometrium over its epithelial one. Correlations were found between the degree of development of the endometrial vasculature and endometrial glands, which reflects their normal relationships in the proliferation phase. In the study group, the correlation between the height of the integumentary epithelium and the development of the endometrial vasculature was moderately positive, which was absent in the control group where this correlation was strong and positive. The findings are evidence in favor of the negative impact of hydrosalpinx on the uterine mucosa. The found changes in the main endometrial structural components (vessels, glands, and stromal cells) reflect impaired mucosal maturation processes during the proliferation phase. The substantial negative impact of hydrosalpinx has an effect on the height of the integumentary epithelium of the endometrium. The given data suggest that there are significant and complex endometrial changes in hydrosalpinx

  10. Neuronal nitric oxide synthase inhibition and regional sympathetic nerve discharge: implications for peripheral vascular control.

    PubMed

    Copp, Steven W; Hirai, Daniel M; Sims, Gabrielle E; Fels, Richard J; Musch, Timothy I; Poole, David C; Kenney, Michael J

    2013-05-01

    Neuronal nitric oxide (NO) synthase (nNOS) inhibition with systemically administered S-methyl-l-thiocitrulline (SMTC) elevates mean arterial pressure (MAP) and reduces rat hindlimb skeletal muscle and renal blood flow. We tested the hypothesis that those SMTC-induced cardiovascular effects resulted, in part, from increased sympathetic nerve discharge (SND). MAP, HR, and lumbar and renal SND (direct nerve recordings) were measured in 9 baroreceptor (sino-aortic)-denervated rats for 20min each following both saline and SMTC (0.56mg/kg i.v.). SMTC increased MAP (peak ΔMAP: 50±8mmHg, p<0.01) compared to saline. Lumbar and renal SND were not different between saline and SMTC conditions at any time (p>0.05). The ΔSND between saline and SMTC conditions for the lumbar and renal nerves were not different from zero (peak ΔSND, lumbar: 2.0±6.8%; renal: 9.7±9.0%, p>0.05 versus zero for both). These data support that SMTC-induced reductions in skeletal muscle and renal blood flow reported previously reflect peripheral nNOS-derived NO vascular control as opposed to increased sympathetic vasoconstriction. Copyright © 2013 Elsevier B.V. All rights reserved.

  11. Romidepsin in peripheral and cutaneous T-cell lymphoma: mechanistic implications from clinical and correlative data.

    PubMed

    Bates, Susan E; Eisch, Robin; Ling, Alexander; Rosing, Douglas; Turner, Maria; Pittaluga, Stefania; Prince, H Miles; Kirschbaum, Mark H; Allen, Steven L; Zain, Jasmine; Geskin, Larisa J; Joske, David; Popplewell, Leslie; Cowen, Edward W; Jaffe, Elaine S; Nichols, Jean; Kennedy, Sally; Steinberg, Seth M; Liewehr, David J; Showe, Louise C; Steakley, Caryn; Wright, John; Fojo, Tito; Litman, Thomas; Piekarz, Richard L

    2015-07-01

    Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3.5 months to 10 years; in four of six patients, re-initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics-mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T-cell lymphoma, but suggests a complex mechanism of action.

  12. Peripheral neuropathy in Parkinson's disease: levodopa exposure and implications for duodenal delivery.

    PubMed

    Müller, Thomas; van Laar, Teus; Cornblath, David R; Odin, Per; Klostermann, Fabian; Grandas, Francisco J; Ebersbach, Georg; Urban, Peter P; Valldeoriola, Francesc; Antonini, Angelo

    2013-05-01

    In advanced Parkinson's disease (PD) patients, continuous intra-duodenal infusion of levodopa/carbidopa intestinal gel (LCIG) is an established approach in the management of motor complications that cannot be further improved by conventional oral therapy. In general, tolerability of LCIG has resembled that of oral dopaminergic therapy; however, cases of symptomatic peripheral neuropathy (PN), sometimes severe, have been reported in patients receiving LCIG. Cases are generally a sensorimotor polyneuropathy with both subacute and chronic onsets, often associated with vitamin B12 and/or B6 deficiency. Rare cases clinically resemble Guillain-Barré syndrome. In the absence of prospectively collected data on possible associations between LCIG and PN, it is prudent to explore potential mechanisms that may explain a possible relationship. The PN may be linked to use of high-dose levodopa, promoting high levels of homocysteine and methylmalonic acid or reduced absorption of vitamins essential for homocysteine metabolism. Cases of LCIG-associated PN often have responded to vitamin supplementation without need for LCIG cessation, although LCIG cessation is sometimes necessary. It may be advisable to monitor vitamin B12/B6 status before and after patients start LCIG and be vigilant for signs of PN. Prospective, large-scale, long-term studies are needed to clarify whether vitamin supplementation and routine use of a catechol-O-methyltransferase inhibitor may help prevent PN in LCIG recipients and whether these measures should be routine practice in patients with PD on high-dose oral levodopa.

  13. The Instructive Role of the Vasculature in Stem Cell Niches

    PubMed Central

    Putnam, Andrew J.

    2014-01-01

    An important hallmark of many adult stem cell niches is their proximity to the vasculature in vivo, a feature common to neural stem cells (NSCs), mesenchymal stem cells (MSCs) from bone marrow, adipose, and other tissues, hematopoietic stem cells (HSCs), and many tumor stem cells. This review summarizes key studies supporting the vasculature’s instructive role in adult stem cell niches, and the putative underlying molecular mechanisms by which blood vessels in these niches exert control over progenitor cell fates. The importance of the perivascular niche for pathology, notably tumor metastasis and dormancy, is also highlighted. Finally, the implications of the perivascular regulation of stem and progenitor cells on biomaterial design and the impact on future research directions are discussed. PMID:25530848

  14. Central orchestration of peripheral nutrient partitioning and substrate utilization: implications for the metabolic syndrome.

    PubMed

    Denis, R G P; Joly-Amado, A; Cansell, C; Castel, J; Martinez, S; Delbes, A S; Luquet, S

    2014-06-01

    Energy homoeostasis is maintained through a complex interplay of nutrient intake and energy expenditure. The central nervous system is an essential component of this regulation, as it integrates circulating signals of hunger and satiety to develop adaptive responses at the behavioural and metabolic levels, while the hypothalamus is regarded as a particularly crucial structure in the brain in terms of energy homoeostasis. The arcuate nucleus (ARC) of the hypothalamus contains at least two intermingled neuronal populations: the neurons that produce neuropeptide Y (NPY); and the Agouti-related protein (AgRP) produced by AgRP/NPY neurons situated below the third ventricle in close proximity to proopiomelanocortin (POMC)-producing neurons. POMC neurons exert their catabolic and anorectic actions by releasing α-melanocyte-stimulating hormone (α-MSH), while AgRP neurons oppose this action by exerting tonic GABAergic inhibition of POMC neurons and releasing the melanocortin receptor inverse agonist AgRP. The release of neurotransmitters and neuropeptides by second-order AgRP neurons appears to take place on a multiple time scale, thereby allowing neuromodulation of preganglionic neuronal activity and subsequent control of nutrient partitioning - in other words, the coordinated regulation of conversion, storage and utilization of carbohydrates vs. lipids. This suggests that the function of AgRP neurons extends beyond the strict regulation of feeding to the regulation of efferent organ activity, such that AgRP neurons may now be viewed as an important bridge between central detection of nutrient availability and peripheral nutrient partitioning, thus providing a mechanistic link between obesity and obesity-related disorders. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  15. Limb-state information encoded by peripheral and central somatosensory neurons: implications for an afferent interface.

    PubMed

    Weber, Douglas J; London, Brian M; Hokanson, James A; Ayers, Christopher A; Gaunt, Robert A; Torres, Ricardo R; Zaaimi, Boubker; Miller, Lee E

    2011-10-01

    A major issue to be addressed in the development of neural interfaces for prosthetic control is the need for somatosensory feedback. Here, we investigate two possible strategies: electrical stimulation of either dorsal root ganglia (DRG) or primary somatosensory cortex (S1). In each approach, we must determine a model that reflects the representation of limb state in terms of neural discharge. This model can then be used to design stimuli that artificially activate the nervous system to convey information about limb state to the subject. Electrically activating DRG neurons using naturalistic stimulus patterns, modeled on recordings made during passive limb movement, evoked activity in S1 that was similar to that of the original movement. We also found that S1 neural populations could accurately discriminate different patterns of DRG stimulation across a wide range of stimulus pulse-rates. In studying the neural coding in S1, we also decoded the kinematics of active limb movement using multi-electrode recordings in the monkey. Neurons having both proprioceptive and cutaneous receptive fields contributed equally to this decoding. Some neurons were most informative of limb state in the recent past, but many others appeared to signal upcoming movements suggesting that they also were modulated by an efference copy signal. Finally, we show that a monkey was able to detect stimulation through a large percentage of electrodes implanted in area 2. We discuss the design of appropriate stimulus paradigms for conveying time-varying limb state information, and the relative merits and limitations of central and peripheral approaches.

  16. Dynamics of axonal mRNA transport and implications for peripheral nerve regeneration

    PubMed Central

    Yoo, Soonmoon; van Niekerk, Erna A.; Merianda, Tanuja T.; Twiss, Jeffery L.

    2009-01-01

    Locally generating new proteins in subcellular regions provides means to spatially and temporally modify protein content in polarized cells. Recent years have seen resurgence of the concept that axonal processes of neurons can locally synthesize proteins. Experiments from a number of groups have now shown that axonal protein synthesis helps to initiate growth, provides a means to respond to guidance cues, and generates retrograde signaling complexes. Additionally, there is increasing evidence that locally synthesized proteins provide functions beyond injury responses and growth in the mature peripheral nervous system. A key regulatory event in this translational regulation is moving the mRNA templates into the axonal compartment. Transport of mRNAs into axons is a highly regulated and specific process that requires interaction of RNA binding proteins with specific cis-elements or structures within the mRNAs. mRNAs are transported in ribonucleoprotein particles that interact with microtubule motor proteins for long-range axonal transport and likely use microfilaments for short-range movement in the axons. The mature axon is able to recruit mRNAs into translation with injury and possibly other stimuli suggesting that mRNAs can be stored in a dormant state in the distal axon until needed. Axotomy triggers a shift in the populations of mRNAs localized to axons indicating a dynamic regulation of the specificity of the axonal transport machinery. In this review, we discuss how axonal mRNA transport and localization are regulated to achieve specific changes in axonal RNA content in response to axonal stimuli. PMID:19699200

  17. Mycolactone Diffuses into the Peripheral Blood of Buruli Ulcer Patients - Implications for Diagnosis and Disease Monitoring

    PubMed Central

    Aka, N'Guetta; Phillips, Richard O.; Amoako, Yaw; Boneca, Ivo G.; Lenormand, Pascal; Dosso, Mireille; Wansbrough-Jones, Mark; Veyron-Churlet, Romain; Guenin-Macé, Laure; Demangel, Caroline

    2011-01-01

    Background Mycobacterium ulcerans, the causative agent of Buruli ulcer (BU), is unique among human pathogens in its capacity to produce a polyketide-derived macrolide called mycolactone, making this molecule an attractive candidate target for diagnosis and disease monitoring. Whether mycolactone diffuses from ulcerated lesions in clinically accessible samples and is modulated by antibiotic therapy remained to be established. Methodology/Principal Finding Peripheral blood and ulcer exudates were sampled from patients at various stages of antibiotic therapy in Ghana and Ivory Coast. Total lipids were extracted from serum, white cell pellets and ulcer exudates with organic solvents. The presence of mycolactone in these extracts was then analyzed by a recently published, field-friendly method using thin layer chromatography and fluorescence detection. This approach did not allow us to detect mycolactone accurately, because of a high background due to co-extracted human lipids. We thus used a previously established approach based on high performance liquid chromatography coupled to mass spectrometry. By this means, we could identify structurally intact mycolactone in ulcer exudates and serum of patients, and evaluate the impact of antibiotic treatment on the concentration of mycolactone. Conclusions/Significance Our study provides the proof of concept that assays based on mycolactone detection in serum and ulcer exudates can form the basis of BU diagnostic tests. However, the identification of mycolactone required a technology that is not compatible with field conditions and point-of-care assays for mycolactone detection remain to be worked out. Notably, we found mycolactone in ulcer exudates harvested at the end of antibiotic therapy, suggesting that the toxin is eliminated by BU patients at a slow rate. Our results also indicated that mycolactone titres in the serum may reflect a positive response to antibiotics, a possibility that it will be interesting to examine

  18. Pulmonary vasculature in COPD: The silent component.

    PubMed

    Blanco, Isabel; Piccari, Lucilla; Barberà, Joan Albert

    2016-08-01

    Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction that results from an inflammatory process affecting the airways and lung parenchyma. Despite major abnormalities taking place in bronchial and alveolar structures, changes in pulmonary vessels also represent an important component of the disease. Alterations in vessel structure are highly prevalent and abnormalities in their function impair gas exchange and may result in pulmonary hypertension (PH), an important complication of the disease associated with reduced survival and worse clinical course. The prevalence of PH is high in COPD, particularly in advanced stages, although it remains of mild to moderate severity in the majority of cases. Endothelial dysfunction, with imbalance between vasodilator/vasoconstrictive mediators, is a key determinant of changes taking place in pulmonary vasculature in COPD. Cigarette smoke products may perturb endothelial cells and play a critical role in initiating vascular changes. The concurrence of inflammation, hypoxia and emphysema further contributes to vascular damage and to the development of PH. The use of drugs that target endothelium-dependent signalling pathways, currently employed in pulmonary arterial hypertension, is discouraged in COPD due to the lack of efficacy observed in randomized clinical trials and because there is compelling evidence indicating that these drugs may worsen pulmonary gas exchange. The subgroup of patients with severe PH should be ideally managed in centres with expertise in both PH and chronic lung diseases because alterations of pulmonary vasculature might resemble those observed in pulmonary arterial hypertension. Because this condition entails poor prognosis, it warrants specialist treatment.

  19. Altered Peripheral Blood Monocyte Phenotype and Function in Chronic Liver Disease: Implications for Hepatic Recruitment and Systemic Inflammation

    PubMed Central

    Gadd, Victoria L.; Patel, Preya J.; Jose, Sara; Horsfall, Leigh

    2016-01-01

    Background and Aims Liver and systemic inflammatory factors influence monocyte phenotype and function, which has implications for hepatic recruitment and subsequent inflammatory and fibrogenic responses, as well as host defence. Methods Peripheral blood monocyte surface marker (CD14, CD16, CD163, CSF1R, CCR2, CCR4, CCR5, CXCR3, CXCR4, CX3CR1, HLA-DR, CD62L, SIGLEC-1) expression and capacity for phagocytosis, oxidative burst and LPS-stimulated TNF production were assessed in patients with hepatitis C (HCV) (n = 39) or non-alcoholic fatty liver disease (NAFLD) (n = 34) (classified as non-advanced disease, compensated cirrhosis and decompensated cirrhosis) and healthy controls (n = 11) by flow cytometry. Results The selected markers exhibited similar monocyte-subset-specific expression patterns between patients and controls. Monocyte phenotypic signatures differed between NAFLD and HCV patients, with an increased proportion of CD16+ non-classical monocytes in NAFLD, but increased expression of CXCR3 and CXCR4 in HCV. In both cohorts, monocyte CCR2 expression was reduced and CCR4 elevated over controls. CD62L expression was specifically elevated in patients with decompensated cirrhosis and positively correlated with the model-for-end-stage-liver-disease score. Functionally, monocytes from patients with decompensated cirrhosis had equal phagocytic capacity, but displayed features of dysfunction, characterised by lower HLA-DR expression and blunted oxidative responses. Lower monocyte TNF production in response to LPS stimulation correlated with time to death in 7 (46%) of the decompensated patients who died within 8 months of recruitment. Conclusions Chronic HCV and NAFLD differentially affect circulating monocyte phenotype, suggesting specific injury-induced signals may contribute to hepatic monocyte recruitment and systemic activation state. Monocyte function, however, was similarly impaired in patients with both HCV and NAFLD, particularly in advanced disease, which

  20. Mechanisms Underlying Drug Delivery to Peripheral Arteries.

    PubMed

    Li, Jun; Tzafriri, Rami; Patel, Sandeep M; Parikh, Sahil A

    2017-04-01

    Delivery of drugs onto arterial targets via endovascular devices commands several principles: dissolution, diffusion, convection, drug binding, barriers to absorption, and interaction between the drug, delivery vehicle, and accepting arterial wall. The understanding of drug delivery in the coronary vasculature is vast; there is ongoing work needed in the peripheral arteries. There are differences that account for some failures of application of coronary technology into the peripheral vascular space. Breakthroughs in peripheral vascular interventional techniques building on current technologies require investigators willing to acknowledge the similarities and differences between these different vascular territories, while developing technologies adapted for peripheral arteries.

  1. What optimization principle explains the zebrafish vasculature?

    NASA Astrophysics Data System (ADS)

    Chang, Shyr-Shea; Baek, Kyung In; Hsiai, Tzung; Roper, Marcus

    2016-11-01

    Many multicellular organisms depend on biological transport networks; from the veins of leaves to the animal circulatory system, to redistribute nutrients internally. Since natural selection rewards efficiency, those networks are thought to minimize the cost of maintaining the flow inside. But optimizing these costs creates tradeoffs with other functions, e.g. mixing or uniform distribution of nutrients. We develop an extended Lagrange multiplier approach that allows the optimization of general network functionals. We also follow the real zebrafish vasculature and blood flows during organism development. Taken together, our work shows that the challenge of uniform oxygen perfusion, and not transport efficiency, explain zebrafish vascular organization. Ruth L. Kirschstein National Research Service Award (T32-GM008185).

  2. Tendon Vasculature in Health and Disease

    PubMed Central

    Tempfer, Herbert; Traweger, Andreas

    2015-01-01

    Tendons represent a bradytrophic tissue which is poorly vascularized and, compared to bone or skin, heal poorly. Usually, a vascularized connective scar tissue with inferior functional properties forms at the injury site. Whether the increased vascularization is the root cause of tissue impairments such as loss of collagen fiber orientation, ectopic formation of bone, fat or cartilage, or is a consequence of these pathological changes remains unclear. This review provides an overview of the role of tendon vasculature in healthy and chronically diseased tendon tissue as well as its relevance for tendon repair. Further, the nature and the role of perivascular tendon stem/progenitor cells residing in the vascular niche will be discussed and compared to multipotent stromal cells in other tissues. PMID:26635616

  3. Genetic determinants of hyaloid and retinal vasculature in zebrafish

    PubMed Central

    Alvarez, Yolanda; Cederlund, Maria L; Cottell, David C; Bill, Brent R; Ekker, Stephen C; Torres-Vazquez, Jesus; Weinstein, Brant M; Hyde, David R; Vihtelic, Thomas S; Kennedy, Breandan N

    2007-01-01

    Background The retinal vasculature is a capillary network of blood vessels that nourishes the inner retina of most mammals. Developmental abnormalities or microvascular complications in the retinal vasculature result in severe human eye diseases that lead to blindness. To exploit the advantages of zebrafish for genetic, developmental and pharmacological studies of retinal vasculature, we characterised the intraocular vasculature in zebrafish. Results We show a detailed morphological and developmental analysis of the retinal blood supply in zebrafish. Similar to the transient hyaloid vasculature in mammalian embryos, vessels are first found attached to the zebrafish lens at 2.5 days post fertilisation. These vessels progressively lose contact with the lens and by 30 days post fertilisation adhere to the inner limiting membrane of the juvenile retina. Ultrastructure analysis shows these vessels to exhibit distinctive hallmarks of mammalian retinal vasculature. For example, smooth muscle actin-expressing pericytes are ensheathed by the basal lamina of the blood vessel, and vesicle vacuolar organelles (VVO), subcellular mediators of vessel-retinal nourishment, are present. Finally, we identify 9 genes with cell membrane, extracellular matrix and unknown identity that are necessary for zebrafish hyaloid and retinal vasculature development. Conclusion Zebrafish have a retinal blood supply with a characteristic developmental and adult morphology. Abnormalities of these intraocular vessels are easily observed, enabling application of genetic and chemical approaches in zebrafish to identify molecular regulators of hyaloid and retinal vasculature in development and disease. PMID:17937808

  4. Hippo Signaling Mediators Yap and Taz Are Required in the Epicardium for Coronary Vasculature Development.

    PubMed

    Singh, Anamika; Ramesh, Sindhu; Cibi, Dasan Mary; Yun, Lim Sze; Li, Jun; Li, Li; Manderfield, Lauren J; Olson, Eric N; Epstein, Jonathan A; Singh, Manvendra K

    2016-05-17

    Formation of the coronary vasculature is a complex and precisely coordinated morphogenetic process that begins with the formation of epicardium. The epicardium gives rise to many components of the coronary vasculature, including fibroblasts, smooth muscle cells, and endothelium. Hippo signaling components have been implicated in cardiac development and regeneration. However, a role of Hippo signaling in the epicardium has not been explored. Employing a combination of genetic and pharmacological approaches, we demonstrate that inhibition of Hippo signaling mediators Yap and Taz leads to impaired epicardial epithelial-to-mesenchymal transition (EMT) and a reduction in epicardial cell proliferation and differentiation into coronary endothelial cells. We provide evidence that Yap and Taz control epicardial cell behavior, in part by regulating Tbx18 and Wt1 expression. Our findings show a role for Hippo signaling in epicardial cell proliferation, EMT, and cell fate specification during cardiac organogenesis.

  5. Hippo signaling mediators Yap and Taz are required in the epicardium for coronary vasculature development

    PubMed Central

    Singh, Anamika; Ramesh, Sindhu; Cibi, Dasan Mary; Yun, Lim Sze; Li, Jun; Li, Li; Manderfield, Lauren J.; Olson, Eric N.; Epstein, Jonathan A.; Singh, Manvendra K.

    2016-01-01

    Summary Formation of the coronary vasculature is a complex and precisely coordinated morphogenetic process that begins with the formation of epicardium. The epicardium gives rise to many components of the coronary vasculature, including fibroblasts, smooth muscle cells and endothelium. Hippo signaling components have been implicated in cardiac development and regeneration. However a role of Hippo signaling in the epicardium has not been explored. Employing a combination of genetic and pharmacological approaches, we demonstrate that inhibition of Hippo signaling mediators Yap and Taz leads to impaired epicardial epithelial-to-mesenchymal transition (EMT) and a reduction in epicardial cell proliferation and differentiation into coronary endothelial cells. We provide evidence that Yap and Taz control epicardial cell behavior, in part by regulating Tbx18 and Wt1 expression. Our findings show a role for Hippo signaling in epicardial cell proliferation, EMT and cell fate specification during cardiac organogenesis. PMID:27160901

  6. Systems analysis of oxidant stress in the vasculature.

    PubMed

    Handy, Diane E; Loscalzo, Joseph; Leopold, Jane A

    2013-11-01

    Systems biology and network analysis are emerging as valuable tools for the discovery of novel relationships, the identification of key regulatory factors, and the prediction of phenotypic changes in complex biological systems. Redox homeostasis in the vasculature is maintained by an intricate balance between oxidant-generating and antioxidant systems. When these systems are perturbed, conditions are permissive for oxidant stress, which, in turn, promotes vascular dysfunction and structural remodeling. Owing to the number of elements involved in redox regulation and the different vascular pathophenotypes associated with oxidant stress, vascular oxidant stress represents an ideal system to study by network analysis. Networks offer a method to organize experimentally derived factors, including proteins, metabolites, and DNA, that are represented as nodes into an unbiased comprehensive platform for study. Through analysis of the network, it is possible to determine essential or regulatory nodes, identify previously unknown connections between nodes, and locate modules, which are groups of nodes located within the same neighborhood that function together and have implications for phenotype. Investigators have only recently begun to construct oxidant stress-related networks to examine vascular structure and function; however, these early studies have provided mechanistic insight to further our understanding of this complicated biological system. © 2013 International Union of Biochemistry and Molecular Biology.

  7. Systems Analysis of Oxidant Stress in the Vasculature

    PubMed Central

    Handy, Diane E.; Loscalzo, Joseph; Leopold, Jane A.

    2014-01-01

    Systems biology and network analysis are emerging as valuable tools for the discovery of novel relationships, the identification of key regulatory factors, and the prediction of phenotypic changes in complex biological systems. Redox homeostasis in the vasculature is maintained by an intricate balance between oxidant-generating and antioxidant systems. When these systems are perturbed, conditions are permissive for oxidant stress, which, in turn, promotes vascular dysfunction and structural remodeling. Owing to the number of elements involved in redox regulation and the different vascular pathophenotypes associated with oxidant stress, vascular oxidant stress represents an ideal system to study by network analysis. Networks offer a method to organize experimentally derived factors, including proteins, metabolites, and DNA, that are represented as nodes into an unbiased comprehensive platform for study. Through analysis of the network it is possible to determine essential or regulatory nodes, identify previously unknown connections between nodes, and locate modules, which are groups of nodes located within the same neighborhood that function together and have implications for phenotype. Investigators have only recently begun to construct oxidant stress-related networks to examine vascular structure and function; however, these early studies have provided mechanistic insight to further our understanding of this complicated biological system. PMID:24265198

  8. Local oestrogenic/androgenic balance in the cerebral vasculature.

    PubMed

    Krause, D N; Duckles, S P; Gonzales, R J

    2011-09-01

    Reproductive effects of sex steroids are well-known; however it is increasingly apparent that these hormones have important actions on non-reproductive tissues such as the vasculature. The latter effects can be relevant throughout the lifespan, not just limited to reproductive years, and are not necessarily restricted to one gender or the other. Our work has established that cerebral blood vessels are a non-reproductive target tissue for sex steroids. We have found that oestrogen and androgens alter vascular tone, endothelial function, oxidative stress and inflammatory responses in cerebral vessels. Often the actions of oestrogen and androgens oppose each other. Moreover, it is clear that cerebral vessels are directly targeted by sex steroids, as they express specific receptors for these hormones. Interestingly, cerebral blood vessels also express enzymes that metabolize sex steroids. These findings suggest that local synthesis of 17ß-estradiol and dihydrotestosterone can occur within the vessel wall. One of the enzymes present, aromatase, converts testosterone to 17ß-estradiol, which would alter the local balance of androgenic and oestrogenic influences. Thus cerebral vessels are affected by circulating sex hormones as well as locally synthesized sex steroids. The presence of vascular endocrine effector mechanisms has important implications for male-female differences in cerebrovascular function and disease. Moreover, the cerebral circulation is a target for gonadal hormones as well as anabolic steroids and therapeutic drugs used to manipulate sex steroid actions. The long-term consequences of these influences are yet to be determined.

  9. Neocortical vasculature abnormalities in the Fragile X mental retardation syndrome.

    PubMed

    Galvan, Ashley M; Galvez, Roberto

    2012-08-30

    The Fragile X syndrome (FXS) is the leading form of inherited mental retardation. To date, the most prominent neuronal phenotype associated with the syndrome is an abundance of long thin spines exhibiting an immature morphology. However, in addition to synaptic abnormalities, recent case studies have demonstrated that Fragile X (FX) patients also exhibit abnormal cerebral blood flow (CBF). To examine the role of the Fragile X mental retardation protein (FMRP) in altering CBF, we examined blood vessel density (BVD) in the visual cortex of Adult and Middle-aged FX mice. Analysis of Middle-aged FX mice demonstrated elevated BVD compared to wildtype controls, suggesting that FX mice exhibit a lack of age-induced BVD plasticity. However, Adult FX and wildtype mice did not exhibit consistent differences in BVD. These data demonstrate that FMRP is required for age-induced neocortical vasculature plasticity. Furthermore, these data suggest a new role for FMRP in blood vessel regulation that would have profound implications towards appropriately timed delivery of neuronal nutrients, thus contributing to or exacerbating FX cognitive and neuronal abnormalities.

  10. Haemodynamics-Driven Developmental Pruning of Brain Vasculature in Zebrafish

    PubMed Central

    Li, Chun; Hu, Dan; Bu, Ji-wen; Cai, David; Du, Jiu-lin

    2012-01-01

    The brain blood vasculature consists of a highly ramified vessel network that is tailored to meet its physiological functions. How the brain vasculature is formed has long been fascinating biologists. Here we report that the developing vasculature in the zebrafish midbrain undergoes not only angiogenesis but also extensive vessel pruning, which is driven by changes in blood flow. This pruning process shapes the initial exuberant interconnected meshwork into a simplified architecture. Using in vivo long-term serial confocal imaging of the same zebrafish larvae during 1.5–7.5 d post-fertilization, we found that the early formed midbrain vasculature consisted of many vessel loops and higher order segments. Vessel pruning occurred preferentially at loop-forming segments via a process mainly involving lateral migration of endothelial cells (ECs) from pruned to unpruned segments rather than EC apoptosis, leading to gradual reduction in the vasculature complexity with development. Compared to unpruned ones, pruned segments exhibited a low and variable blood flow, which further decreased irreversibly prior to the onset of pruning. Local blockade of blood flow with micro-bead obstruction led to vessel pruning, whereas increasing blood flow by noradrenergic elevation of heartbeat impeded the pruning process. Furthermore, the occurrence of vessel pruning could be largely predicted by haemodynamics-based numerical simulation of vasculature refinement. Thus, changes of blood flow drive vessel pruning via lateral migration of ECs, leading to the simplification of the vasculature and possibly efficient routing of blood flow in the developing brain. PMID:22904685

  11. Functional photoacoustic microscopy of diabetic vasculature.

    PubMed

    Krumholz, Arie; Wang, Lidai; Yao, Junjie; Wang, Lihong V

    2012-06-01

    We used functional photoacoustic microscopy to image diabetes-induced damage to the microvasculature. To produce an animal model for Type 1 diabetes, we used streptozotocin (STZ), which is particularly toxic to the insulin-producing beta cells of the pancreas in mammals. A set number of ND4 Swiss Webster mice received intraperitoneal injections of STZ for five consecutive days at 50 mg/kg. Most mice developed a significant rise in blood glucose level (≈ 400 mg/dL) within three weeks of the first injection. Changes in vasculature and hemodynamics were monitored for six weeks. The mouse ear was imaged with an optical-resolution photoacoustic microscope at a main blood vessel branch from the root of the ear. There are noticeable and measurable changes associated with the disease, including decreased vessel diameter and possible occlusion due to vessel damage and polyurea. We also observed an increase in the blood flow speed in the vein and a decrease in the artery, which could be due to compensation for the dehydration and vessel diameter changes. Functional and metabolic parameters such as hemoglobin oxygen saturation, oxygen extraction fraction, and oxygen consumption rate were also measured, but showed no significant change.

  12. Functional photoacoustic microscopy of diabetic vasculature

    NASA Astrophysics Data System (ADS)

    Krumholz, Arie; Wang, Lidai; Yao, Junjie; Wang, Lihong V.

    2012-06-01

    We used functional photoacoustic microscopy to image diabetes-induced damage to the microvasculature. To produce an animal model for Type 1 diabetes, we used streptozotocin (STZ), which is particularly toxic to the insulin-producing beta cells of the pancreas in mammals. A set number of ND4 Swiss Webster mice received intraperitoneal injections of STZ for five consecutive days at 50 mg/kg. Most mice developed a significant rise in blood glucose level (~400 mg/dL) within three weeks of the first injection. Changes in vasculature and hemodynamics were monitored for six weeks. The mouse ear was imaged with an optical-resolution photoacoustic microscope at a main blood vessel branch from the root of the ear. There are noticeable and measurable changes associated with the disease, including decreased vessel diameter and possible occlusion due to vessel damage and polyurea. We also observed an increase in the blood flow speed in the vein and a decrease in the artery, which could be due to compensation for the dehydration and vessel diameter changes. Functional and metabolic parameters such as hemoglobin oxygen saturation, oxygen extraction fraction, and oxygen consumption rate were also measured, but showed no significant change.

  13. Functional photoacoustic microscopy of diabetic vasculature

    PubMed Central

    Krumholz, Arie; Wang, Lidai; Yao, Junjie

    2012-01-01

    Abstract. We used functional photoacoustic microscopy to image diabetes-induced damage to the microvasculature. To produce an animal model for Type 1 diabetes, we used streptozotocin (STZ), which is particularly toxic to the insulin-producing beta cells of the pancreas in mammals. A set number of ND4 Swiss Webster mice received intraperitoneal injections of STZ for five consecutive days at 50 mg/kg. Most mice developed a significant rise in blood glucose level (∼400 mg/dL) within three weeks of the first injection. Changes in vasculature and hemodynamics were monitored for six weeks. The mouse ear was imaged with an optical-resolution photoacoustic microscope at a main blood vessel branch from the root of the ear. There are noticeable and measurable changes associated with the disease, including decreased vessel diameter and possible occlusion due to vessel damage and polyurea. We also observed an increase in the blood flow speed in the vein and a decrease in the artery, which could be due to compensation for the dehydration and vessel diameter changes. Functional and metabolic parameters such as hemoglobin oxygen saturation, oxygen extraction fraction, and oxygen consumption rate were also measured, but showed no significant change. PMID:22734725

  14. Matrix stiffening promotes a tumor vasculature phenotype

    PubMed Central

    Bordeleau, Francois; Mason, Brooke N.; Lollis, Emmanuel Macklin; Mazzola, Michael; Zanotelli, Matthew R.; Somasegar, Sahana; Califano, Joseph P.; Montague, Christine; LaValley, Danielle J.; Huynh, John; Mencia-Trinchant, Nuria; Negrón Abril, Yashira L.; Hassane, Duane C.; Bonassar, Lawrence J.; Butcher, Jonathan T.; Weiss, Robert S.; Reinhart-King, Cynthia A.

    2017-01-01

    Tumor microvasculature tends to be malformed, more permeable, and more tortuous than vessels in healthy tissue, effects that have been largely attributed to up-regulated VEGF expression. However, tumor tissue tends to stiffen during solid tumor progression, and tissue stiffness is known to alter cell behaviors including proliferation, migration, and cell–cell adhesion, which are all requisite for angiogenesis. Using in vitro, in vivo, and ex ovo models, we investigated the effects of matrix stiffness on vessel growth and integrity during angiogenesis. Our data indicate that angiogenic outgrowth, invasion, and neovessel branching increase with matrix cross-linking. These effects are caused by increased matrix stiffness independent of matrix density, because increased matrix density results in decreased angiogenesis. Notably, matrix stiffness up-regulates matrix metalloproteinase (MMP) activity, and inhibiting MMPs significantly reduces angiogenic outgrowth in stiffer cross-linked gels. To investigate the functional significance of altered endothelial cell behavior in response to matrix stiffness, we measured endothelial cell barrier function on substrates mimicking the stiffness of healthy and tumor tissue. Our data indicate that barrier function is impaired and the localization of vascular endothelial cadherin is altered as function of matrix stiffness. These results demonstrate that matrix stiffness, separately from matrix density, can alter vascular growth and integrity, mimicking the changes that exist in tumor vasculature. These data suggest that therapeutically targeting tumor stiffness or the endothelial cell response to tumor stiffening may help restore vessel structure, minimize metastasis, and aid in drug delivery. PMID:28034921

  15. Vascular metallomics: copper in the vasculature

    PubMed Central

    Easter, Renee N.; Chan, Qilin; Lai, Barry; Ritman, Erik L.; Caruso, Joseph A.; Qin, Zhenyu

    2009-01-01

    Due to recent progress in analytical techniques, metallomics are evolving from detecting distinct trace metals in a defined state to monitoring the dynamic changes in the abundance and location of trace metals in vitro and in vivo. Vascular metallomics is an emerging field that studies the role of trace metals in vasculature. This review will introduce common metallomics techniques including atomic absorption spectrometry, inductively coupled plasma-atomic emission spectrometry, inductively coupled plasma-mass spectrometry and X-ray fluorescence spectrometry with a summary table to compare these techniques. Moreover, we will summarize recent research findings that have applied these techniques to human population studies in cardiovascular diseases, with a particular emphasis on the role of copper in these diseases. In order to address the issue of interdisciplinary studies between metallomics and vascular biology, we will review the progress of efforts to understand the role of copper in neovascularization. This recent progress in the metallomics field may be a powerful tool to elucidating the signaling pathways and specific biological functions of these trace metals. Finally, we summarize the evidence to support the notion that copper is a dynamic signaling molecule. As a future direction, vascular metallomics studies may lead to the identification of targets for diagnosis and therapy in cardiovascular disease. PMID:19808712

  16. Live imaging of primary ocular vasculature formation in zebrafish

    PubMed Central

    Fujisawa, Shizuko; Oikawa, Sayuri; Nonaka, Shigenori; Kurosaka, Daijiro; Hitomi, Jiro

    2017-01-01

    Ocular vasculature consists of the central retinal and ciliary vascular systems, which are essential to maintaining visual function. Many researchers have attempted to determine their origins and development; however, the detailed, stepwise process of ocular vasculature formation has not been established. In zebrafish, two angioblast clusters, the rostral and midbrain organizing centers, form almost all of the cranial vasculature, including the ocular vasculature, and these are from where the cerebral arterial and venous angioblast clusters, respectively, differentiate. In this study, we first determined the anatomical architecture of the primary ocular vasculature and then followed its path from the two cerebral angioblast clusters using a time-lapse analysis of living Tg(flk1:EGFP)k7 zebrafish embryos, in which the endothelial cells specifically expressed enhanced green fluorescent protein. We succeeded in capturing images of the primary ocular vasculature formation and were able to determine the origin of each ocular vessel. In zebrafish, the hyaloid and ciliary arterial systems first organized independently, and then anastomosed via the inner optic circle on the surface of the lens by the lateral transfer of the optic vein. Finally, the choroidal vascular plexus formed around the eyeball to complete the primary ocular vasculature formation. To our knowledge, this study is the first to report successful capture of circular integration of the optic artery and vein, lateral transfer of the optic vein to integrate the hyaloidal and superficial ocular vasculatures, and formation of the choroidal vascular plexus. Furthermore, this new morphological information enables us to assess the entire process of the primary ocular vasculature formation, which will be useful for its precise understanding. PMID:28445524

  17. Live imaging of primary ocular vasculature formation in zebrafish.

    PubMed

    Hashiura, Tetsuya; Kimura, Eiji; Fujisawa, Shizuko; Oikawa, Sayuri; Nonaka, Shigenori; Kurosaka, Daijiro; Hitomi, Jiro

    2017-01-01

    Ocular vasculature consists of the central retinal and ciliary vascular systems, which are essential to maintaining visual function. Many researchers have attempted to determine their origins and development; however, the detailed, stepwise process of ocular vasculature formation has not been established. In zebrafish, two angioblast clusters, the rostral and midbrain organizing centers, form almost all of the cranial vasculature, including the ocular vasculature, and these are from where the cerebral arterial and venous angioblast clusters, respectively, differentiate. In this study, we first determined the anatomical architecture of the primary ocular vasculature and then followed its path from the two cerebral angioblast clusters using a time-lapse analysis of living Tg(flk1:EGFP)k7 zebrafish embryos, in which the endothelial cells specifically expressed enhanced green fluorescent protein. We succeeded in capturing images of the primary ocular vasculature formation and were able to determine the origin of each ocular vessel. In zebrafish, the hyaloid and ciliary arterial systems first organized independently, and then anastomosed via the inner optic circle on the surface of the lens by the lateral transfer of the optic vein. Finally, the choroidal vascular plexus formed around the eyeball to complete the primary ocular vasculature formation. To our knowledge, this study is the first to report successful capture of circular integration of the optic artery and vein, lateral transfer of the optic vein to integrate the hyaloidal and superficial ocular vasculatures, and formation of the choroidal vascular plexus. Furthermore, this new morphological information enables us to assess the entire process of the primary ocular vasculature formation, which will be useful for its precise understanding.

  18. People with diabetic peripheral neuropathy display a decreased stepping accuracy during walking: potential implications for risk of tripping.

    PubMed

    Handsaker, J C; Brown, S J; Bowling, F L; Marple-Horvat, D E; Boulton, A J M; Reeves, N D

    2016-05-01

    To examine the stepping accuracy of people with diabetes and diabetic peripheral neuropathy. Fourteen patients with diabetic peripheral neuropathy (DPN), 12 patients with diabetes but no neuropathy (D) and 10 healthy non-diabetic control participants (C). Accuracy of stepping was measured whilst the participants walked along a walkway consisting of 18 stepping targets. Preliminary data on visual gaze characteristics were also captured in a subset of participants (diabetic peripheral neuropathy group: n = 4; diabetes-alone group: n = 4; and control group: n = 4) during the same task. Patients in the diabetic peripheral neuropathy group, and patients in the diabetes-alone group were significantly less accurate at stepping on targets than were control subjects (P < 0.05). Preliminary visual gaze analysis identified that patients diabetic peripheral neuropathy were slower to look between targets, resulting in less time being spent looking at a target before foot-target contact. Impaired motor control is theorized to be a major factor underlying the changes in stepping accuracy, and potentially altered visual gaze behaviour may also play a role. Reduced stepping accuracy may indicate a decreased ability to control the placement of the lower limbs, leading to patients with neuropathy potentially being less able to avoid observed obstacles during walking. © 2015 Diabetes UK.

  19. Quantitative peripheral blood perturbations of γδ T cells in human disease and their clinical implications.

    PubMed

    Bank, Ilan; Marcu-Malina, Victoria

    2014-12-01

    Human γδ T cells, which play innate and adaptive, protective as well as destructive, roles in the immune response, were discovered in 1986, but the clinical significance of alterations of the levels of these cells in the peripheral blood in human diseases has not been comprehensively reviewed. Here, we review patterns of easily measurable changes of this subset of T cells in peripheral blood from relevant publications in PubMed and their correlations with specific disease categories, specific diagnoses within disease categories, and prognostic outcomes. These collective data suggest that enumeration of γδ T cells and their subsets in the peripheral blood of patients could be a useful tool to evaluate diagnosis and prognosis in the clinical setting.

  20. Evaluating the Research Quality of Education Journals in China: Implications for Increasing Global Impact in Peripheral Countries

    ERIC Educational Resources Information Center

    Zhao, Juanjuan; Beckett, Gulbahar H.; Wang, Lihshing Leigh

    2017-01-01

    There has been a rapid growth of academic research and publishing in non-Western countries. However, academic journal articles in these peripheral countries suffer from low citation impact and limited global recognition. This critical review systematically analyzed 1,096 education research journal articles that were published in China in a 10-year…

  1. The Effectiveness of Clinically Indicated Replacement of Peripheral Intravenous Catheters: An Evidence Review With Implications for Clinical Practice.

    PubMed

    Morrison, Kimberly; Holt, Karyn E

    2015-08-01

    Current clinical guidelines from the Centers for Disease Control and Prevention (CDC; 2011) state that peripheral intravenous catheters are to be replaced every 72-96 hr to prevent infection and phlebitis in the adult patient. It is unclear whether this practice reduces the incidence of phlebitis or other infections. The aim of this study was to examine levels I and II evidence to determine if replacing peripheral intravenous catheters only when clinically indicated compared to every 72-96 hr increases the adult patient's risk for infection or phlebitis. The following patient or population, intervention, comparison, outcome question was used to search the literature databases PubMed, ClinicalKey, ProQuest, Ovid SP, and CINAHL: In the adult patient requiring a peripheral vascular catheter (P), does replacing the catheter only when clinically indicated (I) compared to replacing the catheter every 72-96 hr (C) increase the occurrence of phlebitis and infection (O)? A set of specific search criteria along with critical appraisal tools was used to identify relative studies. Four level II randomized controlled trials with no less than 155 subjects, and two level I meta-analyses reviewing a total of 13 research studies indicated that the replacement of peripheral intravenous catheters only when clinically indicated does not increase patient risk of phlebitis or infection when compared to the current practice of routine replacement between 72 and 96 hr in the adult patient population. The current practice of replacing peripheral intravenous catheters every 72-96 hr does not decrease the incidence of phlebitis or infection when compared to replacing catheters when clinically indicated in the adult population. By translating this research into current practice, healthcare costs and nursing care time will decrease, and unnecessary invasive procedures would be eliminated thereby increasing patient safety and satisfaction. © 2015 Sigma Theta Tau International.

  2. GPU accelerating technique for rendering implicitly represented vasculatures.

    PubMed

    Hong, Qingqi; Wang, Beizhan; Li, Qingde; Li, Yan; Wu, Qingqiang

    2014-01-01

    With the flooding datasets of medical Computed Tomography (CT) and Magnetic Resonance Imaging (MRI), implicit modeling techniques are increasingly applied to reconstruct the human organs, especially the vasculature. However, displaying implicitly represented geometric objects arises heavy computational burden. In this study, a Graphics Processing Unit (GPU) accelerating technique was developed for high performance rendering of implicitly represented objects, especially the vasculatures. The experimental results suggested that the rendering performance was greatly enhanced via exploiting the advantages of modern GPUs.

  3. Noninvasive mapping of subcutaneous vasculature with high resolution photoacoustic imaging

    NASA Astrophysics Data System (ADS)

    Lao, Yeqi; Xing, Da; Yang, Sihua

    2007-11-01

    As a novel hybrid imaging modality, photoacoustic (PA) imaging combines the merits of high optical contrast, good ultrasonic resolution and sufficient imaging depth, which may be of great benefit to noninvasively detect and monitor the pathological changes of subcutaneous vasculature, e.g., congenital vascular tumor and vascular malformation. In this paper, we apply a set of photoacoustic imaging system to image a sample of subcutaneous blood vessels, which is used to simulate the location of human's subcutaneous vasculature. Furthermore, an image of subcutaneous vasculature of the abdomen in a mouse is acquired in vivo. Laser pulses at a wavelength of 532 nm from a Q-switched Nd:YAG laser are employed as light source to generate PA signals in the experiments, because the optical absorption of whole blood is much stronger than that of other tissues at this wavelength. A needle polyvinylidene fluoride (PVDF) hydrophone with a diameter of 1mm is used to capture PA signals through a circular scan. The experimental results show that detailed structural information of subcutaneous vasculature, such as the shape and position of the blood vessels and the vessel branching, is clearly revealed by the PA imaging system. The spatial resolution of the PA imaging system reaches 80μm. Moreover, the reconstructed image of a mouse's abdomen in vivo demonstrates that this technique is suitable for noninvasive subcutaneous vasculature imaging. All of the results prove that the PA imaging can be used as a helpful tool for monitoring the pathological changes of subcutaneous vasculature.

  4. Neurotrophin-4/5 is implicated in the enhancement of axon regeneration produced by treadmill training following peripheral nerve injury

    PubMed Central

    English, Arthur W.; Cucoranu, Delia; Mulligan, Amanda; Rodriguez, José A.; Sabatier, Manning J.

    2011-01-01

    The role of neurotrophin-4/5 in the enhancement of axon regeneration in peripheral nerves produced by treadmill training was studied in mice. Common fibular nerves of animals of the H strain of thy-1-YFP mice, in which a subset of axons in peripheral nerves is marked by the presence of yellow fluorescent protein, were cut and surgically repaired using nerve grafts from non-fluorescent mice. Lengths of profiles of fluorescent regenerating axons were measured using optical sections made through whole mounts of harvested nerves. Measurements from mice that had undergone one hour of daily treadmill training at modest speed (10 m/min) were compared to those of untrained (control) mice. Modest treadmill training resulted in fluorescent axon profiles that were nearly twice as long as controls at one, two and four week survival times. Similar enhanced regeneration was found when cut nerves of wild type mice were repaired with grafts from neurotrophin-4/5 knockout mice or grafts made acellular by repeated freezing/thawing. No enhancement was produced by treadmill training in neurotrophin-4/5 knockout mice, irrespective of the nature of the graft used to repair the cut nerve. Much as had been observed previously for the effects of brief electrical stimulation, the effects of treadmill training on axon regeneration in cut peripheral nerves are independent of changes produced in the distal segment of the cut nerve and depend on the promotion of axon regeneration by changes in NT-4/5 expression by cells in the proximal nerve segment. PMID:21623957

  5. Peripheral corticotropin-releasing hormone is produced in the immune and reproductive systems: actions, potential roles and clinical implications.

    PubMed

    Kalantaridou, Sophia; Makrigiannakis, Antonis; Zoumakis, Emmanouil; Chrousos, George P

    2007-01-01

    Corticotropin-releasing hormone (CRH), the principal regulator of the hypothalamic-pituitary-adrenal axis, has been identified in various organ systems, including the immune and the female and male reproductive systems. CRH-like immunoreactivity has been reported in peripheral inflammatory sites and in a number of reproductive organs, including the ovaries, endometrial glands, decidualized endometrial stroma, placenta, decidua, and the testes. Therefore, "immune" and "reproductive" CRH are forms of "tissue" CRH; i.e., CRH found in peripheral tissues. Immune CRH plays a direct immunomodulatory role as an autocrine/paracrine mediator of inflammation. Immune CRH participates in several experimental inflammations and, in humans, in inflamed tissues from patients with autoimmune and inflammatory diseases. One of the early effects of immune CRH is the degranulation of mast cells and the release of histamine and several inflammatory cytokines. Reproductive CRH is regulating reproductive functions with an inflammatory component, such as ovulation, luteolysis, decidualization, implantation, and early maternal tolerance. Placental CRH participates in the physiology of pregnancy and the onset of labor. Circulating placental CRH is responsible for the physiologic hypercortisolism of the latter half of pregnancy. Postpartum, this hypercortisolism is followed by a transient adrenal suppression, which may explain the blues/depression and increased autoimmune phenomena observed during this period.

  6. Expression of the Kynurenine Pathway in Human Peripheral Blood Mononuclear Cells: Implications for Inflammatory and Neurodegenerative Disease.

    PubMed

    Jones, Simon P; Franco, Nunzio F; Varney, Bianca; Sundaram, Gayathri; Brown, David A; de Bie, Josien; Lim, Chai K; Guillemin, Gilles J; Brew, Bruce J

    2015-01-01

    The kynurenine pathway is a fundamental mechanism of immunosuppression and peripheral tolerance. It is increasingly recognized as playing a major role in the pathogenesis of a wide variety of inflammatory, neurodegenerative and malignant disorders. However, the temporal dynamics of kynurenine pathway activation and metabolite production in human immune cells is currently unknown. Here we report the novel use of flow cytometry, combined with ultra high-performance liquid chromatography and gas chromatography-mass spectrometry, to sensitively quantify the intracellular expression of three key kynurenine pathway enzymes and the main kynurenine pathway metabolites in a time-course study. This is the first study to show that up-regulation of indoleamine 2,3-dioxygenase (IDO-1), kynurenine 3-monoxygenase (KMO) and quinolinate phosphoribosyltransferase (QPRT) is lacking in lymphocytes treated with interferon gamma. In contrast, peripheral monocytes showed a significant elevation of kynurenine pathway enzymes and metabolites when treated with interferon gamma. Expression of IDO-1, KMO and QPRT correlated significantly with activation of the kynurenine pathway (kynurenine:tryptophan ratio), quinolinic acid concentration and production of the monocyte derived, pro-inflammatory immune response marker: neopterin. Our results also describe an original and sensitive methodological approach to quantify kynurenine pathway enzyme expression in cells. This has revealed further insights into the potential role of these enzymes in disease processes.

  7. Expression of the Kynurenine Pathway in Human Peripheral Blood Mononuclear Cells: Implications for Inflammatory and Neurodegenerative Disease

    PubMed Central

    Jones, Simon P.; Franco, Nunzio F.; Varney, Bianca; Sundaram, Gayathri; Brown, David A.; de Bie, Josien; Lim, Chai K.; Guillemin, Gilles J.; Brew, Bruce J.

    2015-01-01

    The kynurenine pathway is a fundamental mechanism of immunosuppression and peripheral tolerance. It is increasingly recognized as playing a major role in the pathogenesis of a wide variety of inflammatory, neurodegenerative and malignant disorders. However, the temporal dynamics of kynurenine pathway activation and metabolite production in human immune cells is currently unknown. Here we report the novel use of flow cytometry, combined with ultra high-performance liquid chromatography and gas chromatography-mass spectrometry, to sensitively quantify the intracellular expression of three key kynurenine pathway enzymes and the main kynurenine pathway metabolites in a time-course study. This is the first study to show that up-regulation of indoleamine 2,3-dioxygenase (IDO-1), kynurenine 3-monoxygenase (KMO) and quinolinate phosphoribosyltransferase (QPRT) is lacking in lymphocytes treated with interferon gamma. In contrast, peripheral monocytes showed a significant elevation of kynurenine pathway enzymes and metabolites when treated with interferon gamma. Expression of IDO-1, KMO and QPRT correlated significantly with activation of the kynurenine pathway (kynurenine:tryptophan ratio), quinolinic acid concentration and production of the monocyte derived, pro-inflammatory immune response marker: neopterin. Our results also describe an original and sensitive methodological approach to quantify kynurenine pathway enzyme expression in cells. This has revealed further insights into the potential role of these enzymes in disease processes. PMID:26114426

  8. Hierarchical bioimaging and quantification of vasculature in disease models using corrosion casts and microcomputed tomography

    NASA Astrophysics Data System (ADS)

    Heinzer, Stefan; Krucker, Thomas; Stampanoni, Marco; Abela, Rafael; Meyer, Eric P.; Schuler, Alexandra; Schneider, Philipp; Muller, Ralph

    2004-10-01

    A wide range of disorders are associated with alterations of the central and peripheral vascular system. Modified vascular corrosion casting using a newly developed polymer, allows for the first time hierarchical assessment of 3D vessel data in animals down to the level of capillaries. Imaging of large volumes of vasculature at intermediate resolution (16 um) was performed using a desktop micro-computed tomography system. Subsequently regions of interest were identified for additional high resolution imaging (1.4 um) at the X-ray Tomographic Microscopy (XTM) station of the Swiss Light Source (SLS). A framework for systematic hierarchical imaging and quantification was developed. Issues addressed included enhanced XTM data acquisition, introduction of local tomography, sample navigation, advanced post processing, and data combination. In addition to visual assessment of qualitative changes, morphometrical and architectural indices were determined using direct 3D morphometry software developed in house. Vessel specific parameters included thickness, surface, connectivity, and vessel length. Reconstructions of cerebral vasculature in mutant mice modeling Alzheimer's disease revealed significant changes in vessel architecture and morphology. In the future, a combination of these techniques may support drug discovery. Additionally, future ultra-high-resolution in vivo systems may even allow non-invasive tracking of temporal alterations in vascular morphology.

  9. The Multifaceted Role of the Vasculature in Endochondral Fracture Repair

    PubMed Central

    Bahney, Chelsea S.; Hu, Diane P.; Miclau, Theodore; Marcucio, Ralph S.

    2015-01-01

    Fracture healing is critically dependent upon an adequate vascular supply. The normal rate for fracture delayed or non-union is estimated to be between 10 and 15%, and annual fracture numbers are approximately 15 million cases per year. However, when there is decreased vascular perfusion to the fracture, incidence of impaired healing rises dramatically to 46%. Reduction in the blood supply to the fracture can be the result of traumatic injuries that physically disrupt the vasculature and damage supportive soft tissue, the result of anatomical location (i.e., distal tibia), or attributed to physiological conditions such as age, diabetes, or smoking. The role of the vasculature during repair is multifaceted and changes during the course of healing. In this article, we review recent insights into the role of the vasculature during fracture repair. Taken together these data highlight the need for an updated model for endochondral repair to facilitate improved therapeutic approaches to promote bone healing. PMID:25699016

  10. Modeling Nanoparticle Transport and Distribution in Lung Vasculature

    NASA Astrophysics Data System (ADS)

    Liu, Yaling; Zheng, Junda

    2013-11-01

    The nanoparticle targeted delivery in vascular system involves interplay of transport, hydrodynamic force, and multivalent interactions with targeted biosurfaces. To estimate the percentage of NPs delivered to the targeted region, properties of the vascular environment must be considered, i.e., the vascular geometry and flow conditions. This paper describes a computational model for NP transport and distribution in a complex lung vasculature through combined NP Brownian dynamics and computational fluid dynamics approaches. MRI sliced lung vasculature images are transferred into vascular geometry, discretized into tetrahedral meshes, and used in blood velocity calculation and particle deposition simulation. A non-uniform NP distribution is observed on the vascular surface, with a high NP concentration in the bifurcation region. The simulation results show that NPs with different size have different distribution pattern in lung vasculature. This study provides a tool to predict NP distribution in a complex vascular network.

  11. Central and peripheral regulation of feeding and nutrition by the mammalian circadian clock: implications for nutrition during manned space flight

    NASA Technical Reports Server (NTRS)

    Cassone, Vincent M.; Stephan, Friedrich K.

    2002-01-01

    Circadian clocks have evolved to predict and coordinate physiologic processes with the rhythmic environment on Earth. Space studies in non-human primates and humans have suggested that this clock persists in its rhythmicity in space but that its function is altered significantly in long-term space flight. Under normal circumstances, the clock is synchronized by the light-dark cycle via the retinohypothalamic tract and the suprachiasmatic nucleus. It is also entrained by restricted feeding regimes via a suprachiasmatic nucleus-independent circadian oscillator. The site of this suboscillator (or oscillators) is not known, but new evidence has suggested that peripheral tissues in the liver and viscera may express circadian clock function when forced to do so by restricted feeding schedules or other homeostatic disruptions. New research on the role of the circadian clock in the control of feeding on Earth and in space is warranted.

  12. Central and peripheral regulation of feeding and nutrition by the mammalian circadian clock: implications for nutrition during manned space flight

    NASA Technical Reports Server (NTRS)

    Cassone, Vincent M.; Stephan, Friedrich K.

    2002-01-01

    Circadian clocks have evolved to predict and coordinate physiologic processes with the rhythmic environment on Earth. Space studies in non-human primates and humans have suggested that this clock persists in its rhythmicity in space but that its function is altered significantly in long-term space flight. Under normal circumstances, the clock is synchronized by the light-dark cycle via the retinohypothalamic tract and the suprachiasmatic nucleus. It is also entrained by restricted feeding regimes via a suprachiasmatic nucleus-independent circadian oscillator. The site of this suboscillator (or oscillators) is not known, but new evidence has suggested that peripheral tissues in the liver and viscera may express circadian clock function when forced to do so by restricted feeding schedules or other homeostatic disruptions. New research on the role of the circadian clock in the control of feeding on Earth and in space is warranted.

  13. Regulation of peripheral blood flow in Complex Regional Pain Syndrome: clinical implication for symptomatic relief and pain management

    PubMed Central

    Groeneweg, George; Huygen, Frank JPM; Coderre, Terence J; Zijlstra, Freek J

    2009-01-01

    Background During the chronic stage of Complex Regional Pain Syndrome (CRPS), impaired microcirculation is related to increased vasoconstriction, tissue hypoxia, and metabolic tissue acidosis in the affected limb. Several mechanisms may be responsible for the ischemia and pain in chronic cold CPRS. Discussion The diminished blood flow may be caused by either sympathetic dysfunction, hypersensitivity to circulating catecholamines, or endothelial dysfunction. The pain may be of neuropathic, inflammatory, nociceptive, or functional nature, or of mixed origin. Summary The origin of the pain should be the basis of the symptomatic therapy. Since the difference in temperature between both hands fluctuates over time in cold CRPS, when in doubt, the clinician should prioritize the patient's report of a persistent cold extremity over clinical tests that show no difference. Future research should focus on developing easily applied methods for clinical use to differentiate between central and peripheral blood flow regulation disorders in individual patients. PMID:19775468

  14. [Change of Th22 cells in peripheral blood of patients with primary immune thrombocytopenia and clinical implication].

    PubMed

    Liu, Li-min; Zhang, Xing-xia; Zhao, Guang-sheng; Si, Ye-jun; Lin, Guo-qiang; Zhang, Yan-ming; He, Guang-sheng; Wu, De-pei

    2012-12-01

    To investigate the change of Th22 cells in the peripheral blood of the patients with primary immune thrombocytopenia (ITP) and evaluate the significance of Th22 cells in ITP. The proportion of Th22 cells in the peripheral blood of ITP patients before therapy (group 1), ITP patients in complete response after therapy (ITP-CR, group 2) and healthy donors (group 3) was evaluated by flow cytometry. The cytokines IL-22, TGF-β, TNF-α and IL-6 of each group were measured by ELISA. The level of IL-22 mRNA of each group was examined by RT-PCR. The proportion of Th22 cells and the levels of IL-22, TNF-α, IL-6 and IL-22 mRNA in group l and group 2 were significantly higher than those in group 3 (P<0.01). The proportion of Th22 cells and the levels of IL-22, TNF-α, IL-6 and IL-22 mRNA in group 2 were lower than those in group 1(P<0.05). But the level of TGF-β in group l [(3.27±1.02) ng/L] and group 2 [(5.41±1.69) ng/L] was significantly lower than that in group 3 [(9.65±2.78) ng/L] (P<0.01), and the level of TGF-β in group 1 was lower than that in group 2 (P<0.05). In ITP patients, the number of Th22 cells and the levels of TNF-α and IL-6 increase, and the level of TGF-β decrease.

  15. TRPA1 channels in the vasculature

    PubMed Central

    Earley, Scott

    2012-01-01

    This review is focused on the role of the ankyrin (A) transient receptor potential (TRP) channel TRPA1 in vascular regulation. TRPA1 is activated by environmental irritants, pungent compounds found in foods such as garlic, mustard and cinnamon, as well as metabolites produced during oxidative stress. The structure of the channel is distinguished by the ∼14–19 ankyrin repeat (AR) domains present in the intracellular amino terminus. TRPA1 has a large unitary conductance (98 pS) and slight selectivity for Ca2+ versus Na+ ions (PCa/PNa ≍ 7.9). TRPA1 is involved in numerous important physiological processes, including nociception, mechanotransduction, and thermal and oxygen sensing. TRPA1 agonists cause arterial dilation through two distinctive pathways. TRPA1 channels present in perivascular nerves mediate vasodilatation of peripheral arteries in response to chemical agonists through a mechanism requiring release of calcitonin gene-related peptide. In the cerebral circulation, TRPA1 channels are present in the endothelium, concentrated within myoendothelial junction sites. Activation of TRPA1 channels in this vascular bed causes endothelium-dependent smooth muscle cell hyperpolarization and vasodilatation that requires the activity of small and intermediate conductance Ca2+-activated K+ channels. Systemic administration of TRPA1 agonists causes transient depressor responses, followed by sustained increases in heart rate and blood pressure that may result from elevated sympathetic nervous activity. These findings indicate that TRPA1 activity influences vascular function, but the precise role and significance of the channel in the cardiovascular system remains to be determined. PMID:22563804

  16. Human Flt3L generates dendritic cells from canine peripheral blood precursors: implications for a dog glioma clinical trial.

    PubMed

    Xiong, Weidong; Candolfi, Marianela; Liu, Chunyan; Muhammad, A K M Ghulam; Yagiz, Kader; Puntel, Mariana; Moore, Peter F; Avalos, Julie; Young, John D; Khan, Dorothy; Donelson, Randy; Pluhar, G Elizabeth; Ohlfest, John R; Wawrowsky, Kolja; Lowenstein, Pedro R; Castro, Maria G

    2010-06-11

    Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and carries a dismal prognosis. We have developed a conditional cytotoxic/immunotherapeutic approach using adenoviral vectors (Ads) encoding the immunostimulatory cytokine, human soluble fms-like tyrosine kinase 3 ligand (hsFlt3L) and the conditional cytotoxic molecule, i.e., Herpes Simplex Type 1- thymide kinase (TK). This therapy triggers an anti-tumor immune response that leads to tumor regression and anti-tumor immunological memory in intracranial rodent cancer models. We aim to test the efficacy of this immunotherapy in dogs bearing spontaneous GBM. In view of the controversy regarding the effect of human cytokines on dog immune cells, and considering that the efficacy of this treatment depends on hsFlt3L-stimulated dendritic cells (DCs), in the present work we tested the ability of Ad-encoded hsFlt3L to generate DCs from dog peripheral blood and compared its effects with canine IL-4 and GM-CSF. Our results demonstrate that hsFlT3L expressed form an Ad vector, generated DCs from peripheral blood cultures with very similar morphological and phenotypic characteristics to canine IL-4 and GM-CSF-cultured DCs. These include phagocytic activity and expression of CD11c, MHCII, CD80 and CD14. Maturation of DCs cultured under both conditions resulted in increased secretion of IL-6, TNF-alpha and IFN-gamma. Importantly, hsFlt3L-derived antigen presenting cells showed allostimulatory potential highlighting their ability to present antigen to T cells and elicit their proliferation. These results demonstrate that hsFlt3L induces the proliferation of canine DCs and support its use in upcoming clinical trials for canine GBM. Our data further support the translation of hsFlt3L to be used for dendritic cells' vaccination and gene therapeutic approaches from rodent models to canine patients and its future implementation in human clinical trials.

  17. Human Flt3L Generates Dendritic Cells from Canine Peripheral Blood Precursors: Implications for a Dog Glioma Clinical Trial

    PubMed Central

    Liu, Chunyan; Muhammad, A. K. M. Ghulam; Yagiz, Kader; Puntel, Mariana; Moore, Peter F.; Avalos, Julie; Young, John D.; Khan, Dorothy; Donelson, Randy; Pluhar, G. Elizabeth; Ohlfest, John R.; Wawrowsky, Kolja; Lowenstein, Pedro R.; Castro, Maria G.

    2010-01-01

    Background Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and carries a dismal prognosis. We have developed a conditional cytotoxic/immunotherapeutic approach using adenoviral vectors (Ads) encoding the immunostimulatory cytokine, human soluble fms-like tyrosine kinase 3 ligand (hsFlt3L) and the conditional cytotoxic molecule, i.e., Herpes Simplex Type 1- thymide kinase (TK). This therapy triggers an anti-tumor immune response that leads to tumor regression and anti-tumor immunological memory in intracranial rodent cancer models. We aim to test the efficacy of this immunotherapy in dogs bearing spontaneous GBM. In view of the controversy regarding the effect of human cytokines on dog immune cells, and considering that the efficacy of this treatment depends on hsFlt3L-stimulated dendritic cells (DCs), in the present work we tested the ability of Ad-encoded hsFlt3L to generate DCs from dog peripheral blood and compared its effects with canine IL-4 and GM-CSF. Methodology/Principal Findings Our results demonstrate that hsFlT3L expressed form an Ad vector, generated DCs from peripheral blood cultures with very similar morphological and phenotypic characteristics to canine IL-4 and GM-CSF-cultured DCs. These include phagocytic activity and expression of CD11c, MHCII, CD80 and CD14. Maturation of DCs cultured under both conditions resulted in increased secretion of IL-6, TNF-α and IFN-γ. Importantly, hsFlt3L-derived antigen presenting cells showed allostimulatory potential highlighting their ability to present antigen to T cells and elicit their proliferation. Conclusions/Significance These results demonstrate that hsFlt3L induces the proliferation of canine DCs and support its use in upcoming clinical trials for canine GBM. Our data further support the translation of hsFlt3L to be used for dendritic cells' vaccination and gene therapeutic approaches from rodent models to canine patients and its future implementation in human clinical

  18. Imaging and treating tumor vasculature with targeted radiolabeled carbon nanotubes.

    PubMed

    Ruggiero, Alessandro; Villa, Carlos H; Holland, Jason P; Sprinkle, Shanna R; May, Chad; Lewis, Jason S; Scheinberg, David A; McDevitt, Michael R

    2010-10-05

    Single wall carbon nanotube (SWCNT) constructs were covalently appended with radiometal-ion chelates (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [DOTA] or desferrioxamine B [DFO]) and the tumor neovascular-targeting antibody E4G10. The E4G10 antibody specifically targeted the monomeric vascular endothelial-cadherin (VE-cad) epitope expressed in the tumor angiogenic vessels. The construct specific activity and blood compartment clearance kinetics were significantly improved relative to corresponding antibodyalone constructs. We performed targeted radioimmunotherapy with a SWCNT-([(225)Ac]DOTA) (E4G10) construct directed at the tumor vasculature in a murine xenograft model of human colon adenocarcinoma (LS174T). The specific construct reduced tumor volume and improved median survival relative to controls. We also performed positron emission tomographic (PET) radioimmunoimaging of the tumor vessels with a SWCNT-([(89)Zr]DFO)(E4G10) construct in the same murine LS174T xenograft model and compared the results to appropriate controls. Dynamic and longitudinal PET imaging of LS174T tumor-bearing mice demonstrated rapid blood clearance (<1 hour) and specific tumor accumulation of the specific construct. Incorporation of the SWCNT scaffold into the construct design permitted us to amplify the specific activity to improve the signal-to-noise ratio without detrimentally impacting the immunoreactivity of the targeting antibody moiety. Furthermore, we were able to exploit the SWCNT pharmacokinetic (PK) profile to favorably alter the blood clearance and provide an advantage for rapid imaging. Near-infrared three-dimensional fluorescent-mediated tomography was used to image the LS174T tumor model, collect antibody-alone PK data, and calculate the number of copies of VE-cad epitope per cell. All of these studies were performed as a single administration of construct and were found to be safe and well tolerated by the murine model. These data have implications that

  19. Imaging and treating tumor vasculature with targeted radiolabeled carbon nanotubes

    PubMed Central

    Ruggiero, Alessandro; Villa, Carlos H; Holland, Jason P; Sprinkle, Shanna R; May, Chad; Lewis, Jason S; Scheinberg, David A; McDevitt, Michael R

    2010-01-01

    Single wall carbon nanotube (SWCNT) constructs were covalently appended with radiometal-ion chelates (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [DOTA] or desferrioxamine B [DFO]) and the tumor neovascular-targeting antibody E4G10. The E4G10 antibody specifically targeted the monomeric vascular endothelial-cadherin (VE-cad) epitope expressed in the tumor angiogenic vessels. The construct specific activity and blood compartment clearance kinetics were significantly improved relative to corresponding antibodyalone constructs. We performed targeted radioimmunotherapy with a SWCNT-([225Ac]DOTA) (E4G10) construct directed at the tumor vasculature in a murine xenograft model of human colon adenocarcinoma (LS174T). The specific construct reduced tumor volume and improved median survival relative to controls. We also performed positron emission tomographic (PET) radioimmunoimaging of the tumor vessels with a SWCNT-([89Zr]DFO)(E4G10) construct in the same murine LS174T xenograft model and compared the results to appropriate controls. Dynamic and longitudinal PET imaging of LS174T tumor-bearing mice demonstrated rapid blood clearance (<1 hour) and specific tumor accumulation of the specific construct. Incorporation of the SWCNT scaffold into the construct design permitted us to amplify the specific activity to improve the signal-to-noise ratio without detrimentally impacting the immunoreactivity of the targeting antibody moiety. Furthermore, we were able to exploit the SWCNT pharmacokinetic (PK) profile to favorably alter the blood clearance and provide an advantage for rapid imaging. Near-infrared three-dimensional fluorescent-mediated tomography was used to image the LS174T tumor model, collect antibody-alone PK data, and calculate the number of copies of VE-cad epitope per cell. All of these studies were performed as a single administration of construct and were found to be safe and well tolerated by the murine model. These data have implications that

  20. Probing the structural and molecular diversity of tumor vasculature.

    PubMed

    Pasqualini, Renata; Arap, Wadih; McDonald, Donald M

    2002-12-01

    The molecular diversity of the vasculature provides a rational basis for developing targeted diagnostics and therapeutics for cancer. Targeted imaging agents would offer better localization of primary tumors and metastases, and targeted therapies would improve efficacy and reduce side effects. The development of targeted pharmaceuticals requires the identification of specific ligand-receptor pairs, and knowledge of their cellular distribution and accessibility. Using in vivo phage display, a technique by which we can identify organ-specific and disease-specific proteins expressed on the endothelial surface, it is now possible to decipher the molecular signature of blood vessels in normal and diseased tissues. These studies have already led to the identification of peptides that target the normal vasculature of the brain, kidney, pancreas, lung and skin, as well as the abnormal vasculature of tumors, arthritis and atherosclerosis. Membrane dipeptidase in the lungs, interleukin-11 receptor in the prostate, and aminopeptidase N in tumors are examples of molecular targets on blood vessels. Corresponding confocal-microscopic imaging and ultrastructural studies are providing a more complete understanding of the cellular abnormalities of tumor blood vessels, and the distribution and accessibility of potential targets. The combined approach offers a strategy for creating a ligand-receptor map of the human vasculature, and forms a foundation for the development and application of targeted therapies in cancer and other diseases.

  1. Thermal modelling using discrete vasculature for thermal therapy: a review

    PubMed Central

    Kok, H.P.; Gellermann, J.; van den Berg, C.A.T.; Stauffer, P.R.; Hand, J.W.; Crezee, J.

    2013-01-01

    Reliable temperature information during clinical hyperthermia and thermal ablation is essential for adequate treatment control, but conventional temperature measurements do not provide 3D temperature information. Treatment planning is a very useful tool to improve treatment quality and substantial progress has been made over the last decade. Thermal modelling is a very important and challenging aspect of hyperthermia treatment planning. Various thermal models have been developed for this purpose, with varying complexity. Since blood perfusion is such an important factor in thermal redistribution of energy in in vivo tissue, thermal simulations are most accurately performed by modelling discrete vasculature. This review describes the progress in thermal modelling with discrete vasculature for the purpose of hyperthermia treatment planning and thermal ablation. There has been significant progress in thermal modelling with discrete vasculature. Recent developments have made real-time simulations possible, which can provide feedback during treatment for improved therapy. Future clinical application of thermal modelling with discrete vasculature in hyperthermia treatment planning is expected to further improve treatment quality. PMID:23738700

  2. The lymphatic vasculature: development and role in shaping immunity.

    PubMed

    Betterman, Kelly L; Harvey, Natasha L

    2016-05-01

    The lymphatic vasculature is an integral component of the immune system. Lymphatic vessels are a key highway via which immune cells are trafficked, serving not simply as a passive route of transport, but to actively shape and coordinate immune responses. Reciprocally, immune cells provide signals that impact the growth, development, and activity of the lymphatic vasculature. In addition to immune cell trafficking, lymphatic vessels are crucial for fluid homeostasis and lipid absorption. The field of lymphatic vascular research is rapidly expanding, fuelled by rapidly advancing technology that has enabled the manipulation and imaging of lymphatic vessels, together with an increasing recognition of the involvement of lymphatic vessels in a myriad of human pathologies. In this review we provide an overview of the genetic pathways and cellular processes important for development and maturation of the lymphatic vasculature, discuss recent work revealing important roles for the lymphatic vasculature in directing immune cell traffic and coordinating immune responses and highlight the involvement of lymphatic vessels in a range of pathological settings. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Identification of functional progenitor cells in the pulmonary vasculature

    PubMed Central

    Firth, Amy L.; Yuan, Jason X. -J.

    2012-01-01

    The pulmonary vasculature comprises a complex network of branching arteries and veins all functioning to reoxygenate the blood for circulation around the body. The cell types of the pulmonary artery are able to respond to changes in oxygen tension in order to match ventilation to perfusion. Stem and progenitor cells in the pulmonary vasculature are also involved, be it in angiogenesis, endothelial dysfunction or formation of vascular lesions. Stem and progenitor cells may be circulating around the body, residing in the pulmonary artery wall or stimulated for release from a central niche like the bone marrow and home to the pulmonary vasculature along a chemotactic gradient. There may currently be some controversy over the pathogenic versus therapeutic roles of stem and progenitor cells and, indeed, it is likely both chains of evidence are correct due to the specific influence of the immediate environmental niche a progenitor cell may be in. Due to their great plasticity and a lack of specific markers for stem and progenitor cells, they can be difficult to precisely identify. This review discusses the methodological approaches used to validate the presence of and subtype of progenitors cells in the pulmonary vasculature while putting it in context of the current knowledge of the therapeutic and pathogenic roles for such progenitor cells. PMID:22558524

  4. Exercise limits the production of endothelin in the coronary vasculature

    PubMed Central

    de Beer, Vincent J.; Bender, Shawn B.; Taverne, Yannick J.; Gao, Fen; Duncker, Dirk J.; Laughlin, M. Harold

    2011-01-01

    We previously demonstrated that endothelin (ET)-mediated coronary vasoconstriction wanes with increasing exercise intensity via a nitric oxide- and prostacyclin-dependent mechanism (Ref. 23). Therefore, we hypothesized that the waning of ET coronary vasoconstriction during exercise is the result of decreased production of ET and/or decreased ET receptor sensitivity. We investigated coronary ET receptor sensitivity using intravenous infusion of ET and coronary ET production using intravenous infusion of the ET precursor Big ET, at rest and during continuous treadmill exercise at 3 km/h in 16 chronically instrumented swine. In the systemic vasculature, Big ET and ET induced similar changes in hemodynamic parameters at rest and during continuous exercise at 3 km/h, indicating that exercise does not alter ET production or receptor sensitivity in the systemic vasculature. In the coronary vasculature, infusion of ET resulted in similar dose-dependent decreases in coronary blood flow and coronary venous oxygen tension and saturation at rest and during exercise. In contrast, administration of Big ET resulted in dose-dependent decreases in coronary blood flow, as well as coronary venous oxygen tension and saturation at rest. These effects of Big ET were significantly reduced during exercise. Altogether, our data indicate that continuous exercise at 3 km/h attenuates ET-mediated coronary vasoconstriction through reduced production of ET from Big ET rather than through reduced ET sensitivity of the coronary vasculature. The decreased ET production during exercise likely contributes to metabolic coronary vasodilation. PMID:21317308

  5. Effect of Ergot Alkaloids on Bovine Foregut Vasculature

    USDA-ARS?s Scientific Manuscript database

    Ergot alkaloids induce vasoconstriction of bovine foregut vasculature. Ergovaline induced the greatest response in ruminal artery while ergovaline and ergotamine induced the greatest response in ruminal vein. Lysergic acid did not stimulate a contractile response in either the ruminal artery or vein...

  6. Implications of peripheral muscular and anatomical development for the acquisition of lingual control for speech production: a review.

    PubMed

    Denny, Margaret; McGowan, Richard S

    2012-01-01

    Normally developing children learn to produce intelligible speech during rapid, non-uniform growth of their articulators and other vocal tract structures. The purpose of this review is to focus attention on the consequences of peripheral growth and development for the acquisition of lingual control for speech production. This paper (1) reviews physiological underpinnings of tongue shaping and movements that are likely to be changing in young children; (2) estimates, from previously published studies, the net consequences of growth of multiple vocal tract structures on lingual control; (3) integrates our findings with the example of [R] production, and (4) highlights areas where further investigations would be most helpful. The authors searched the literature, including the PubMed database, for studies of the development of muscle proteins, muscle fibers, and motor units of the tongue, and of the growth of the tongue, jaw, adenoids, soft and hard palates, oral and pharyngeal cavities, and the vocal tract as a whole. Substantial anatomical and muscular data sets focused on children from 1-4 years of age, and rigorous definitions of the tongue boundaries are needed. Copyright © 2012 S. Karger AG, Basel.

  7. High-dose mitoxantrone with peripheral blood progenitor cell rescue: toxicity, pharmacokinetics and implications for dosage and schedule.

    PubMed Central

    Ballestrero, A.; Ferrando, F.; Garuti, A.; Basta, P.; Gonella, R.; Esposito, M.; Vannozzi, M. O.; Sorice, G.; Friedman, D.; Puglisi, M.; Brema, F.; Mela, G. S.; Sessarego, M.; Patrone, F.

    1997-01-01

    The optimal use of mitoxantrone (NOV) in the high-dose range requires elucidation of its maximum tolerated dose with peripheral blood progenitor cell (PBPC) support and the time interval needed between drug administration and PBPC reinfusion in order to avoid graft toxicity. The aims of this study were: (1) to verify the feasibility and haematological toxicity of escalating NOV up to 90 mg m(-2) with PBPC support; and (2) to verify the safeness of a short (96 h) interval between NOV administration and PBPC reinfusion. Three cohorts of ten patients with breast cancer (BC) or non-Hodgkin's lymphoma (NHL) received escalating doses of NOV, 60, 75 and 90 mg m(-2) plus melphalan (L-PAM), 140-180 mg m(-2), with PBPC rescue 96 h after NOV. Haematological toxicity was evaluated daily (WHO criteria). NOV plasma pharmacokinetics was also evaluated, as well as NOV cytotoxicity against PBPCs. Haematological recovery was rapid and complete at each NOV dose level without statistically significant differences, and there were no major toxicities. NOV plasma concentrations at the time of PBPC reinfusion were below the toxicity threshold against haemopoietic progenitors. It is concluded that, when adequately supported with PBPCs, NOV can be escalated up to 90 mg m(-2) with acceptable haematological toxicity. PBPCs can be safely reinfused as early as 96 h after NOV administration. PMID:9310249

  8. Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy.

    PubMed

    Leandro-García, Luis J; Inglada-Pérez, Lucía; Pita, Guillermo; Hjerpe, Elisabet; Leskelä, Susanna; Jara, Carlos; Mielgo, Xabier; González-Neira, Anna; Robledo, Mercedes; Avall-Lundqvist, Elisabeth; Gréen, Henrik; Rodríguez-Antona, Cristina

    2013-09-01

    Peripheral neuropathy is the dose limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat solid tumours. This toxicity exhibits great inter-individual variability of unknown origin. The present study aimed to identify genetic variants associated with paclitaxel induced neuropathy via a whole genome approach. A genome-wide association study (GWAS) was performed in 144 white European patients uniformly treated with paclitaxel/carboplatin and for whom detailed data on neuropathy was available. Per allele single nucleotide polymorphism (SNP) associations were assessed by Cox regression, modelling the cumulative dose of paclitaxel up to the development of grade 2 sensory neuropathy. The strongest evidence of association was observed for the ephrin type A receptor 4 (EPHA4) locus (rs17348202, p=1.0×10(-6)), and EPHA6 and EPHA5 were among the top 25 and 50 hits (rs301927, p=3.4×10(-5) and rs1159057, p=6.8×10(-5)), respectively. A meta-analysis of EPHA5-rs7349683, the top marker for paclitaxel induced neuropathy in a previous GWAS (r(2)=0.79 with rs1159057), gave a hazard ratio (HR) estimate of 1.68 (p=1.4×10(-9)). Meta-analysis of the second hit of this GWAS, XKR4-rs4737264, gave a HR of 1.71 (p=3.1×10(-8)). Imputed SNPs at LIMK2 locus were also strongly associated with this toxicity (HR=2.78, p=2.0×10(-7)). This study provides independent support of EPHA5-rs7349683 and XKR4-rs4737264 as the first markers of risk of paclitaxel induced neuropathy. In addition, it suggests that other EPHA genes also involved in axonal guidance and repair following neural injury, as well as LIMK2 locus, may play an important role in the development of this toxicity. The identified SNPs could form the basis for individualised paclitaxel chemotherapy.

  9. Down-regulation of caveolin-1 in glioma vasculature: modulation by radiotherapy.

    PubMed

    Régina, Anthony; Jodoin, Julie; Khoueir, Paul; Rolland, Yannève; Berthelet, France; Moumdjian, Robert; Fenart, Laurence; Cecchelli, Romeo; Demeule, Michel; Béliveau, Richard

    2004-01-15

    Primary brain tumors, particularly glioblastomas (GB), remain a challenge for oncology. An element of the malignant brain tumors' aggressive behavior is the fact that GB are among the most densely vascularized tumors. To determine some of the molecular regulations occuring at the brain tumor endothelium level during tumoral progression would be an asset in understanding brain tumor biology. Caveolin-1 is an essential structural constituent of caveolae that has been implicated in mitogenic signaling, oncogenesis, and angiogenesis. In this work we investigated regulation of caveolin-1 expression in brain endothelial cells (ECs) under angiogenic conditions. In vitro, brain EC caveolin-1 is down-regulated by angiogenic factors treament and by hypoxia. Coculture of brain ECs with tumoral cells induced a similar down-regulation. In addition, activation of the p42/44 MAP kinase is demonstrated. By using an in vivo brain tumor model, we purified ECs from gliomas as well as from normal brain to investigate possible regulation of caveolin-1 expression in tumoral brain vasculature. We show that caveolin-1 expression is strikingly down-regulated in glioma ECs, whereas an increase of phosphorylated caveolin-1 is observed. Whole-brain radiation treatment, a classical way in which GB is currently being treated, resulted in increased caveolin-1 expression in tumor isolated ECs. The level of tumor cells spreading around newly formed blood vessels was also elevated. The regulation of caveolin-1 expression in tumoral ECs may reflect the tumoral vasculature state and correlates with angiogenesis kinetics.

  10. Peripherin Is a Subunit of Peripheral Nerve Neurofilaments: Implications for Differential Vulnerability of CNS and PNS Axons

    PubMed Central

    Yuan, Aidong; Sasaki, Takahiro; Kumar, Asok; Peterhoff, Corrinne M.; Rao, Mala V.; Liem, Ronald K.; Julien, Jean-Pierre; Nixon, Ralph A.

    2012-01-01

    Peripherin, a neuronal intermediate filament protein implicated in neurodegenerative disease, coexists with the neurofilament triplet proteins (NFL, NFM, and NFH) but has an unknown function. The earlier peak expression of peripherin than the triplet during brain development and its ability to form homopolymers, unlike the triplet, which are obligate heteropolymers, have supported a widely held view that peripherin and neurofilament triplet form separate filament systems. Here, we demonstrate, however, that despite a postnatal decline in expression, peripherin is as abundant as the triplet in the adult PNS and exists in a relatively fixed stoichiometry with these subunits. Peripherin exhibits a distribution pattern identical to those of triplet proteins in sciatic axons and co-localizes with NFL on single neurofilament by immunogold electron microscopy. Peripherin also co-assembles into a single network of filaments containing NFL, NFM, NFH with and without α-internexin in quadruple- or quintuple-transfected SW13 vim (−) cells. Genetically deleting NFL in mice dramatically reduces peripherin content in sciatic axons. Moreover, peripherin mutations has been shown to disrupt the neurofilament network in transfected SW13 vim(−) cells. These data show that peripherin and the neurofilament proteins are functionally interdependent. The results strongly support the view that rather than forming an independent structure, peripherin is a subunit of neurofilaments in the adult PNS. Our findings provide a basis for its close relationship with neurofilaments in PNS diseases associated with neurofilament accumulation. PMID:22723690

  11. Post-thaw viability of cryopreserved peripheral blood stem cells (PBSC) does not guarantee functional activity: important implications for quality assurance of stem cell transplant programmes.

    PubMed

    Morgenstern, Daniel A; Ahsan, Gulrukh; Brocklesby, Margaret; Ings, Stuart; Balsa, Carmen; Veys, Paul; Brock, Penelope; Anderson, John; Amrolia, Persis; Goulden, Nicholas; Cale, Catherine M; Watts, Michael J

    2016-09-01

    Standard quality assurance (QA) of cryopreserved peripheral blood stem cells (PBSC) uses post-thaw viable CD34(+) cell counts. In 2013, concerns arose at Great Ormond Street Hospital (GOSH) about 8 patients with delayed engraftment following myeloablative chemotherapy with cryopreserved cell rescue, despite adequate post-thaw viable cell counts in all cases. Root cause analysis was undertaken; investigations suggested the freeze process itself was a contributing factor to suboptimal engraftment. Experiments were undertaken in which a single PBSC product was divided into three and cryopreserved in parallel using a control-rate freezer (CRF) or passive freezing method (-80°C freezer) at GOSH, or the same passive freezing at another laboratory. Viable CD34(+) counts were equivalent and adequate in each. Granulocyte-monocyte colony-forming unit assays demonstrated colonies from the products cryopreserved using passive freezing (both laboratories), but no colonies from products cryopreserved using the CRF. The CRF was shown to be operating within manufacturer's specifications with freeze-profile within acceptable limits. This experience has important implications for quality assurance for all transplant programmes, particularly those using cryopreserved products. The failure of post-thaw viable CD34(+) counts, the most widely used routine QA test available, to ensure PBSC function is of great concern and should prompt reassessment of protocols and QA procedures. © 2016 John Wiley & Sons Ltd.

  12. Ligating the ductus arteriosus before birth remodels the pulmonary vasculature of the lamb.

    PubMed

    Wild, L M; Nickerson, P A; Morin, F C

    1989-03-01

    The clinical syndrome of persistent pulmonary hypertension of the newborn includes a developmentally abnormal pulmonary microvasculature which contains excessive amounts of muscle and which cannot adapt to air breathing in the perinatal period. Surgical ligation of the ductus arteriosus of the fetal lamb has produced a physiologic model of pulmonary hypertension of the newborn. The aim of the present investigation is to determine whether surgical ligation of the ductus arteriosus in fetal sheep produces anatomic changes in the pulmonary blood vessels. The pulmonary vasculature of seven neonatal lambs that underwent surgical ligation of the ductus arteriosus from 6 to 17 d before birth was compared to that of five control lambs with a patent ductus arteriosus without fetal surgery and three control lambs with a patent ductus arteriosus that underwent sham surgery. Quantitative microscopic analysis of the barium gelatin-filled peripheral pulmonary vascular bed revealed an increase in the proportion of partially and fully muscularized pulmonary arteries at the level of the terminal bronchiole and within the acinus (p less than 0.0001). This finding demonstrates that medial muscle develops in areas of the distal pulmonary vascular bed where it is normally absent. Periadventitial fibrosis surrounding intraacinar pulmonary arteries was also present. No change in the number of small intraacinar arteries was detected. This structural remodeling of the peripheral pulmonary vascular bed was initiated in utero by ductus arteriosus occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. Imaging of retinal vasculature using adaptive optics SLO/OCT.

    PubMed

    Felberer, Franz; Rechenmacher, Matthias; Haindl, Richard; Baumann, Bernhard; Hitzenberger, Christoph K; Pircher, Michael

    2015-04-01

    We use our previously developed adaptive optics (AO) scanning laser ophthalmoscope (SLO)/ optical coherence tomography (OCT) instrument to investigate its capability for imaging retinal vasculature. The system records SLO and OCT images simultaneously with a pixel to pixel correspondence which allows a direct comparison between those imaging modalities. Different field of views ranging from 0.8°x0.8° up to 4°x4° are supported by the instrument. In addition a dynamic focus scheme was developed for the AO-SLO/OCT system in order to maintain the high transverse resolution throughout imaging depth. The active axial eye tracking that is implemented in the OCT channel allows time resolved measurements of the retinal vasculature in the en-face imaging plane. Vessel walls and structures that we believe correspond to individual erythrocytes could be visualized with the system.

  14. Imaging of retinal vasculature using adaptive optics SLO/OCT

    PubMed Central

    Felberer, Franz; Rechenmacher, Matthias; Haindl, Richard; Baumann, Bernhard; Hitzenberger, Christoph K.; Pircher, Michael

    2015-01-01

    We use our previously developed adaptive optics (AO) scanning laser ophthalmoscope (SLO)/ optical coherence tomography (OCT) instrument to investigate its capability for imaging retinal vasculature. The system records SLO and OCT images simultaneously with a pixel to pixel correspondence which allows a direct comparison between those imaging modalities. Different field of views ranging from 0.8°x0.8° up to 4°x4° are supported by the instrument. In addition a dynamic focus scheme was developed for the AO-SLO/OCT system in order to maintain the high transverse resolution throughout imaging depth. The active axial eye tracking that is implemented in the OCT channel allows time resolved measurements of the retinal vasculature in the en-face imaging plane. Vessel walls and structures that we believe correspond to individual erythrocytes could be visualized with the system. PMID:25909024

  15. System for definition of the central-chest vasculature

    NASA Astrophysics Data System (ADS)

    Taeprasartsit, Pinyo; Higgins, William E.

    2009-02-01

    Accurate definition of the central-chest vasculature from three-dimensional (3D) multi-detector CT (MDCT) images is important for pulmonary applications. For instance, the aorta and pulmonary artery help in automatic definition of the Mountain lymph-node stations for lung-cancer staging. This work presents a system for defining major vascular structures in the central chest. The system provides automatic methods for extracting the aorta and pulmonary artery and semi-automatic methods for extracting the other major central chest arteries/veins, such as the superior vena cava and azygos vein. Automatic aorta and pulmonary artery extraction are performed by model fitting and selection. The system also extracts certain vascular structure information to validate outputs. A semi-automatic method extracts vasculature by finding the medial axes between provided important sites. Results of the system are applied to lymph-node station definition and guidance of bronchoscopic biopsy.

  16. First-in-Human Study of Acoustic Angiography in the Breast and Peripheral Vasculature.

    PubMed

    Shelton, Sarah E; Lindsey, Brooks D; Dayton, Paul A; Lee, Yueh Z

    2017-10-02

    Screening with mammography has been found to increase breast cancer survival rates by about 20%. However, the current system in which mammography is used to direct patients toward biopsy or surgical excision also results in relatively high rates of unnecessary biopsy, as 66.8% of biopsies are benign. A non-ionizing radiation imaging approach with increased specificity might reduce the rate of unnecessary biopsies. Quantifying the vascular characteristics within and surrounding lesions represents one potential target for assessing likelihood of malignancy via imaging. In this clinical note, we describe the translation of a contrast-enhanced ultrasound technique, acoustic angiography, to human imaging. We illustrate the feasibility of this technique with initial studies in imaging the hand, wrist and breast using Definity microbubble contrast agent and a mechanically steered prototype dual-frequency transducer in healthy volunteers. Finally, this approach was used to image pre-biopsy Breast Imaging Reporting and Data System (BI-RADS) 4 and 5 lesions <2 cm in depth in 11 patients. Results indicate that sensitivity and spatial resolution are sufficient to image vessels as small as 0.2 mm in diameter at depths of ~15 mm in the human breast. Challenges observed include motion artifacts, as well as limited depth of field and sensitivity, which could be improved by correction algorithms and improved transducer technologies. Copyright © 2017. Published by Elsevier Inc.

  17. 3D morphological measurement of whole slide histological vasculature reconstructions

    NASA Astrophysics Data System (ADS)

    Xu, Yiwen; Pickering, J. G.; Nong, Zengxuan; Ward, Aaron D.

    2016-03-01

    Properties of the microvasculature that contribute to tissue perfusion can be assessed using immunohistochemistry on 2D histology sections. However, the vasculature is inherently 3D and the ability to measure and visualize the vessel wall components in 3D will aid in detecting focal pathologies. Our objectives were (1) to develop a method for 3D measurement and visualization of microvasculature in 3D, (2) to compare the normal and regenerated post-ischemia mouse hind limb microvasculature, and (3) to compare the 2D and 3D vessel morphology measures. Vessels were stained for smooth muscle using 3,3'-Diaminobenzidine (DAB) immunostain for both normal (n = 6 mice) and regenerated vasculature (n = 5 mice). 2D vessel segmentations were reconstructed into 3D using landmark based registration. No substantial bias was found in the 2D measurements relative to 3D, but larger differences were observed for individual vessels oriented non-orthogonally to the plane of sectioning. A larger value of area, perimeter, and vessel wall thickness was found in the normal vasculature as compared to the regenerated vasculature, for both the 2D and 3D measurements (p < 0.01). Aggregated 2D measurements are sufficient for identifying morphological differences between groups of mice; however, one must interpret individual 2D measurements with caution if the vessel centerline direction is unknown. Visualization of 3D measurements permits the detection of localized vessel morphology aberrations that are not revealed by 2D measurements. With vascular measure visualization methodologies in 3D, we are now capable of locating focal pathologies on a whole slide level.

  18. Effect of tamsulosin on iris vasculature and morphology.

    PubMed

    Shtein, Roni M; Hussain, Munira T; Cooney, Theresa M; Elner, Victor M; Hood, Christopher T

    2014-05-01

    To determine whether preoperative iris vasculature and morphology are altered in patients who have taken tamsulosin (Flomax). Academic multispecialty practice. Case series. Patients with current or past tamsulosin use and age- and sex-matched control patients were included. Anterior segment optical coherence tomography (AS-OCT) and iris fluorescein angiography were performed to measure iris vasculature and thickness before cataract surgery. Data collected at surgery included pupil diameter, clinical signs of intraoperative floppy-iris syndrome, and surgical complications. Tamsulosin was currently used by 16 patients and in the past by 4 patients; the control group comprised 10 patients. Pharmacologically dilated pupil diameter was statistically significantly smaller preoperatively and immediately postoperatively in the tamsulosin group than in the control group (P=.009 and P=.003, respectively). There was a statistically significant decrease in pupil size intraoperatively in the tamsulosin group (P=.05) but not in the control group (P=.3). Iris-vasculature parameters, specifically time to first vessel fill and percentage of vessel fill on iris fluorescein angiography, were not significantly different between the 2 groups. The AS-OCT measurements of iris morphology were not statistically significantly different between the groups. No surgical complications occurred. No fluorescein dye leakage, staining, or other vascular anomalies were observed. Although there were differences in pupil measurements and intraoperative iris behavior between patients who had been on tamsulosin and control patients, there were no significant differences in iris vasculature on iris fluorescein angiography or in iris morphology on AS-OCT. Copyright © 2014 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.

  19. Frontal Lobe Lipoma Associated with Cortical Dysplasia and Abnormal Vasculature

    PubMed Central

    Baskan, Ozdil; Geyik, Serdar

    2014-01-01

    Summary Intracranial lipomas (ICLs) are rare lesions, the vast majority encountered as incidental findings on imaging studies. ICLs are generally pericallosal midline lesions and thought to be asymptomatic and can be accompanied by additional intracranial congenital malformations. We describe a 17-year old male with an unusual case of ICL on the frontal lobe associated with cortical dysplasia and abnormal vasculature mimicking arteriovenous malformation on magnetic resonance images. PMID:25489889

  20. Segmentation and separation of venous vasculatures in liver CT images

    NASA Astrophysics Data System (ADS)

    Wang, Lei; Hansen, Christian; Zidowitz, Stephan; Hahn, Horst K.

    2014-03-01

    Computer-aided analysis of venous vasculatures including hepatic veins and portal veins is important in liver surgery planning. The analysis normally consists of two important pre-processing tasks: segmenting both vasculatures and separating them from each other by assigning different labels. During the acquisition of multi-phase CT images, both of the venous vessels are enhanced by injected contrast agent and acquired either in a common phase or in two individual phases. The enhanced signals established by contrast agent are often not stably acquired due to non-optimal acquisition time. Inadequate contrast and the presence of large lesions in oncological patients, make the segmentation task quite challenging. To overcome these diffculties, we propose a framework with minimal user interactions to analyze venous vasculatures in multi-phase CT images. Firstly, presented vasculatures are automatically segmented adopting an efficient multi-scale Hessian-based vesselness filter. The initially segmented vessel trees are then converted to a graph representation, on which a series of graph filters are applied in post-processing steps to rule out irrelevant structures. Eventually, we develop a semi-automatic workow to refine the segmentation in the areas of inferior vena cava and entrance of portal veins, and to simultaneously separate hepatic veins from portal veins. Segmentation quality was evaluated with intensive tests enclosing 60 CT images from both healthy liver donors and oncological patients. To quantitatively measure the similarities between segmented and reference vessel trees, we propose three additional metrics: skeleton distance, branch coverage, and boundary surface distance, which are dedicated to quantifying the misalignment induced by both branching patterns and radii of two vessel trees.

  1. Physics of the tumor vasculature: Theory and experiment

    NASA Astrophysics Data System (ADS)

    Rieger, Heiko; Fredrich, Thierry; Welter, Michael

    2016-02-01

    Growing solid tumors recruit the blood vessel network of the host tissue for nutrient supply, continuous growth and gain of metastatic potential. Consequently the tumor vasculature has been a major target of anti cancer therapies since four decades. The main underlying strategic concepts range from "starving a tumor to death" over "blood vessel normalization" to "blood vessel growth promotion" for improved drug delivery and oxygenation for increased success rates of radiation therapy. A mechanistic understanding of the these strategies is often elusive and call for a quantitative analysis of the underlying physics. Oxygen supply as well as drug delivery is determined by blood and interstitial fluid flow, for which reason such an analysis must focus on the relation between the intra- and extra-vascular transport characteristics and the tumor vasculature morphology. Here we review the current status of theoretical concepts and computational analysis of physical determinants of the tumor vasculature and the emerging predictions for blood flow, oxygen distribution, interstitial fluid pressure and efficiency of drug delivery.

  2. Image fusion for visualization of hepatic vasculature and tumors

    NASA Astrophysics Data System (ADS)

    Chou, Jin-Shin; Chen, Shiuh-Yung J.; Sudakoff, Gary S.; Hoffmann, Kenneth R.; Chen, Chin-Tu; Dachman, Abraham H.

    1995-05-01

    We have developed segmentation and simultaneous display techniques to facilitate the visualization of the three-dimensional spatial relationships between organ structures and organ vasculature. We concentrate on the visualization of the liver based on spiral computed tomography images. Surface-based 3-D rendering and maximal intensity projection algorithms are used for data visualization. To extract the liver in the serial of images accurately and efficiently, we have developed a user-friendly interactive program with a deformable-model segmentation. Surface rendering techniques are used to visualize the extracted structures, adjacent contours are aligned and fitted with a Bezier surface to yield a smooth surface. Visualization of the vascular structures, portal and hepatic veins, is achieved by applying a MIP technique to the extracted liver volume. To integrate the extracted structures they are surface-rendered and their MIP images are aligned and a color table is designed for simultaneous display of the combined liver/tumor and vasculature images. By combining the 3-D surface rendering and MIP techniques, portal veins, hepatic veins, and hepatic tumor can be inspected simultaneously and their spatial relationships can be more easily perceived. The proposed technique will be useful for visualization of both hepatic neoplasm and vasculature in surgical planning for tumor resection or living-donor liver transplantation.

  3. Effects of dietary amines on the gut and its vasculature.

    PubMed

    Broadley, Kenneth J; Akhtar Anwar, M; Herbert, Amy A; Fehler, Martina; Jones, Elen M; Davies, Wyn E; Kidd, Emma J; Ford, William R

    2009-06-01

    Trace amines, including tyramine and beta-phenylethylamine (beta-PEA), are constituents of many foods including chocolate, cheeses and wines and are generated by so-called 'friendly' bacteria such as Lactobacillus, Lactococcus and Enterococcus species, which are found in probiotics. We therefore examined whether these dietary amines could exert pharmacological effects on the gut and its vasculature. In the present study we examined the effects of tyramine and beta-PEA on the contractile activity of guinea-pig and rat ileum and upon the isolated mesenteric vasculature and other blood vessels. Traditionally, these amines are regarded as sympathomimetic amines, exerting effects through the release of noradrenaline from sympathetic nerve endings, which should relax the gut. A secondary aim was therefore to confirm this mechanism of action. However, contractile effects were observed in the gut and these were independent of noradrenaline, acetylcholine, histamine and serotonin receptors. They were therefore probably due to the recently described trace amine-associated receptors. These amines relaxed the mesenteric vasculature. In contrast, the aorta and coronary arteries were constricted, a response that was also independent of a sympathomimetic action. From these results, we propose that after ingestion, trace amines could stimulate the gut and improve intestinal blood flow. Restriction of blood flow elsewhere diverts blood to the gut to aid digestion. Thus, trace amines in the diet may promote the digestive process through stimulation of the gut and improved gastrointestinal circulation.

  4. CD146(+) cells are essential for kidney vasculature development.

    PubMed

    Halt, Kimmo J; Pärssinen, Heikki E; Junttila, Sanna M; Saarela, Ulla; Sims-Lucas, Sunder; Koivunen, Peppi; Myllyharju, Johanna; Quaggin, Susan; Skovorodkin, Ilya N; Vainio, Seppo J

    2016-08-01

    The kidney vasculature is critical for renal function, but its developmental assembly mechanisms remain poorly understood and models for studying its assembly dynamics are limited. Here, we tested whether the embryonic kidney contains endothelial cells (ECs) that are heterogeneous with respect to VEGFR2/Flk1/KDR, CD31/PECAM, and CD146/MCAM markers. Tie1Cre;R26R(YFP)-based fate mapping with a time-lapse in embryonic kidney organ culture successfully depicted the dynamics of kidney vasculature development and the correlation of the process with the CD31(+) EC network. Depletion of Tie1(+) or CD31(+) ECs from embryonic kidneys, with either Tie1Cre-induced diphtheria toxin susceptibility or cell surface marker-based sorting in a novel dissociation and reaggregation technology, illustrated substantial EC network regeneration. Depletion of the CD146(+) cells abolished this EC regeneration. Fate mapping of green fluorescent protein (GFP)-marked CD146(+)/CD31(-) cells indicated that they became CD31(+) cells, which took part in EC structures with CD31(+) wild-type ECs. EC network development depends on VEGF signaling, and VEGF and erythropoietin are expressed in the embryonic kidney even in the absence of any external hypoxic stimulus. Thus, the ex vivo embryonic kidney culture models adopted here provided novel ways for targeting renal EC development and demonstrated that CD146(+) cells are critical for kidney vasculature development. Copyright © 2016 International Society of Nephrology. All rights reserved.

  5. Response of the cerebral vasculature following traumatic brain injury.

    PubMed

    Salehi, Arjang; Zhang, John H; Obenaus, Andre

    2017-01-01

    The critical role of the vasculature and its repair in neurological disease states is beginning to emerge particularly for stroke, dementia, epilepsy, Parkinson's disease, tumors and others. However, little attention has been focused on how the cerebral vasculature responds following traumatic brain injury (TBI). TBI often results in significant injury to the vasculature in the brain with subsequent cerebral hypoperfusion, ischemia, hypoxia, hemorrhage, blood-brain barrier disruption and edema. The sequalae that follow TBI result in neurological dysfunction across a host of physiological and psychological domains. Given the importance of restoring vascular function after injury, emerging research has focused on understanding the vascular response after TBI and the key cellular and molecular components of vascular repair. A more complete understanding of vascular repair mechanisms are needed and could lead to development of new vasculogenic therapies, not only for TBI but potentially vascular-related brain injuries. In this review, we delineate the vascular effects of TBI, its temporal response to injury and putative biomarkers for arterial and venous repair in TBI. We highlight several molecular pathways that may play a significant role in vascular repair after brain injury.

  6. Lung vasculature imaging using speckle variance optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Cua, Michelle; Lee, Anthony M. D.; Lane, Pierre M.; McWilliams, Annette; Shaipanich, Tawimas; MacAulay, Calum E.; Yang, Victor X. D.; Lam, Stephen

    2012-02-01

    Architectural changes in and remodeling of the bronchial and pulmonary vasculature are important pathways in diseases such as asthma, chronic obstructive pulmonary disease (COPD), and lung cancer. However, there is a lack of methods that can find and examine small bronchial vasculature in vivo. Structural lung airway imaging using optical coherence tomography (OCT) has previously been shown to be of great utility in examining bronchial lesions during lung cancer screening under the guidance of autofluorescence bronchoscopy. Using a fiber optic endoscopic OCT probe, we acquire OCT images from in vivo human subjects. The side-looking, circumferentially-scanning probe is inserted down the instrument channel of a standard bronchoscope and manually guided to the imaging location. Multiple images are collected with the probe spinning proximally at 100Hz. Due to friction, the distal end of the probe does not spin perfectly synchronous with the proximal end, resulting in non-uniform rotational distortion (NURD) of the images. First, we apply a correction algorithm to remove NURD. We then use a speckle variance algorithm to identify vasculature. The initial data show a vascaulture density in small human airways similar to what would be expected.

  7. Pericytes on the tumor vasculature: jekyll or hyde?

    PubMed

    Barlow, Keith D; Sanders, Anne M; Soker, Shay; Ergun, Suleyman; Metheny-Barlow, Linda J

    2013-04-01

    The induction of tumor vasculature, known as the 'angiogenic switch', is a rate-limiting step in tumor progression. Normal blood vessels are composed of two distinct cell types: endothelial cells which form the channel through which blood flows, and mural cells, the pericytes and smooth muscle cells which serve to support and stabilize the endothelium. Most functional studies have focused on the responses of endothelial cells to pro-angiogenic stimuli; however, there is mounting evidence that the supporting mural cells, particularly pericytes, may play key regulatory roles in both promoting vessel growth as well as terminating vessel growth to generate a mature, quiescent vasculature. Tumor vessels are characterized by numerous structural and functional abnormalities, including altered association between endothelial cells and pericytes. These dysfunctional, unstable vessels contribute to hypoxia, interstitial fluid pressure, and enhanced susceptibility to metastatic invasion. Increasing evidence points to the pericyte as a critical regulator of endothelial activation and subsequent vessel development, stability, and function. Here we discuss both the stimulatory and inhibitory effects of pericytes on the vasculature and the possible utilization of vessel normalization as a therapeutic strategy to combat cancer.

  8. Contrasting Patterns of Genetic Variation in Central and Peripheral Populations of Dryopteris fragrans (Fragrant Wood Fern) and Implications for Colonization Dynamics and Conservation

    Treesearch

    J. R. Bouchard; D. D. Fernando; S.W. Bailey; J. Weber-Townsend; D. J. Leopold

    2017-01-01

    Premise of research. Ferns are vital components of temperate and tropical ecosystems, but they have not been examined in the context of a central-peripheral hypothesis. Dryopteris fragrans is an ideal species to examine the genetic variation between central and peripheral populations because of its arctic north to temperate...

  9. Oxytocin and its receptors are synthesized in the rat vasculature.

    PubMed

    Jankowski, M; Wang, D; Hajjar, F; Mukaddam-Daher, S; McCann, S M; Gutkowska, J

    2000-05-23

    Produced and released by the heart, oxytocin (OT) acts on its cardiac receptors to decrease the cardiac rate and force of contraction. We hypothesized that it might also be produced in the vasculature and regulate vascular tone. Consequently, we prepared acid extracts of the pulmonary artery and vena cava of female rats. OT concentrations in dog and sheep aortae were equivalent to those of rat aorta (2745 +/- 180 pg/mg protein), indicating that it is present in the vasculature of several mammalian species. Reverse-phase HPLC of aorta and vena cava extracts revealed a single peak corresponding to the amidated OT nonapeptide. Reverse-transcribed PCR confirmed OT synthesis in these tissues. Using the selective OT receptor ligand compound VI, we detected a high number of OT-binding sites in the rat vena cava and aorta. Furthermore, OT receptor (OTR) mRNA was found in the vena cava, pulmonary vein, and pulmonary artery with lower levels in the aorta, suggesting vessel-specific OTR distribution. The abundance of OTR mRNA in the vena cava and pulmonary vein was associated with high atrial natriuretic peptide mRNA. In addition, we have demonstrated that diethylstilbestrol treatment of immature female rats increased OT significantly in the vena cava but not in the aorta and augmented OTR mRNA in both the aorta (4-fold) and vena cava (2-fold), implying regulation by estrogen. Altogether, these data suggest that the vasculature contains an intrinsic OT system, which may be involved in the regulation of vascular tone as well as vascular regrowth and remodeling.

  10. Oxytocin and its receptors are synthesized in the rat vasculature

    PubMed Central

    Jankowski, Marek; Wang, Donghao; Hajjar, Fadi; Mukaddam-Daher, Suhayla; McCann, Samuel M.; Gutkowska, Jolanta

    2000-01-01

    Produced and released by the heart, oxytocin (OT) acts on its cardiac receptors to decrease the cardiac rate and force of contraction. We hypothesized that it might also be produced in the vasculature and regulate vascular tone. Consequently, we prepared acid extracts of the pulmonary artery and vena cava of male rats. OT concentrations in dog and sheep aortae were equivalent to those of rat aorta (2745 ± 180 pg/mg protein), indicating that it is present in the vasculature of several mammalian species. Reverse-phase HPLC of aorta and vena cava extracts revealed a single peak corresponding to the amidated OT nonapeptide. Reverse-transcribed PCR confirmed OT synthesis in these tissues. Using the selective OT receptor ligand compound VI, we detected a high number of OT-binding sites in the rat vena cava and aorta. Furthermore, OT receptor (OTR) mRNA was found in the vena cava, pulmonary vein, and pulmonary artery with lower levels in the aorta, suggesting vessel-specific OTR distribution. The abundance of OTR mRNA in the vena cava and pulmonary vein was associated with high atrial natriuretic peptide mRNA. In addition, we have demonstrated that diethylstilbestrol treatment of immature female rats increased OT significantly in the vena cava but not in the aorta and augmented OTR mRNA in both the aorta (4-fold) and vena cava (2-fold), implying regulation by estrogen. Altogether, these data suggest that the vasculature contains an intrinsic OT system, which may be involved in the regulation of vascular tone as well as vascular regrowth and remodeling. PMID:10811917

  11. Three-dimensional morphometric analysis of the renal vasculature.

    PubMed

    Khan, Zohaib; Ngo, Jennifer P; Le, Bianca; Evans, Roger G; Pearson, James Todd; Gardiner, Bruce S; Smith, David W

    2017-09-20

    Vascular topology and morphology is critical in the regulation of blood flow and the transport of small solutes including oxygen, carbon dioxide, nitric oxide and hydrogen sulfide. Renal vascular morphology is particularly challenging as many arterial walls are partially wrapped by the walls of veins. In the absence of a precise characterization of three-dimensional branching vascular geometry, accurate computational modeling of the intrarenal transport of small diffusible molecules is impossible. An enormous manual effort was required to achieve a relatively precise characterization of rat renal vascular geometry, highlighting the need for an automated method for analysis of branched vasculature morphology to allow characterization of the renal vascular geometry of other species, including humans. We present a semi-supervised method for three-dimensional morphometric analysis of renal vasculature images generated by computed tomography. We derive quantitative vascular attributes important to mass transport between arteries, veins and the renal tissue, and present methods for their computation for a three-dimensional vascular geometry. To validate the algorithm, we compare automated vascular estimates with subjective manual measurements for a portion of rabbit kidney. While increased image resolution can improve outcomes, our results demonstrate that the method can quantify the morphological characteristics of artery-vein pairs, comparing favorably with manual measurements. Similar to the rat, we show that rabbit artery-vein pairs become less intimate along the course of the renal vasculature, but the total wrapped mass transfer coefficient increases then decreases. This new method will facilitate new quantitative physiological models describing the transport of small molecules within the kidney. Copyright © 2017, American Journal of Physiology-Renal Physiology.

  12. Role of lymphatic vasculature in regional and distant metastases.

    PubMed

    Podgrabinska, Simona; Skobe, Mihaela

    2014-09-01

    In cancer, lymphatic vasculature has been traditionally viewed only as a transportation system for metastatic cells. It has now become clear that lymphatics perform many additional functions which could influence cancer progression. Lymphangiogenesis, induced at the primary tumor site and at distant sites, potently augments metastasis. Lymphatic endothelial cells (LECs) control tumor cell entry and exit from the lymphatic vessels. LECs also control immune cell traffic and directly modulate adaptive immune responses. This review highlights advances in our understanding of the mechanisms by which lymphatic vessels, and in particular lymphatic endothelium, impact metastasis. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Preserving Parathyroid Gland Vasculature to Reduce Post-thyroidectomy Hypocalcemia.

    PubMed

    Park, Inhye; Rhu, Jinsoo; Woo, Jung-Woo; Choi, Jun-Ho; Kim, Jee Soo; Kim, Jung-Han

    2016-06-01

    The failure to preserve parathyroid function in patients who have undergone total thyroidectomy is of major concern, because hypocalcemia is difficult to prevent and remains a common postoperative complication. Here, we describe procedures designed to preserve the vasculature supplying the parathyroid glands and examine both recent outcomes and retrospective reports of results obtained prior to the application of these preservation techniques. Our technique for preserving parathyroid function during thyroidectomy was adopted in 2009 and involves separating a relatively long segment of a vessel distally from the thyroid gland. We reviewed the medical records of 1,411 patients who underwent total thyroidectomy, with or without lateral neck dissection, at the Samsung Medical Center from January 2006 through June 2014 to determine outcomes. Patients were divided into three groups according to the time period during which the surgery took place: Group A, 2006-2008 (before the vasculature-preserving technique was applied); Group B, 2009-2011 (the time when the technique was first adopted); and Group C, 2012-2014 (more recent results of the technique). We analyzed the incidence of hypoparathyroidism in the three groups, as well as risk factors that influenced its development. The rates of transient and permanent hypoparathyroidism in Group A were 25.4 and 4.3 %, respectively. However, the incidence of hypoparathyroidism decreased significantly over time after the vasculature-preserving procedure was adopted. Transient hypoparathyroidism developed in 4.8 % of Group C patients, and only four (0.7 %) of the 565 patients in this group required calcium supplementation, despite the fact that a greater number of patients were included who underwent total thyroidectomy combined with lateral neck dissection. Although female sex and lateral neck dissection tended to increase the rate of transient hypoparathyroidism, multivariate analysis showed that the vasculature

  14. Vascular Tissue Engineering: Building Perfusable Vasculature for Implantation

    PubMed Central

    Gui, Liqiong; Niklason, Laura E.

    2014-01-01

    Tissue and organ replacement is required when there are no alternative therapies available. Although vascular tissue engineering was originally developed to meet the clinical demands of small-diameter vascular conduits as bypass grafts, it has evolved into a highly advanced field where perfusable vasculatures are generated for implantation. Herein, we review several cutting-edge techniques that have led to implantable human blood vessels in clinical trials, the novel approaches that build complex perfusable microvascular networks in functional tissues, the use of stem cells to generate endothelial cells for vascularization, as well as the challenges in bringing vascular tissue engineering technologies into the clinics. PMID:24533306

  15. Biologic Effects of Dopamine on Tumor Vasculature in Ovarian Carcinoma12

    PubMed Central

    Moreno-Smith, Myrthala; Lee, Sun Joo; Lu, Chunhua; Nagaraja, Archana S; He, Guangan; Rupaimoole, Rajesha; Han, Hee Dong; Jennings, Nicholas B; Roh, Ju-Won; Nishimura, Masato; Kang, Yu; Allen, Julie K; Armaiz, Guillermo N; Matsuo, Koji; Shahzad, Mian M K; Bottsford-Miller, Justin; Langley, Robert R; Cole, Steve W; Lutgendorf, Susan K; Siddik, Zahid H; Sood, Anil K

    2013-01-01

    Chronic sympathetic nervous system activation results in increased angiogenesis and tumor growth in orthotopic mouse models of ovarian carcinoma. However, the mechanistic effects of such activation on the tumor vasculature are not well understood. Dopamine (DA), an inhibitory catecholamine, regulates the functions of normal and abnormal blood vessels. Here, we examined whether DA, an inhibitory catecholamine, could block the effects of chronic stress on tumor vasculature and tumor growth. Exogenous administration of DA not only decreased tumor microvessel density but also increased pericyte coverage of tumor vessels following daily restraint stress in mice. Daily restraint stress resulted in significantly increased tumor growth in the SKOV3ip1 and HeyA8 ovarian cancer models. DA treatment blocked stress-mediated increases in tumor growth and increased pericyte coverage of tumor endothelial cells. Whereas the antiangiogenic effect of DA is mediated by dopamine receptor 2 (DR2), our data indicate that DA, through DR1, stimulates vessel stabilization by increasing pericyte recruitment to tumor endothelial cells. DA significantly stimulated migration of mouse 10T1/2 pericyte-like cells in vitro and increased cyclic adenosine mono-phosphate (cAMP) levels in these cells. Moreover, DA or the DR1 agonist SKF 82958 increased platinum concentration in SKOV3ip1 tumor xenografts following cisplatin administration. In conclusion, DA stabilizes tumor blood vessels through activation of pericyte cAMP-protein kinase A signaling pathway by DR1. These findings could have implications for blocking the stimulatory effects of chronic stress on tumor growth. PMID:23633922

  16. Peripheral Artery Disease

    MedlinePlus

    ... Physician Resources Professions Site Index A-Z Peripheral Artery Disease (PAD) Peripheral artery disease (PAD) refers to ... is peripheral artery disease treated? What is peripheral artery disease (PAD)? Peripheral artery disease, or PAD, refers ...

  17. FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature

    PubMed Central

    Sabine, Amélie; Bovay, Esther; Demir, Cansaran Saygili; Kimura, Wataru; Jaquet, Muriel; Agalarov, Yan; Zangger, Nadine; Scallan, Joshua P.; Graber, Werner; Gulpinar, Elgin; Kwak, Brenda R.; Mäkinen, Taija; Martinez-Corral, Inés; Ortega, Sagrario; Delorenzi, Mauro; Kiefer, Friedemann; Davis, Michael J.; Djonov, Valentin; Miura, Naoyuki; Petrova, Tatiana V.

    2015-01-01

    Biomechanical forces, such as fluid shear stress, govern multiple aspects of endothelial cell biology. In blood vessels, disturbed flow is associated with vascular diseases, such as atherosclerosis, and promotes endothelial cell proliferation and apoptosis. Here, we identified an important role for disturbed flow in lymphatic vessels, in which it cooperates with the transcription factor FOXC2 to ensure lifelong stability of the lymphatic vasculature. In cultured lymphatic endothelial cells, FOXC2 inactivation conferred abnormal shear stress sensing, promoting junction disassembly and entry into the cell cycle. Loss of FOXC2-dependent quiescence was mediated by the Hippo pathway transcriptional coactivator TAZ and, ultimately, led to cell death. In murine models, inducible deletion of Foxc2 within the lymphatic vasculature led to cell-cell junction defects, regression of valves, and focal vascular lumen collapse, which triggered generalized lymphatic vascular dysfunction and lethality. Together, our work describes a fundamental mechanism by which FOXC2 and oscillatory shear stress maintain lymphatic endothelial cell quiescence through intercellular junction and cytoskeleton stabilization and provides an essential link between biomechanical forces and endothelial cell identity that is necessary for postnatal vessel homeostasis. As FOXC2 is mutated in lymphedema-distichiasis syndrome, our data also underscore the role of impaired mechanotransduction in the pathology of this hereditary human disease. PMID:26389677

  18. Targeting tumor vasculature through oncolytic virotherapy: recent advances.

    PubMed

    Toro Bejarano, Marcela; Merchan, Jaime R

    2015-01-01

    The oncolytic virotherapy field has made significant advances in the last decade, with a rapidly increasing number of early- and late-stage clinical trials, some of them showing safety and promising therapeutic efficacy. Targeting tumor vasculature by oncolytic viruses (OVs) is an attractive strategy that offers several advantages over nontargeted viruses, including improved tumor viral entry, direct antivascular effects, and enhanced antitumor efficacy. Current understanding of the biological mechanisms of tumor neovascularization, novel vascular targets, and mechanisms of resistance has allowed the development of oncolytic viral vectors designed to target tumor neovessels. While some OVs (such as vaccinia and vesicular stomatitis virus) can intrinsically target tumor vasculature and induce vascular disruption, the majority of reported vascular-targeted viruses are the result of genetic manipulation of their viral genomes. Such strategies include transcriptional or transductional endothelial targeting, "armed" viruses able to downregulate angiogenic factors, or to express antiangiogenic molecules. The above strategies have shown preclinical safety and improved antitumor efficacy, either alone, or in combination with standard or targeted agents. This review focuses on the recent efforts toward the development of vascular-targeted OVs for cancer treatment and provides a translational/clinical perspective into the future development of new generation biological agents for human cancers.

  19. Flat detector computed tomography angiography with intravenous contrast application: feasibility for visualization of cerebral arterial vasculature.

    PubMed

    Saake, Marc; Breuer, Lorenz; Goelitz, Philipp; Ott, Sabine; Struffert, Tobias; Doerfler, Arnd

    2013-07-01

    The aim of our study was to evaluate flat detector computed tomography angiography with peripheral intravenous contrast material application (FD-CTA) for visualization of cerebral arteries in comparison with intravenous multidetector computed tomography angiography (CTA) and intraarterial digital subtraction angiography (DSA). The study was approved by the local institutional review board and informed consent was obtained by all participants. Ten patients underwent FD-CTA, CTA, and DSA of the cerebral arterial vasculature for suspected cerebrovascular disease. The image data were evaluated by two readers in consensus for the visualization of cerebral arterial segments on a 5-point scale (0 = vessel cannot be distinguished; 4 = excellent image quality). The Wilcoxon signed-rank test was used for statistical analysis. Note that P < .05 was considered to indicate a significant difference. The depiction of cerebral arterial segments with FD-CTA was significantly superior compared to CTA in most vessel segments (P < .05 in 20 of 23 anatomic regions) and was without significant difference compared with DSA in large and medium intracranial vessels. The results suggest that the cerebral arteries can be visualized by FD-CTA in high resolution, in many vessel segments comparable to DSA. Copyright © 2012 by the American Society of Neuroimaging.

  20. Molecular specialization of breast vasculature: A breast-homing phage-displayed peptide binds to aminopeptidase P in breast vasculature

    NASA Astrophysics Data System (ADS)

    Essler, Markus; Ruoslahti, Erkki

    2002-02-01

    In vivo phage display identifies peptides that selectively home to the vasculature of individual organs, tissues, and tumors. Here we report the identification of a cyclic nonapeptide, CPGPEGAGC, which homes to normal breast tissue with a 100-fold selectivity over nontargeted phage. The homing of the phage is inhibited by its cognate synthetic peptide. Phage localization in tissue sections showed that the breast-homing phage binds to the blood vessels in the breast, but not in other tissues. The phage also bound to the vasculature of hyperplastic and malignant lesions in transgenic breast cancer mice. Expression cloning with a phage-displayed cDNA library yielded a phage that specifically bound to the breast-homing peptide. The cDNA insert was homologous to a fragment of aminopeptidase P. The homing peptide bound aminopeptidase P from malignant breast tissue in affinity chromatography. Antibodies against aminopeptidase P inhibited the in vitro binding of the phage-displayed cDNA to the peptide and the in vivo homing of phage carrying the peptide. These results indicate that aminopeptidase P is the receptor for the breast-homing peptide. This peptide may be useful in designing drugs for the prevention and treatment of breast cancer.

  1. Three-dimensional stereotactic atlas of the extracranial vasculature correlated with the intracranial vasculature, cranial nerves, skull and muscles

    PubMed Central

    Shoon Let Thaung, Thant; Choon Chua, Beng; Hnin Wut Yi, Su; Yang, Yili; Urbanik, Andrzej

    2015-01-01

    Our objective was to construct a 3D, interactive, and reference atlas of the extracranial vasculature spatially correlated with the intracranial blood vessels, cranial nerves, skull, glands, and head muscles. The atlas has been constructed from multiple 3T and 7T magnetic resonance angiogram (MRA) brain scans, and 3T phase contrast and inflow MRA neck scans of the same specimen in the following steps: vessel extraction from the scans, building 3D tubular models of the vessels, spatial registration of the extra- and intracranial vessels, vessel editing, vessel naming and color-coding, vessel simplification, and atlas validation. This new atlas contains 48 names of the extracranial vessels (25 arterial and 23 venous) and it has been integrated with the existing brain atlas. The atlas is valuable for medical students and residents to easily get familiarized with the extracranial vasculature with a few clicks; is useful for educators to prepare teaching materials; and potentially can serve as a reference in the diagnosis of vascular disease and treatment, including craniomaxillofacial surgeries and radiologic interventions of the face and neck. PMID:25923683

  2. Three-dimensional stereotactic atlas of the extracranial vasculature correlated with the intracranial vasculature, cranial nerves, skull and muscles.

    PubMed

    Nowinski, Wieslaw L; Shoon Let Thaung, Thant; Choon Chua, Beng; Hnin Wut Yi, Su; Yang, Yili; Urbanik, Andrzej

    2015-04-01

    Our objective was to construct a 3D, interactive, and reference atlas of the extracranial vasculature spatially correlated with the intracranial blood vessels, cranial nerves, skull, glands, and head muscles.The atlas has been constructed from multiple 3T and 7T magnetic resonance angiogram (MRA) brain scans, and 3T phase contrast and inflow MRA neck scans of the same specimen in the following steps: vessel extraction from the scans, building 3D tubular models of the vessels, spatial registration of the extra- and intracranial vessels, vessel editing, vessel naming and color-coding, vessel simplification, and atlas validation.This new atlas contains 48 names of the extracranial vessels (25 arterial and 23 venous) and it has been integrated with the existing brain atlas.The atlas is valuable for medical students and residents to easily get familiarized with the extracranial vasculature with a few clicks; is useful for educators to prepare teaching materials; and potentially can serve as a reference in the diagnosis of vascular disease and treatment, including craniomaxillofacial surgeries and radiologic interventions of the face and neck. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  3. Peripheral neuropathies.

    PubMed

    Hanewinckel, R; Ikram, M A; Van Doorn, P A

    2016-01-01

    Peripheral neuropathies are diseases of the peripheral nervous system that can be divided into mononeuropathies, multifocal neuropathies, and polyneuropathies. Symptoms usually include numbness and paresthesia. These symptoms are often accompanied by weakness and can be painful. Polyneuropathies can be divided into axonal and demyelinating forms, which is important for diagnostic reasons. Most peripheral neuropathies develop over months or years, but some are rapidly progressive. Some patients only suffer from mild, unilateral, slowly progressive tingling in the fingers due to median nerve compression in the wrist (carpal tunnel syndrome), while other patients can be tetraplegic, with respiratory insufficiency within 1-2 days due to Guillain-Barré syndrome. Carpal tunnel syndrome, with a prevalence of 5% and incidence of 1-2 per 1000 person-years, is the most common mononeuropathy. Population-based data for chronic polyneuropathy are relatively scarce. Prevalence is estimated at 1% and increases to 7% in persons over 65 years of age. Incidence is approximately 1 per 1000 person-years. Immune-mediated polyneuropathies like Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy are rare diseases, with an annual incidence of approximately 1-2 and 0.2-0.5 per 100 000 persons respectively. Most peripheral neuropathies are more prevalent in older adults and in men, except for carpal tunnel syndrome, which is more common in women. Diabetes is a common cause of peripheral neuropathy and is associated with both mono- and polyneuropathies. Among the group of chronic polyneuropathies, in about 20-25% no direct cause can be found. These are slowly progressive axonal polyneuropathies. © 2016 Elsevier B.V. All rights reserved.

  4. Tall fescue ergot alkaloids are vasoactive in equine vasculature

    USDA-ARS?s Scientific Manuscript database

    Mares grazing endophyte-infected (Epichloë coenophiala) tall fescue (Lolium arundinaceum) typically exhibit reproductive dysfunction rather than problems associated with peripheral vasoconstriction as a primary sign of the fescue toxicosis syndrome. Research using Doppler ultrasonography demonstrate...

  5. Visualization of vasculature with convolution surfaces: method, validation and evaluation.

    PubMed

    Oeltze, Steffen; Preim, Bernhard

    2005-04-01

    We present a method for visualizing vasculature based on clinical computed tomography or magnetic resonance data. The vessel skeleton as well as the diameter information per voxel serve as input. Our method adheres to these data, while producing smooth transitions at branchings and closed, rounded ends by means of convolution surfaces. We examine the filter design with respect to irritating bulges, unwanted blending and the correct visualization of the vessel diameter. The method has been applied to a large variety of anatomic trees. We discuss the validation of the method by means of a comparison to other visualization methods. Surface distance measures are carried out to perform a quantitative validation. Furthermore, we present the evaluation of the method which has been accomplished on the basis of a survey by 11 radiologists and surgeons.

  6. Contrast-enhanced imaging of cerebral vasculature with laser speckle

    NASA Astrophysics Data System (ADS)

    Murari, K.; Li, N.; Rege, A.; Jia, X.; All, A.; Thakor, N.

    2007-08-01

    High-resolution cerebral vasculature imaging has applications ranging from intraoperative procedures to basic neuroscience research. Laser speckle, with spatial contrast processing, has recently been used to map cerebral blood flow. We present an application of the technique using temporal contrast processing to image cerebral vascular structures with a field of view a few millimeters across and approximately 20 μm resolution through a thinned skull. We validate the images using fluorescent imaging and demonstrate a factor of 2-4 enhancement in contrast-to-noise ratios over reflectance imaging using white or spectrally filtered green light. The contrast enhancement enables the perception of approximately 10%-30% more vascular structures without the introduction of any contrast agent.

  7. Emerging concepts regarding pannexin 1 in the vasculature

    PubMed Central

    Good, Miranda E.; Begandt, Daniela; DeLalio, Leon J.; Keller, Alexander S.; Billaud, Marie; Isakson, Brant E.

    2016-01-01

    Pannexin channels are newly discovered ATP release channels expressed throughout the body. Pannexin 1 (Panx1) channels have become of great interest as they appear to participate in a multitude of signalling cascades, including regulation of vascular function. Although numerous Panx1 pharmacological inhibitors have been discovered, these inhibitors are not specific for Panx1 and have additional effects on other proteins. Therefore, molecular tools, such as RNA interference and knockout animals, are needed to demonstrate the role of pannexins in various cellular functions. This review focuses on the known roles of Panx1 related to purinergic signalling in the vasculature focusing on post-translational modifications and channel gating mechanisms that may participate in the regulated release of ATP. PMID:26009197

  8. Imaging Nanotherapeutics in Inflamed Vasculature by Intravital Microscopy

    PubMed Central

    Wang, Zhenjia

    2016-01-01

    Intravital microscopy (IVM) is the application of light microscopy to real time study biology of live animal tissues in intact and physiological conditions with the high spatial and temporal resolution. Advances in imaging systems, genetic animal models and imaging probes, IVM has offered quantitative and dynamic insight into cell biology, immunology, neurobiology and cancer. In this review, we will focus on the targeting of nanotherapeutics to inflamed vasculature. We will introduce the basic concept and principle of IVM and demonstrate that IVM is a powerful tool used to quantitatively determine the molecular mechanisms of interactions between nanotherapeutics and neutrophils or endothelium in living mice. In the future, it is needed to develop new imaging systems and novel imaging contrast agents to better understand molecular mechanisms of tissue processing of nanotherapeutics in vivo. PMID:27877245

  9. Studying Cerebral Vasculature Using Structure Proximity and Graph Kernels

    PubMed Central

    Kwitt, Roland; Pace, Danielle; Niethammer, Marc; Aylward, Stephen

    2014-01-01

    An approach to study population differences in cerebral vasculature is proposed. This is done by 1) extending the concept of encoding cerebral blood vessel networks as spatial graphs and 2) quantifying graph similarity in a kernel-based discriminant classifier setup. We argue that augmenting graph vertices with information about their proximity to selected brain structures adds discriminative information and consequently leads to a more expressive encoding. Using graph-kernels then allows us to quantify graph similarity in a principled way. To demonstrate our approach, we assess the hypothesis that gender differences manifest as variations in the architecture of cerebral blood vessels, an observation that previously had only been tested and confirmed for the Circle of Willis. Our results strongly support this hypothesis, i.e, we can demonstrate non-trivial, statistically significant deviations from random gender classification in a cross-validation setup on 40 healthy patients. PMID:24579182

  10. 3D visualization of the human cerebral vasculature

    NASA Astrophysics Data System (ADS)

    Zrimec, Tatjana; Mander, Tom; Lambert, Timothy; Parker, Geoffrey

    1995-04-01

    Computer assisted 3D visualization of the human cerebro-vascular system can help to locate blood vessels during diagnosis and to approach them during treatment. Our aim is to reconstruct the human cerebro-vascular system from the partial information collected from a variety of medical imaging instruments and to generate a 3D graphical representation. This paper describes a tool developed for 3D visualization of cerebro-vascular structures. It also describes a symbolic approach to modeling vascular anatomy. The tool, called Ispline, is used to display the graphical information stored in a symbolic model of the vasculature. The vascular model was developed to assist image processing and image fusion. The model consists of a structural symbolic representation using frames and a geometrical representation of vessel shapes and vessel topology. Ispline has proved to be useful for visualizing both the synthetically constructed vessels of the symbolic model and the vessels extracted from a patient's MR angiograms.

  11. Oligodendrocyte precursors migrate along vasculature in the developing nervous system.

    PubMed

    Tsai, Hui-Hsin; Niu, Jianqin; Munji, Roeben; Davalos, Dimitrios; Chang, Junlei; Zhang, Haijing; Tien, An-Chi; Kuo, Calvin J; Chan, Jonah R; Daneman, Richard; Fancy, Stephen P J

    2016-01-22

    Oligodendrocytes myelinate axons in the central nervous system and develop from oligodendrocyte precursor cells (OPCs) that must first migrate extensively during brain and spinal cord development. We show that OPCs require the vasculature as a physical substrate for migration. We observed that OPCs of the embryonic mouse brain and spinal cord, as well as the human cortex, emerge from progenitor domains and associate with the abluminal endothelial surface of nearby blood vessels. Migrating OPCs crawl along and jump between vessels. OPC migration in vivo was disrupted in mice with defective vascular architecture but was normal in mice lacking pericytes. Thus, physical interactions with the vascular endothelium are required for OPC migration. We identify Wnt-Cxcr4 (chemokine receptor 4) signaling in regulation of OPC-endothelial interactions and propose that this signaling coordinates OPC migration with differentiation.

  12. The effects of clonidine on human digital vasculature.

    PubMed

    Talke, P O; Caldwell, J E; Richardson, C A; Heier, T

    2000-10-01

    Large concentrations of alpha(2) agonists cause vasoconstriction. However, the threshold of the vasoconstrictive effect in humans is not known. We studied seven volunteers to determine the lower limit of the vasoconstrictive effect of clonidine. Subjects were studied while they were awake, and they were anesthetized with propofol/alfentanil/N(2)O. Arterial blood pressure was continuously monitored via radial arterial catheter and vasoconstriction via finger volume plethysmography measuring infrared light transmitted through a fingertip (LTF). Clonidine was administered, targeting plasma clonidine concentrations of 0.3, 0.45, 0.68, 1.0, 1.5, and 2.25 ng/mL. The maximum change from preclonidine values for systolic blood pressure (SBP) and LTF was analyzed by using repeated measures analysis of variance. In awake subjects, clonidine (2.25 ng/mL) decreased LTF by 14%+/-13% and SBP from 141+/-7 to 110+/-15 mm Hg (P<0.0001). In contrast, clonidine (2.25 ng/mL) increased LTF in anesthetized subjects by 21%+/-16% and SBP from 91+/-7 to 106+/-19 mm Hg (P<0.0001). We conclude that the same dose of clonidine that decreased blood pressure and caused vasodilation in awake subjects had the opposite effect in anesthetized subjects with reduced sympathetic tone, increasing blood pressure and causing vasoconstriction in human digital vasculature. Our findings suggest that the lower threshold for clonidine-induced vasoconstriction in human digital vasculature is 1.0 ng/mL.

  13. Ultrasound imaging beyond the vasculature with new generation contrast agents.

    PubMed

    Perera, Reshani H; Hernandez, Christopher; Zhou, Haoyan; Kota, Pavan; Burke, Alan; Exner, Agata A

    2015-01-01

    Current commercially available ultrasound contrast agents are gas-filled, lipid- or protein-stabilized microbubbles larger than 1 µm in diameter. Because the signal generated by these agents is highly dependent on their size, small yet highly echogenic particles have been historically difficult to produce. This has limited the molecular imaging applications of ultrasound to the blood pool. In the area of cancer imaging, microbubble applications have been constrained to imaging molecular signatures of tumor vasculature and drug delivery enabled by ultrasound-modulated bubble destruction. Recently, with the rise of sophisticated advancements in nanomedicine, ultrasound contrast agents, which are an order of magnitude smaller (100-500 nm) than their currently utilized counterparts, have been undergoing rapid development. These agents are poised to greatly expand the capabilities of ultrasound in the field of targeted cancer detection and therapy by taking advantage of the enhanced permeability and retention phenomenon of many tumors and can extravasate beyond the leaky tumor vasculature. Agent extravasation facilitates highly sensitive detection of cell surface or microenvironment biomarkers, which could advance early cancer detection. Likewise, when combined with appropriate therapeutic agents and ultrasound-mediated deployment on demand, directly at the tumor site, these nanoparticles have been shown to contribute to improved therapeutic outcomes. Ultrasound's safety profile, broad accessibility and relatively low cost make it an ideal modality for the changing face of healthcare today. Aided by the multifaceted nano-sized contrast agents and targeted theranostic moieties described herein, ultrasound can considerably broaden its reach in future applications focused on the diagnosis and staging of cancer. © 2015 Wiley Periodicals, Inc.

  14. Ultrasound Imaging Beyond the Vasculature with New Generation Contrast Agents

    PubMed Central

    Perera, Reshani H.; Hernandez, Christopher; Zhou, Haoyan; Kota, Pavan; Burke, Alan

    2015-01-01

    Current commercially available ultrasound contrast agents are gas-filled, lipid- or protein-stabilized microbubbles larger than 1 μm in diameter. Because the signal generated by these agents is highly dependent on their size, small yet highly echogenic particles have been historically difficult to produce. This has limited the molecular imaging applications of ultrasound to the blood pool. In the area of cancer imaging, microbubble applications have been constrained to imaging molecular signatures of tumor vasculature and drug delivery enabled by ultrasound-modulated bubble destruction. Recently, with the rise of sophisticated advancements in nanomedicine, ultrasound contrast agents, which are an order of magnitude smaller (100-500 nm) than their currently utilized counterparts, have been undergoing rapid development. These agents are poised to greatly expand the capabilities of ultrasound in the field of targeted cancer detection and therapy by taking advantage of the enhanced permeability and retention phenomenon of many tumors and can extravasate beyond the leaky tumor vasculature. Agent extravasation facilitates highly sensitive detection of cell surface or microenvironment biomarkers, which could advance early cancer detection. Likewise, when combined with appropriate therapeutic agents and ultrasound-mediated deployment on demand, directly at the tumor site, these nanoparticles have been shown to contribute to improved therapeutic outcomes. Ultrasound's safety profile, broad accessibility and relatively low cost make it an ideal modality for the changing face of healthcare today. Aided by the multifaceted nano-sized contrast agents and targeted theranostic moieties described herein, ultrasound can considerably broaden its reach in future applications focused on the diagnosis and staging of cancer. PMID:25580914

  15. ABC efflux transporters in brain vasculature of Alzheimer's subjects.

    PubMed

    Wijesuriya, Hasini C; Bullock, Jocelyn Y; Faull, Richard L M; Hladky, Stephen B; Barrand, Margery A

    2010-10-28

    Multidrug efflux transporters of the ATP-Binding cassette (ABC) family, P-glycoprotein (Pgp), multidrug-resistance associated protein 4 (MRP4) and breast cancer resistance protein (BCRP), located on endothelial cells lining brain vasculature play important roles in limiting movement of substances into and enhancing their efflux from the brain. Signals from the surrounding brain normally maintain such barrier function but these may become altered in CNS pathologies such as Alzheimer's disease (AD). Previous studies have reported decreases in the glucose transporter, Glut-1, in brain vasculature of AD patients. The present study investigates the status of the multidrug efflux transporters. Sections of frozen brain from hippocampal region obtained from male AD and age-matched non-demented cases were examined for amyloid plaques and Dkk-1 expression and subjected to dual fluorescence immunochemical staining using antibodies against Pgp, BCRP or MRP4 and von Willebrand factor. Protein expression of each transporter was assessed using confocal microscopy, quantifying peak fluorescence values of cross sectional profiles across brain microvessels. Results in brain microvessels revealed expression of Pgp protein to be significantly lower in hippocampal vessels of patients with AD compared to normal individuals whereas that of MRP4 or BCRP protein was not. By contrast, analysis of the sections at protein level via Western blotting or at transcript level by qRT-PCR did not reveal significantly lower expression for either Pgp or BCRP. Such analysis did however reveal higher than normal expression in the AD brains of MRP4, probably due to gliosis, MRP4 being present also in glial cells. Copyright © 2010 Elsevier B.V. All rights reserved.

  16. Enhanced external counterpulsation improves peripheral resistance artery blood flow in patients with coronary artery disease.

    PubMed

    Avery, Joseph C; Beck, Darren T; Casey, Darren P; Sardina, Paloma D; Braith, Randy W

    2014-03-01

    Enhanced external counterpulsation (EECP) increases coronary artery perfusion and improves endothelium-dependent vasodilation in peripheral muscular conduit arteries. It is unknown whether vasodilatory capacity is improved in the peripheral resistance vasculature. Here we provide novel evidence from the first randomized, sham-controlled study that EECP increases peak limb blood flow and improves endothelium-dependent vasodilation in both calf and forearm resistance arteries in patients with coronary artery disease.

  17. Long-term immunological reconstitution by peripheral blood leucocytes in severe combined immune deficiency disease: implications for the role of mature lymphocytes in histocompatible bone marrow transplantation.

    PubMed Central

    Polmar, S H; Schacter, B Z; Sorensen, R U

    1986-01-01

    A 7 month old girl with severe combined immunodeficiency disease (SCID) received a single transfusion of peripheral blood leucocytes from her histocompatible grandfather in an attempt to achieve immunological reconstitution. There was rapid restoration of humoral and cellular immunity which has persisted undiminished over a 54 month follow-up period and the patient has remained free of any significant infections. Lymphocytes of donor karyotype were repeatedly demonstrated in the patient's peripheral blood. In contrast, no evidence of donor cell engraftment in her bone marrow could be obtained by karyotypic, antigenic or enzyme phenotypic analyses. These observations suggest that long term immunological reconstitution may be achieved solely by peripheral engraftment of mature lymphocytes. A review of the literature reveals that this mechanism of immunological reconstitution may not be uncommon following histocompatible bone marrow transplantation for treatment of SCID. PMID:3539420

  18. Dilated iris vasculature in the setting of the neonatal hypoxic encephelopathy.

    PubMed

    Gorovoy, Ian R; Vaccari, Jordan C

    2015-07-01

    The differential diagnosis of dilated iris vasculature in a neonate includes retinopathy of prematurity with anterior segment plus disease, persistent fetal vasculature, intrauterine cocaine exposure, maternal diabetes, and other pathologies associated with iris neovascularization and ischemia seen in adult populations, such as central retinal vein occlusions, ocular ischemic syndrome, and chronic retinal detachment. We present neonatal hypoxic ischemic encephalopathy as a new etiology of dilated iris vasculature in a male baby who suffered a large in-utero brain vasculature insult three weeks prior to delivery but with normal fundi, no risk factors for retinopathy of prematurity (normal birth weight, and gestational age), and no other explanatory etiologies. The mechanism of the dilated iris vasculature is likely also ischemic and therefore its presence likely portends a poor prognosis. We recommend that the neonatologist evaluate for this sign for this reason and consult ophthalmology to ensure its correct etiology.

  19. Studies on entry and egress of poliomyelitic infection. VI. Centrifugal spread of the virus into peripheral nerve with notes on its possible implications.

    PubMed

    FABER, H K; SILVERBERG, R J; DONG, L

    1953-03-01

    We have demonstrated a progressive centrifugal migration of poliomyelitis virus from the CNS into various peripheral ganglia and into peripheral nerves, including their distal portions. This phenomenon appears to be a regular occurrence in experimental animals, and is similar to that found in two other neurotropic infections, rabies and Borna disease. Viremia appears to be secondary to primary neural infection. The presence of virus in the lumen of the alimentary tract appears to be secondary to primary neural infection and not to viremia, and to be associated with the centrifugal spread of virus in peripheral nerves. The presence of virus in "extraneural" tissues is not per se referable to infection of their constituent cells but rather to infection of their supplying nerves or, in some instances, to their content of virus-bearing blood. The finding of virus in the vagus nerve may throw light on some of the electrocardiographic changes noted in certain cases of human poliomyelitis. The presence of virus in peripheral nerves may throw light on the etiology of the most frequent clinical manifestations of human poliomyelitis, localized pain and tenderness.

  20. Epigenetics and Peripheral Artery Disease.

    PubMed

    Golledge, Jonathan; Biros, Erik; Bingley, John; Iyer, Vikram; Krishna, Smriti M

    2016-04-01

    The term epigenetics is usually used to describe inheritable changes in gene function which do not involve changes in the DNA sequence. These typically include non-coding RNAs, DNA methylation and histone modifications. Smoking and older age are recognised risk factors for peripheral artery diseases, such as occlusive lower limb artery disease and abdominal aortic aneurysm, and have been implicated in promoting epigenetic changes. This brief review describes studies that have associated epigenetic factors with peripheral artery diseases and investigations which have examined the effect of epigenetic modifications on the outcome of peripheral artery diseases in mouse models. Investigations have largely focused on microRNAs and have identified a number of circulating microRNAs associated with human peripheral artery diseases. Upregulating or antagonising a number of microRNAs has also been reported to limit aortic aneurysm development and hind limb ischemia in mouse models. The importance of DNA methylation and histone modifications in peripheral artery disease has been relatively little studied. Whether circulating microRNAs can be used to assist identification of patients with peripheral artery diseases and be modified in order to improve the outcome of peripheral artery disease will require further investigation.

  1. An immunocytochemical study of the germinal layer vasculature in the developing fetal brain using Ulex europaeus 1 lectin.

    PubMed

    Gould, S J; Howard, S

    1988-10-01

    The characteristics of the germinal matrix vasculature were studied in the developing fetal brain using immunocytochemical methods. A preliminary comparative immunocytochemical study was made on six fetal brains to compare endothelial staining by Ulex europaeus I lectin with that of antibody to Factor VIII related antigen. Ulex was found to stain germinal layer vessels better than Factor VIII related antigen. Subsequently, the germinal layers of a further 15 fetal and preterm infant brains ranging from 13 to 35 weeks' gestation were stained with Ulex europaeus I to demonstrate the vasculature. With increasing gestation, there was a gradual increase in vessel density, particularly of capillaries. This was not a uniform process. A plexus of capillaries was prominent immediately beneath the ependyma while the more central parts of the germinal matrix contained fewer, but often larger diameter, vessels. The variation in vessel density which was a feature of the later gestation brains may have implications for local blood flow and may be a factor in haemorrhage at this site.

  2. Deoxypodophyllotoxin suppresses tumor vasculature in HUVECs by promoting cytoskeleton remodeling through LKB1-AMPK dependent Rho A activation

    PubMed Central

    Wang, Yurong; Wang, Bin; Guerram, Mounia; Sun, Li; Shi, Wei; Tian, Chongchong; Zhu, Xiong; Jiang, Zhenzhou; Zhang, Luyong

    2015-01-01

    Angiogenesis plays a critical role in the growth and metastasis of tumors, which makes it an attractive target for anti-tumor drug development. Deoxypodophyllotoxin (DPT), a natural product isolated from Anthriscus sylvestris, inhibits cell proliferation and migration in various cancer cell types. Our previous studies indicate that DPT possesses both anti-angiogenic and vascular-disrupting activities. Although the RhoA/ RhoA kinase (ROCK) signaling pathway is implicated in DPT-stimulated cytoskeleton remodeling and tumor vasculature suppressing, the detailed mechanisms by which DPT mediates these effects are poorly understood. In the current study, we found that DPT promotes cytoskeleton remodeling in human umbilical vein endothelial cells (HUVECs) via stimulation of AMP-activated protein kinase (AMPK) and that this effect is abolished by either treatment with a selective AMPK inhibitor or knockdown. Moreover, the cellular levels of LKB1, a kinase upstream of AMPK, were enhanced following DPT exposure. DPT-induced activation of AMPK in tumor vasculature effect was also verified by transgenic zebrafish (VEGFR2:GFP), Matrigel plug assay, and xenograft model in nude mice. The present findings may lay the groundwork for a novel therapeutic approach in treating cancer. PMID:26470595

  3. [Peripheral pancytopenia].

    PubMed

    Bello-González, S A; Bergés-García, A

    1990-11-01

    Peripheral pancytopenia is a syndrome which allows for an early diagnosis, and although is may cover a large number of pathological entities, it can be clearly defined into three groups of illnesses which evolve with this syndromal manifestations. The first group includes non-neoplastic illnesses which include aplastic anemia, hemophagocytic syndrome associated to infection, immunological diseases and the deficiency of folates or vitamin B12. The second group includes neoplastic diseases as acute leukemia, non-Hodgkin lymphoma, and Hodgkin's lymphoma with myelofibrosis, malignant histiocytosis and non-hematological neoplasms, like the neuroblastoma and the embryonal rhabdomyosarcoma. The third group is formed by illnesses which have some similarity with neoplasms.

  4. Localization of myosin II regulatory light chain in the cerebral vasculature.

    PubMed

    Ishmael, Jane E; Löhr, Christiane V; Fischer, Kay; Kioussi, Chrissa

    2008-01-01

    The cytoskeleton of cerebral microvascular endothelial cells is a critical determinant of blood-brain barrier (BBB) function. Barrier integrity appears to be particularly sensitive to the phosphorylation state of specific residues within myosin regulatory light chain (RLC), one of two accessory light chains of the myosin II motor complex. Phosphorylation of myosin RLC by myosin light chain kinase (MLCK) has been implicated in BBB dysfunction associated with alcohol abuse and hypoxia, whereas dephosphorylation may enhance BBB integrity following exposure to lipid-lowering statin drugs. Using immunohistochemistry we provide evidence of widespread myosin II RLC distribution throughout the cerebral vasculature of the mouse. Light microscopy revealed immunolocalization of myosin II RLC protein in the endothelium of brain capillaries, the endothelial cell layer of arterioles and in association with venules. Immunolabeling of myosin RLC in non-muscle endothelial cells could be distinguished from myosin RLC immunoreactivity associated with the smooth muscle layer of the tunica media in larger muscular arterioles. These findings support an emerging role for myosin II RLC as a component of the actomyosin cytoskeleton of cerebral endothelial cells with the potential to contribute to the selective vulnerability of the brain in vivo.

  5. Impact of Immune Deficiency on Remodeling of Maternal Resistance Vasculature 4 Weeks Postpartum in Mice.

    PubMed

    Bonney, Elizabeth A; Howard, Ann; Krebs, Kendall; Begin, Kelly; Veilleux, Kelsey; Gokina, Natalia I

    2017-04-01

    Pregnancy manifests changes in the vascular and immune systems that persist postpartum (PP), have important implications for future pregnancies, and may modify responses to cardiovascular stress in late life. The association between immune and vascular function and the generation or progression of cardiovascular disease beg the question of whether altered immunity modifies pregnancy-induced changes in the vasculature. Our objective was to compare changes in the function and remodeling of systemic resistance vessels 4 weeks PP in normal C57BL/6 (B6), and immunodeficient mice recombinase 1-deficient/B6 ( Rag1(-/-)). Immune deficiency did not change the responsiveness to acetylcholine (ACh) and phenylephrine at baseline but decreased arterial distensibility and increased stiffness PP. Adoptive transfer of CD8 T cells into Rag1(-/-) mice decreased the response to ACh while increasing distensibility and wall thickness. When compared to PP Rag1(-/-), vessels from PP CD4-deficient mice, which have B cells and CD8 T cells, but no CD4 cells, show increased distensibility and decreased responsiveness to ACh in a pattern similar to that seen in Rag1(-/-) given CD8 T cells prior to mating. These studies suggest a key role for T cell, particularly CD8 T cell, associated factors in the PP remodeling of maternal resistance vessels.

  6. Platelets play an essential role in separating the blood and lymphatic vasculatures during embryonic angiogenesis.

    PubMed

    Carramolino, Laura; Fuentes, Joana; García-Andrés, Clara; Azcoitia, Valeria; Riethmacher, Dieter; Torres, Miguel

    2010-04-16

    Several mutations that impair the development of blood lineages in the mouse also impair the formation of the lymphatic vasculature and its separation from the blood vasculature. However, the basis for these defects has remained unknown because the mutations characterized affect more than one blood lineage. We tested the hypothesis that megakaryocytes/platelets are required for the formation of the lymphatic vasculature and its separation from the blood vascular system. We characterized the vascular patterning defects of mice deficient for the homeodomain transcription factor Meis1 (myeloid ecotropic viral integration site 1), which completely lack megakaryocyte/platelets. Meis1 null embryos fail to separate the blood and lymphatic vasculature, showing blood-filled primary lymphatic sacs and superficial lymphatic vessels. To test the involvement of megakaryocytes/platelets in this phenotype, we generated megakaryocyte/platelet-specific deficient mice by targeted lineage ablation, without affecting other blood lineages. This model reproduces the lymphatic/blood vasculature separation defects observed in Meis1 mutants. A similar phenotype was induced by antibody-mediated ablation of circulating platelets in wild type mice. Strong association of platelets with vascular endothelium at regions of contact between lymphatic sacs and veins confirmed a direct role of platelets in the separation of the 2 vasculatures. In addition to their known protective function in the response accidental vascular injury, platelets are also required during embryonic lymphangiogenesis for the separation of the nascent lymphatic vasculature from blood vessels.

  7. Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature

    PubMed Central

    Ayata, Cenk; Lauritzen, Martin

    2015-01-01

    Spreading depression (SD) is a transient wave of near-complete neuronal and glial depolarization associated with massive transmembrane ionic and water shifts. It is evolutionarily conserved in the central nervous systems of a wide variety of species from locust to human. The depolarization spreads slowly at a rate of only millimeters per minute by way of grey matter contiguity, irrespective of functional or vascular divisions, and lasts up to a minute in otherwise normal tissue. As such, SD is a radically different breed of electrophysiological activity compared with everyday neural activity, such as action potentials and synaptic transmission. Seventy years after its discovery by Leão, the mechanisms of SD and its profound metabolic and hemodynamic effects are still debated. What we did learn of consequence, however, is that SD plays a central role in the pathophysiology of a number of diseases including migraine, ischemic stroke, intracranial hemorrhage, and traumatic brain injury. An intriguing overlap among them is that they are all neurovascular disorders. Therefore, the interplay between neurons and vascular elements is critical for our understanding of the impact of this homeostatic breakdown in patients. The challenges of translating experimental data into human pathophysiology notwithstanding, this review provides a detailed account of bidirectional interactions between brain parenchyma and the cerebral vasculature during SD and puts this in the context of neurovascular diseases. PMID:26133935

  8. Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature.

    PubMed

    Ayata, Cenk; Lauritzen, Martin

    2015-07-01

    Spreading depression (SD) is a transient wave of near-complete neuronal and glial depolarization associated with massive transmembrane ionic and water shifts. It is evolutionarily conserved in the central nervous systems of a wide variety of species from locust to human. The depolarization spreads slowly at a rate of only millimeters per minute by way of grey matter contiguity, irrespective of functional or vascular divisions, and lasts up to a minute in otherwise normal tissue. As such, SD is a radically different breed of electrophysiological activity compared with everyday neural activity, such as action potentials and synaptic transmission. Seventy years after its discovery by Leão, the mechanisms of SD and its profound metabolic and hemodynamic effects are still debated. What we did learn of consequence, however, is that SD plays a central role in the pathophysiology of a number of diseases including migraine, ischemic stroke, intracranial hemorrhage, and traumatic brain injury. An intriguing overlap among them is that they are all neurovascular disorders. Therefore, the interplay between neurons and vascular elements is critical for our understanding of the impact of this homeostatic breakdown in patients. The challenges of translating experimental data into human pathophysiology notwithstanding, this review provides a detailed account of bidirectional interactions between brain parenchyma and the cerebral vasculature during SD and puts this in the context of neurovascular diseases.

  9. Importance Rat Liver Morphology and Vasculature in Surgical Research.

    PubMed

    Vdoviaková, Katarína; Vdoviaková, Katarína; Petrovová, Eva; Krešáková, Lenka; Maloveská, Marcela; Teleky, Jana; Jenčová, Janka; Živčák, Jozef; Jenča, Andrej

    2016-12-02

    BACKGROUND The laboratory rat is one of the most popular experimental models for the experimental surgery of the liver. The objective of this study was to investigate the morphometric parameters, physiological data, differences in configuration of liver lobes, biliary system, and vasculature (arteries, veins, and lymphatic vessels) of the liver in laboratory rats. In addition, this study supports the anatomic literature and identified similarities and differences with human and other mammals. MATERIAL AND METHODS Forty laboratory rats were dissected to prepare corrosion casts of vascular system specimens (n=20), determine the lymph vessels and lymph nodes (n=10), and for macroscopic anatomical dissection (n=10) of the rat liver. The results are listed in percentages. The anatomical nomenclature of the liver morphology, its arteries, veins, lymph nodes, and lymphatic vessels are in accordance with Nomina Anatomica Veterinaria. RESULTS We found many variations in origin, direction, and division of the arterial, venous, and lymphatic systems in rat livers, and found differences in morphometric parameters compared to results reported by other authors. The portal vein was formed by 4 tributaries in 23%, by 3 branches in 64%, and by 2 tributaries in 13%. The liver lymph was drained to the 2 different lymph nodes. The nomenclature and morphological characteristics of the rat liver vary among authors. CONCLUSIONS Our results may be useful for the planing of experimental surgery and for cooperation with other investigation methods to help fight liver diseases in human populations.

  10. Importance Rat Liver Morphology and Vasculature in Surgical Research

    PubMed Central

    Vdoviaková, Katarína; Petrovová, Eva; Krešáková, Lenka; Maloveská, Marcela; Teleky, Jana; Jenčová, Janka; Živčák, Jozef; Jenča, Andrej

    2016-01-01

    Background The laboratory rat is one of the most popular experimental models for the experimental surgery of the liver. The objective of this study was to investigate the morphometric parameters, physiological data, differences in configuration of liver lobes, biliary system, and vasculature (arteries, veins, and lymphatic vessels) of the liver in laboratory rats. In addition, this study supports the anatomic literature and identified similarities and differences with human and other mammals. Material/Methods Forty laboratory rats were dissected to prepare corrosion casts of vascular system specimens (n=20), determine the lymph vessels and lymph nodes (n=10), and for macroscopic anatomical dissection (n=10) of the rat liver. The results are listed in percentages. The anatomical nomenclature of the liver morphology, its arteries, veins, lymph nodes, and lymphatic vessels are in accordance with Nomina Anatomica Veterinaria. Results We found many variations in origin, direction, and division of the arterial, venous, and lymphatic systems in rat livers, and found differences in morphometric parameters compared to results reported by other authors. The portal vein was formed by 4 tributaries in 23%, by 3 branches in 64%, and by 2 tributaries in 13%. The liver lymph was drained to the 2 different lymph nodes. The nomenclature and morphological characteristics of the rat liver vary among authors. Conclusions Our results may be useful for the planing of experimental surgery and for cooperation with other investigation methods to help fight liver diseases in human populations. PMID:27911356

  11. Endothelial cell metabolism in normal and diseased vasculature

    PubMed Central

    Eelen, Guy; de Zeeuw, Pauline; Simons, Michael; Carmeliet, Peter

    2015-01-01

    Higher organisms rely on a closed cardiovascular circulatory system with blood vessels supplying vital nutrients and oxygen to distant tissues. Not surprisingly, vascular pathologies rank among the most life-threatening diseases. At the crux of most of these vascular pathologies are (dysfunctional) endothelial cells (ECs), the cells lining the blood vessel lumen. ECs display the remarkable capability to switch rapidly from a quiescent state to a highly migratory and proliferative state during vessel sprouting. This angiogenic switch has long been considered to be dictated by angiogenic growth factors (eg vascular endothelial growth factor; VEGF) and other signals (eg Notch) alone, but recent findings show that it is also driven by a metabolic switch in ECs. Furthermore, these changes in metabolism may even override signals inducing vessel sprouting. Here, we review how EC metabolism differs between the normal and dysfunctional/diseased vasculature and how it relates to or impacts the metabolism of other cell types contributing to the pathology. We focus on the biology of ECs in tumor blood vessel and diabetic ECs in atherosclerosis as examples of the role of endothelial metabolism in key pathological processes. Finally, current as well as unexplored ‘EC metabolism’-centric therapeutic avenues are discussed. PMID:25814684

  12. Three-dimensional volume analysis of vasculature in engineered tissues

    NASA Astrophysics Data System (ADS)

    YousefHussien, Mohammed; Garvin, Kelley; Dalecki, Diane; Saber, Eli; Helguera, María.

    2013-01-01

    Three-dimensional textural and volumetric image analysis holds great potential in understanding the image data produced by multi-photon microscopy. In this paper, an algorithm that quantitatively analyzes the texture and the morphology of vasculature in engineered tissues is proposed. The investigated 3D artificial tissues consist of Human Umbilical Vein Endothelial Cells (HUVEC) embedded in collagen exposed to two regimes of ultrasound standing wave fields under different pressure conditions. Textural features were evaluated using the normalized Gray-Scale Cooccurrence Matrix (GLCM) combined with Gray-Level Run Length Matrix (GLRLM) analysis. To minimize error resulting from any possible volume rotation and to provide a comprehensive textural analysis, an averaged version of nine GLCM and GLRLM orientations is used. To evaluate volumetric features, an automatic threshold using the gray level mean value is utilized. Results show that our analysis is able to differentiate among the exposed samples, due to morphological changes induced by the standing wave fields. Furthermore, we demonstrate that providing more textural parameters than what is currently being reported in the literature, enhances the quantitative understanding of the heterogeneity of artificial tissues.

  13. PHACE syndrome with lip haemangioma, microphthalmos and persistent fetal vasculature.

    PubMed

    Nayak, Lipika; Nayak, Bhagabat; Sinha, Gautam; Khokhar, Sudarshan

    2016-03-31

    An 11-month-old baby girl presented with white reflex in her left eye. On examination, there was a 6.5×5 mm(2)haemangioma present over her face involving on her lower lip. Systemic examinations were within normal limits. The left eye was small, with an axial length of 16.08 mm and had a cataract. Ultrasonography of the left eye was suggestive of the presence of a vascular stalk, persistent hyperplasia of a primary vitreous, or persistent fetal vasculature with vitreous haemorrhage. On MRI, the left eye was small with vitreous haemorrhage. Left eye lens aspiration was performed and the bleeding vascular stalk behind the lens was cauterised with diathermy. The right eye was normal. The patient was diagnosed as having PHACE syndrome (Posterior fossa malformations, Hemangiomas, Arterial anomalies, Coarctation of the aorta and other cardiac defects, and Eye abnormalities syndrome). On follow-up, she was able to follow light with her left eye. 2016 BMJ Publishing Group Ltd.

  14. Three-dimensional ultrasound imaging of the vasculature.

    PubMed

    Fenster, A; Lee, D; Sherebrin, S; Rankin, R; Downey, D

    1998-02-01

    With conventional ultrasonography, the diagnostician must view a series of two-dimensional images in order to form a mental impression of the three-dimensional anatomy, an efficient and time consuming practice prone to operator variability, which may cause variable or even incorrect diagnoses. Also, a conventional two-dimensional ultrasound image represents a thin slice of the patients anatomy at a single location and orientation, which is difficult to reproduce at a later time. These factors make conventional ultrasonography non-optimal for prospective or follow-up studies. Our efforts have focused on overcoming these deficiencies by developing three-dimensional ultrasound imaging techniques that are capable of acquiring B-mode, colour Doppler and power Doppler images of the vasculature, by using a conventional ultrasound system to acquire a series of two-dimensional images and then mathematically reconstructing them into a single three-dimensional image, which may then be viewed interactively on an inexpensive desktop computer. We report here on two approaches: (1) free-hand scanning, in which a magnetic positioning device is attached to the ultrasound transducer to record the position and orientation of each two-dimensional image needed for the three-dimensional image reconstruction; and (2) mechanical scanning, in which a motor-driven assembly is used to translate the transducer linearly across the neck, yielding a set of uniformly-spaced parallel two-dimensional images.

  15. The lymphatic vasculature revisited-new developments in the zebrafish.

    PubMed

    Padberg, Y; Schulte-Merker, S; van Impel, A

    2017-01-01

    The lymphatic system is lined by endothelial cells and part of the vasculature. It is essential for tissue fluid homeostasis, absorption of dietary fats, and immune surveillance in vertebrates. Misregulation of lymphatic vessel formation and dysfunction of the lymphatic system have been indicated in a number of pathological conditions including lymphedema formation, obesity or chronic inflammatory diseases such as rheumatoid arthritis. In zebrafish, lymphatics were discovered about 10years ago, and the underlying molecular pathways involved in its development have since been studied in detail. Due to its superior live cell imaging possibilities and the broad tool kit for forward and reverse genetics, the zebrafish has become an important model organism to study the development of the lymphatic system during early embryonic development. In the current review, we will focus on the key players during zebrafish lymphangiogenesis and compare the roles of these genes to their mammalian counterparts. In particular, we will focus on novel findings that shed new light on the molecular mechanisms of lymphatic cell fate specification, as well as sprouting and migration of lymphatic precursor cells.

  16. The heart and pulmonary vasculature of the llama (Lama glama)

    PubMed Central

    Heath, D.; Smith, P.; Williams, D.; Harris, P.; Arias-Stella, J.; Krüger, H.

    1974-01-01

    Heath, D., Smith, P., Williams, D., Harris, P., Arias-Stella, J., and Krüger, H. (1974).Thorax, 29, 463-471. The heart and pulmonary vasculature of the llama (Lama glama). A qualitative and quantitative histological study was made of the pulmonary trunk and muscular pulmonary arteries of a male and a pregnant female llama born and living at an altitude of 4,720 m above sea-level in the Peruvian Andes. A similar study was made on the fetal llama. The individual cardiac chambers of the two adults were weighed. Our results show that in the adult llama there is no hypertrophy of the right ventricle or of the media of the pulmonary trunk or small pulmonary arteries. This appears to be of evolutionary significance in respect of survival at high altitude and suggests that the llama does not have a sustained significant pulmonary hypertension. The pulmonary arteries of the fetal llama are thick-walled and we associate this with the physiological pulmonary hypertension of fetal life. Images PMID:4854860

  17. Schistosomiasis and the pulmonary vasculature (2013 Grover Conference series)

    PubMed Central

    2014-01-01

    Abstract Inflammation is associated with multiple forms of pulmonary arterial hypertension (PAH), including autoimmune (scleroderma) and infectious (HIV, schistosomiasis) etiologies. More than 200 million people worldwide are infected with Schistosoma, predominantly in Brazil, Africa, the Middle East, and South Asia. Schistosomiasis causes PAH in about 6.1% of those chronically infected and is particularly associated with the species Schistosoma mansoni. Treatment for schistosomiasis-associated PAH includes antihelminthic treatment, if active infection is present (although associated with little immediate benefit to the pulmonary hypertension), and then pharmacologic treatment with targeted pulmonary vascular therapies, including phosphodiesterase type 5 inhibitors and endothelin receptor antagonists. The pathophysiological mechanism by which this parasitic infection causes pulmonary hypertension is unknown but is unlikely to be simple mechanical obstruction of the pulmonary vasculature by parasite eggs. Preexisting hepatosplenic disease due to Schistosoma infection is likely important because of portopulmonary hypertension and/or because it allows egg embolization to the lung by portocaval shunts. Potential immune signaling originating in the periegg granulomas causing the pulmonary vascular disease includes the cytokines interleukin (IL)-4, IL-6, IL-13, and transforming growth factor β. Modulating these pathways may be possible targets for future therapy of schistosomiasis-associated PAH specifically, and study of this disease may provide novel insights into other inflammatory causes of PAH. PMID:25621148

  18. Optimum Topical Delivery of Adrenergic Agonists to Oral Mucosa Vasculature

    PubMed Central

    Soref, Cheryl M.

    2015-01-01

    Purpose Identify an orotopical vehicle to deliver an α-adrenergic vasoconstrictor to submucosal vasculature that is readily palatable to cancer/bone marrow transplant patients that suppresses chemo-radiotherapy-associated oral mucositis. Methods A [3H] norepinephrine ligand binding assay was developed to quantify receptor binding in hamster oral mucosa. Vehicle components (alcohols, polyols, cellulose, PVP) were tested versus [3H] norepinephrine binding. Vehicle refinement was also done to mask phenylephrine bitter taste and achieve human subject acceptance. The optimized vehicle was tested with α-adrenergic active agents to suppress radiation-induced oral mucositis in mice. Results The ligand binding assay quantified dose- and time-dependent, saturable binding of [3H] norepinephrine. An ethanol:glycerol:propylene glycol:water (6:6:8:80) vehicle provided the best delivery and binding. Further vehicle modification (flavoring and sucralose) yielded a vehicle with excellent taste scores in humans. Addition of phenylephrine, norepinephrine or epinephrine to the optimized vehicle and painting into mouse mouths 20 min before 19 Gy irradiation conferred significant suppression of the weight loss (P < 0.001) observed in mice who received oral vehicle. Conclusion We identified a highly efficient vehicle for the topical delivery of phenylephrine to the oral mucosa of both hamster and human subjects. This will enable its testing to suppress oral mucositis in an upcoming human clinical trial. PMID:25079392

  19. Hematopoietic progenitors are required for proper development of coronary vasculature

    PubMed Central

    Lluri, Gentian; Huang, Vincent; Touma, Marlin; Liu, Xiaoqian; Harmon, Andrew W.; Nakano, Atsushi

    2015-01-01

    Rationale During embryogenesis, hematopoietic cells appear in the myocardium prior to the initiation of coronary formation. However, their role is unknown. Objective Here we investigate whether pre-existing hematopoietic cells are required for the formation of coronary vasculature. Methods and Results As a model of for hematopoietic cell deficient animals, we used Runx1 knockout embryos and Vav1-cre; R26-DTA embryos, latter of which genetically ablates 2/3 of CD45+ hematopoietic cells. Both Runx1 knockout embryos and Vav1-cre; R26-DTA embryos revealed disorganized, hypoplastic microvasculature of coronary vessels on section and whole-mount stainings. Furthermore, coronary explant experiments showed that the mouse heart explants from Runx1 and Vav1-cre; R26-DTA embryos exhibited impaired coronary formation ex vivo. Interestingly, in both models it appears that epicardial to mesenchymal transition is adversely affected in the absence of hematopoietic progenitors. Conclusion Hematopoietic cells are not merely passively transported via coronary vessel, but substantially involved in the induction of the coronary growth. Our findings suggest a novel mechanism of coronary growth. PMID:26241844

  20. Modulation of the Tumor Vasculature and Oxygenation to Improve Therapy

    PubMed Central

    Siemann, Dietmar W.; Horsman, Michael R.

    2015-01-01

    The tumor microenvironment is increasingly recognized as a major factor influencing the success of therapeutic treatments and has become a key focus for cancer research. The progressive growth of a tumor results in an inability of normal tissue blood vessels to oxygenate and provide sufficient nutritional support to tumor cells. As a consequence the expanding neoplastic cell population initiates its own vascular network which is both structurally and functionally abnormal. This aberrant vasculature impacts all aspects of the tumor microenvironment including the cells, extracellular matrix, and extracellular molecules which together are essential for the initiation, progression and spread of tumor cells. The physical conditions that arise are imposing and manifold, and include elevated interstitial pressure, localized extracellular acidity, and regions of oxygen and nutrient deprivation. No less important are the functional consequences experienced by the tumor cells residing in such environments: adaptation to hypoxia, cell quiescence, modulation of transporters and critical signaling molecules, immune escape, and enhanced metastatic potential. Together these factors lead to therapeutic barriers that create a significant hindrance to the control of cancers by conventional anticancer therapies. However, the aberrant nature of the tumor microenvironments also offers unique therapeutic opportunities. Particularly interventions that seek to improve tumor physiology and alleviate tumor hypoxia will selectively impair the neoplastic cell populations residing in these environments. Ultimately, by combining such therapeutic strategies with conventional anticancer treatments it may be possible to bring cancer growth, invasion, and metastasis to a halt. PMID:26073310

  1. Fractal analysis of the retinal vasculature and chronic kidney disease.

    PubMed

    Sng, Chelvin C A; Sabanayagam, Charumathi; Lamoureux, Ecosse L; Liu, Erica; Lim, Su Chi; Hamzah, Haslina; Lee, Jeannette; Tai, E Shyong; Wong, Tien Y

    2010-07-01

    BACKGROUND. Fractal analysis provides a global index of the geometric complexity and optimality of vascular networks. In this study, we investigated the relationship between fractal measurements of the retinal vasculature and chronic kidney disease (CKD). METHODS. This was a population-based case-control study which included participants from the Singapore Prospective Study Program. We identified 261 participants with CKD, defined as estimated glomerular filtration rate of <60 mL/min/1.73 m(2), and 651 controls. The retinal fractal dimension (D(f)) was quantified from digitized fundus photographs using a computer-based programme. RESULTS. The mean D(f) was 1.43 +/- 0.048 in the participants with CKD and 1.44 +/- 0.042 in controls (P = 0.013). Suboptimal D(f) in the lowest (first) and highest (fifth) quintiles were associated with an increased prevalence of CKD after adjusting for age, systolic blood pressure, diabetes and other risk factors [odds ratio (OR) 2.10, 95% confidence interval (CI) 1.15, 3.83 and OR 1.84, 95% CI 1.06, 3.17; compared to the fourth quintile, respectively). This association was present even in participants without diabetes or hypertension. CONCLUSIONS. Our study found that an abnormal retinal vascular network is associated with an increased risk of CKD, supporting the hypothesis that deviations from optimal microvascular architecture may be related to kidney damage.

  2. Chemokine guided angiogenesis directs coronary vasculature formation in zebrafish

    PubMed Central

    Harrison, Michael R.M.; Bussmann, Jeroen; Huang, Ying; Zhao, Long; Osorio, Arthela; Burns, C. Geoffrey; Burns, Caroline E.; Sucov, Henry M.; Siekmann, Arndt F.; Lien, Ching-Ling

    2015-01-01

    SUMMARY Interruption of coronary blood supply severely impairs heart function with often-fatal consequences for heart disease patients. However the formation and maturation of these coronary vessels is not fully understood. Here we provide a detailed analysis of coronary vessel development in zebrafish. We observe that coronary vessels form in zebrafish by angiogenic sprouting of arterial cells derived from the endocardium at the atrioventricular canal. Endothelial cells express the CXC-motif chemokine receptor Cxcr4a and migrate to vascularize the ventricle under the guidance of the myocardium-expressed ligand Cxcl12b. cxcr4a mutant zebrafish fail to form a vascular network, whereas ectopic expression of Cxcl12b ligand induces coronary vessel formation. Importantly, cxcr4a mutant zebrafish fail to undergo heart regeneration following injury. Our results suggest that chemokine-signaling has an essential role in coronary vessel formation by directing migration of endocardium-derived endothelial cells. Poorly developed vasculature in cxcr4a mutants likely underlies decreased regenerative potential in adults. PMID:26017769

  3. Comparative evaluation of 64-slice CT angiography and digital subtraction angiography in assessing the cervicocranial vasculature.

    PubMed

    Klingebiel, Randolf; Kentenich, Max; Bauknecht, Hans-Christian; Masuhr, Florian; Siebert, Eberhard; Busch, Markus; Bohner, Georg

    2008-01-01

    Noninvasive 64-slice computed tomography angiography (64-MSCTA) closely approximates conventional catheter angiography (DSA) in terms of detail resolution. Retrospective evaluation of cervicocranial (cc) 64-MSCTA in comparison with DSA in patients with presumptive cc vascular disorders. Twenty-four 64-MSCTA studies (32 mm detector width, slice thickness 0.5 mm, 120 kv, 150 mAs, pitch 0.75) of patients with presumptive cc vascular pathology (13 men, 11 women, mean age 38.3 +/- 11.3 yrs, range 19-54 yrs) were assessed in comparison with DSA studies without abnormal findings in age-matched patients (11 men, 13 women, mean age 39.7 +/- 11.9 yrs, range 18-54 yrs). Study readings were performed in a blinded manner by two neuroradiologists with respect to image quality and assessibility of various cc vascular segments by using a five-point scale. Radiation exposure was calculated for 64-MSCTA. Each reader assessed 384/528 different vessel segments (64-MSCTA/DSA). Superior image quality was attributed to DSA with respect to the C1 ICA-C6 ICA, A3 ACA, and P3 PCA segments as well the AICA and SCA. 64-MSCTA was scored superior for C7 ICA and V4 VA segments. A significantly increased number ofnonassessable V2- and V3 VA segments in DSA studies was noted. The effective dose for 64-MSCTA amounted to 2.2 mSv. 64-MSCTA provides near-equivalent diagnostic information of the cc vasculature as compared with DSA. According to our results, DSA should be considered primarily when peripheral vessels (A3/P3) or ICA segments close to the skull base (C2-5) are of interest, such as in primary angiitis or stenoocclusive ICA disease, respectively.

  4. NORMALIZATION OF THE VASCULATURE FOR TREATMENT OF CANCER AND OTHER DISEASES

    PubMed Central

    Goel, Shom; Duda, Dan G.; Xu, Lei; Munn, Lance L.; Boucher, Yves; Fukumura, Dai; Jain, Rakesh K.

    2012-01-01

    New vessel formation (angiogenesis) is an essential physiological process for embryologic development, normal growth, and tissue repair. Angiogenesis is tightly regulated at the molecular level. Dysregulation of angiogenesis occurs in various pathologies and is one of the hallmarks of cancer. The imbalance of pro- and anti-angiogenic signaling within tumors creates an abnormal vascular network that is characterized by dilated, tortuous, and hyperpermeable vessels. The physiological consequences of these vascular abnormalities include temporal and spatial heterogeneity in tumor blood flow and oxygenation and increased tumor interstitial fluid pressure. These abnormalities and the resultant microenvironment fuel tumor progression, and also lead to a reduction in the efficacy of chemotherapy, radiotherapy, and immunotherapy. With the discovery of vascular endothelial growth factor (VEGF) as a major driver of tumor angiogenesis, efforts have focused on novel therapeutics aimed at inhibiting VEGF activity, with the goal of regressing tumors by starvation. Unfortunately, clinical trials of anti-VEGF monotherapy in patients with solid tumors have been largely negative. Intriguingly, the combination of anti-VEGF therapy with conventional chemotherapy has improved survival in cancer patients compared with chemotherapy alone. These seemingly paradoxical results could be explained by a “normalization” of the tumor vasculature by anti-VEGF therapy. Preclinical studies have shown that anti-VEGF therapy changes tumor vasculature towards a more “mature” or “normal” phenotype. This “vascular normalization” is characterized by attenuation of hyperpermeability, increased vascular pericyte coverage, a more normal basement membrane, and a resultant reduction in tumor hypoxia and interstitial fluid pressure. These in turn can lead to an improvement in the metabolic profile of the tumor microenvironment, the delivery and efficacy of exogenously administered therapeutics

  5. In vivo imaging of pulmonary nodule and vasculature using endoscopic co-registered optical coherence tomography and autofluorescence imaging (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Pahlevaninezhad, Hamid; Lee, Anthony; Hohert, Geoffrey; Schwartz, Carely; Shaipanich, Tawimas; Ritchie, Alexander J.; Zhang, Wei; MacAulay, Calum E.; Lam, Stephen; Lane, Pierre M.

    2016-03-01

    Peripheral lung nodules found by CT-scans are difficult to localize and biopsy bronchoscopically particularly for those ≤ 2 cm in diameter. In this work, we present the results of endoscopic co-registered optical coherence tomography and autofluorescence imaging (OCT-AFI) of normal and abnormal peripheral airways from 40 patients using 0.9 mm diameter fiber optic rotary pullback catheter. Optical coherence tomography (OCT) can visualize detailed airway morphology endoscopically in the lung periphery. Autofluorescence imaging (AFI) can visualize fluorescing tissue components such as collagen and elastin, enabling the detection of airway lesions with high sensitivity. Results indicate that AFI of abnormal airways is different from that of normal airways, suggesting that AFI can provide a sensitive visual presentation for rapidly identifying possible sites of pulmonary nodules. AFI can also rapidly visualize in vivo vascular networks using fast scanning parameters resulting in vascular-sensitive imaging with less breathing/cardiac motion artifacts compared to Doppler OCT imaging. It is known that tumor vasculature is structurally and functionally different from normal vessels. Thus, AFI can be potentially used for differentiating normal and abnormal lung vasculature for studying vascular remodeling.

  6. Mitochondrial dynamics in peripheral neuropathies.

    PubMed

    Sajic, Marija

    2014-08-01

    Mitochondrial dynamics describes the continuous change in the position, size, and shape of mitochondria within cells. The morphological and functional complexity of neurons, the remarkable length of their processes, and the rapid changes in metabolic requirements arising from their intrinsic excitability render these cells particularly dependent on effective mitochondrial function and positioning. The rules that govern these changes and their functional significance are not fully understood, yet the dysfunction of mitochondrial dynamics has been implicated as a pathogenetic factor in a number of diseases, including disorders of the central and peripheral nervous systems. In recent years, a number of mutations of genes encoding proteins that play important roles in mitochondrial dynamics and function have been discovered in patients with Charcot-Marie-Tooth (CMT) disease, a hereditary peripheral neuropathy. These findings have directly linked mitochondrial pathology to the pathology of peripheral nerve and have identified certain aspects of mitochondrial dynamics as potential early events in the pathogenesis of CMT. In addition, mitochondrial dysfunction has now been implicated in the pathogenesis of noninherited neuropathies, including diabetic and inflammatory neuropathies. The role of mitochondria in peripheral nerve diseases has been mostly examined in vitro, and less so in animal models. This review examines available evidence for the role of mitochondrial dynamics in the pathogenesis of peripheral neuropathies, their relevance in human diseases, and future challenges for research in this field.

  7. [Peripheral alexias].

    PubMed

    Jianu, Silviana Nina; Jianu, Dragoş Cătălin

    2004-01-01

    The brain lesions could lead to impairments of the comprehension and production of written language. This acquired inability is named alexia. It is a significant problem for neurologists and ophthalmologists. Our study presents a classification of the alexias, whose pathology was describe first by Dejerine (1891; 1892). There are two varieties of alexias: central alexias and peripheral alexias (especially agnozic alexia and attentional alexia). In agnozic alexia, the patient cannot read, but can write, understand and speak. It results from a type of cerebral disconnection in which the angular gyrus of the dominant hemisphere is disconnected from its bilateral visual input. The most commonly reported pathology is occlusion of the dominant (left) posterior cerebral artery, which leads to infarction of both the left occipital lobe (causing partial or complete right homonymous hemianpsia) and the splenium of the corpus callosum.

  8. A mutagenesis-derived Lrp5 mouse mutant with abnormal retinal vasculature and low bone mineral density

    PubMed Central

    Charette, Jeremy R.; Earp, Sarah E.; Bell, Brent A.; Ackert-Bicknell, Cheryl L.; Godfrey, Dana A.; Rao, Sujata; Anand-Apte, Bela; Nishina, Patsy M.

    2017-01-01

    Purpose Familial exudative vitreoretinopathy (FEVR) is caused by mutations in the genes encoding low-density lipoprotein receptor-related protein (LRP5) or its interacting partners, namely frizzled class receptor 4 (FZD4) and norrin cystine knot growth factor (NDP). Mouse models for Lrp5, Fzd4, and Ndp have proven to be important for understanding the retinal pathophysiology underlying FEVR and systemic abnormalities related to defective Wnt signaling. Here, we report a new mouse mutant, tvrm111B, which was identified by electroretinogram (ERG) screening of mice generated in the Jackson Laboratory Translational Vision Research Models (TVRM) mutagenesis program. Methods ERGs were used to examine outer retinal physiology. The retinal vasculature was examined by in vivo retinal imaging, as well as by histology and immunohistochemistry. The tvrm111B locus was identified by genetic mapping of mice generated in a cross to DBA/2J, and subsequent sequencing analysis. Gene expression was examined by real-time PCR of retinal RNA. Bone mineral density (BMD) was examined by peripheral dual-energy X-ray absorptiometry. Results The tvrm111B allele is inherited as an autosomal recessive trait. Genetic mapping of the decreased ERG b-wave phenotype of tvrm111B mice localized the mutation to a region on chromosome 19 that included Lrp5. Sequencing of Lrp5 identified the insertion of a cytosine (c.4724_4725insC), which is predicted to cause a frameshift that disrupts the last three of five conserved PPPSPxS motifs in the cytoplasmic domain of LRP5, culminating in a premature termination. In addition to a reduced ERG b-wave, Lrp5tvrm111B homozygotes have low BMD and abnormal features of the retinal vasculature that have been reported previously in Lrp5 mutant mice, including persistent hyaloid vessels, leakage on fluorescein angiography, and an absence of the deep retinal capillary bed. Conclusions The phenotype of the Lrp5tvrm111B mutant includes abnormalities of the retinal

  9. Normal Doppler velocimetry of renal vasculature in Persian cats.

    PubMed

    Carvalho, Cibele F; Chammas, Maria C

    2011-06-01

    Renal diseases are common in older cats. Decreased renal blood flow may be the first sign of dysfunction and can be evaluated by Doppler ultrasound. But previous studies suggest that the resistive index (RI) has a low sensitivity for detecting renal disease. Doppler waveforms of renal and intrarenal arteries demonstrate decreased blood flow before there are any changes in the RI. The purpose of this study was to evaluate the normal Doppler flowmetrics parameters of renal arteries (RAs), interlobar arteries (IAs) and abdominal aorta (AO) in adult healthy, Persian cats. Twenty-five Persian cats (13 females and 12 males with mean age of 30 months and an age range 12-60 months) with normal clinical examinations and biochemical tests and normal systemic blood pressure were given B-mode ultrasonographies in order to exclude all nephropathies, including polycystic kidney disease. All measurements were performed on both kidneys. Both kidneys (n=50) were examined by color mapping of the renal vasculature. Pulsed Doppler was used to examine both RAs, the IAs at cranial, middle and caudal sites, and the AO. The RI was calculated for all of the vessels. Early systolic acceleration (ESA) of RA and IA was obtained with Doppler spectral analysis. Furthermore, the ratio indices between RA/AO, and IA/RA velocities were calculated. The mean values of peak systolic velocity (PSV) and the diameter for AO were 53.17±13.46 cm/s and 0.38±0.08 cm, respectively. The mean RA diameter for all 50 kidneys was 0.15±0.02 cm. Considering the velocimetric values in both RAs, the mean PSV and RI that were obtained were 41.17±9.40 cm/s and 0.54±0.07. The RA had a mean ESA of 1.12±1.14 m/s(2) and the calculated upper limit of the reference value was 3.40 m/s(2). The mean renal-aortic ratio was 0.828±0.296. The IA showed PSV and RI values of 32.16±9.33 cm/s and 0.52±0.06, respectively. The mean ESA of all IAs was 0.73±0.61 m/s(2). The calculated upper limit of the reference value was 2.0m

  10. A multifactorial conceptual model of peripheral neuromusculoskeletal predisposing factors in task-specific focal hand dystonia in musicians: etiologic and therapeutic implications.

    PubMed

    Leijnse, J N A L; Hallett, M; Sonneveld, G J

    2015-02-01

    A model is presented showing how peripheral factors may cause a process of movement adaptation that leads to task-specific focal hand dystonia in musicians (FHDM). To acquire a playing technique, the hand must find effective and physiologically sustainable movements within a complex set of functional demands and anatomic, ergonomic, and physiological constraints. In doing so, individually discriminating constraints may become effective, such as limited anatomic independence of finger muscles/tendons, limited joint ranges of motion, or (subclinical) neuromusculoskeletal defects. These factors may, depending on the instrument-specific playing requirements, compromise or exclude functional playing movements. The controller (i.e., the brain) then needs to develop alternative motions to execute the task, which is called compensation. We hypothesize that, if this compensation process does not converge to physiologically sustainable muscle activation patterns that satisfy all constraints, compensation could increase indefinitely under the pressure of practice. Dystonic symptoms would become manifest when overcompensation occurs, resulting in motor patterns that fail in proper task execution. The model presented in this paper only concerns the compensatory processes preceding such overcompensations and does not aim to explain the nature of the dystonic motions themselves. While the model considers normal learning processes in the development of compensations, neurological predispositions could facilitate developing overcompensations or further abnormal motor programs. The model predicts that if peripheral factors are involved, FHDM symptoms would be preceded by long-term gradual changes in playing movements, which could be validated by prospective studies. Furthermore, the model implies that treatment success might be enhanced by addressing the conflict between peripheral factors and playing tasks before decompensating/retraining the affected movements.

  11. Homology of lungs and gas bladders: insights from arterial vasculature.

    PubMed

    Longo, Sarah; Riccio, Mark; McCune, Amy R

    2013-06-01

    Gas bladders of ray-finned fishes serve a variety of vital functions and are thus an important novelty of most living vertebrates. The gas bladder has long been regarded as an evolutionary modification of lungs. Critical evidence for this hypothesized homology is whether pulmonary arteries supply the gas bladder as well as the lungs. Pulmonary arteries, paired branches of the fourth efferent branchial arteries, deliver blood to the lungs in osteichthyans with functional lungs (lungfishes, tetrapods, and the ray-finned polypterid fishes). The fact that pulmonary arteries also supply the respiratory gas bladder of Amia calva (bowfin) has been used to support the homology of lungs and gas bladders, collectively termed air-filled organs (AO). However, the homology of pulmonary arteries in bowfin and lunged osteichthyans has been uncertain, given the apparent lack of pulmonary arteries in critical taxa. To re-evaluate the homology of pulmonary arteries in bowfin and lunged osteichthyans, we studied, using micro-CT technology, the arterial vasculature of Protopterus, Polypterus, Acipenser, Polyodon, Amia, and Lepisosteus, and analyzed these data using a phylogenetic approach. Our data reveal that Acipenser and Polyodon have paired posterior branches of the fourth efferent branchial arteries, which are thus similar in origin to pulmonary arteries. We hypothesize that these arteries are vestigial pulmonary arteries that have been coopted for new functions due to the dorsal shift of the AO and/or the loss of respiration in these taxa. Ancestral state reconstructions support pulmonary arteries as a synapomorphy of the Osteichthyes, provide the first concrete evidence for the retention of pulmonary arteries in Amia, and support thehomology of lungs and gas bladders due to a shared vascular supply. Finally, we use ancestral state reconstructions to show that arterial AO supplies from the celiacomesenteric artery or dorsal aorta appear to be convergent between teleosts and

  12. Differences in vasculature between pilocytic and anaplastic astrocytomas of childhood.

    PubMed

    Gesundheit, Benjamin; Klement, Giannoula; Senger, Christof; Kerbel, Robert; Kieran, Mark; Baruchel, Sylvain; Becker, Laurence

    2003-12-01

    The clinical manifestations of childhood pilocytic astrocytoma (PA) and anaplastic astrocytoma (AA) markedly differ, especially in the time to progression and prognosis. Because of the aggressive course and poor survival rate of AA, one would expect it to be associated with a high angiogenic index. Counterintuitively, we often find higher microvessel density counts in PA than in AA. We examined the differences in type or density of microvasculature between the two neoplasms. To differentiate established, mature vessels from immature growing ones, we used antibodies to Factor VIII (FVIII) to stain endothelial cells (ECs) of blood vessels and alpha-smooth muscle actin (alpha-SMA) antibodies to stain vessels supported by adventitia. We found that large, mature, alpha-SMA-positive vessels predominated in PA, and small, immature, alpha-SMA-negative vessels in AA. The vessel maturation index was 54.5% for PA, and 6.1% for AA. Immunostaining with vascular endothelial growth factor (VEGF) and anti-flt-1/VEGF receptor-1 antibodies showed distinct tissue patterns. VEGF immunoreactivity occurred mainly in the processes of the tumor astrocytes in PA; the opposite was observed in AA. flt-1/VEGFR-1 was detected in the tumor cells of AA but not in those of PA. We propose that the predominance of small, alpha-SMA-negative vessels in AA represents immature, unstable vasculature with a potentially greater susceptibility to anti-angiogenic therapy. The expression of both flt-1 and VEGF by AA tumor cells also suggests a possible autocrine growth-promoting function for VEGF in addition to its role as paracrine pro-angiogenic growth factor for activated ECs, thus making anti-angiogenesis an attractive therapeutic target in the treatment of AA. Copyright 2003 Wiley-Liss, Inc.

  13. Multiscale modelling of the feto–placental vasculature

    PubMed Central

    Clark, A. R.; Lin, M.; Tawhai, M.; Saghian, R.; James, J. L.

    2015-01-01

    The placenta provides all the nutrients required for the fetus through pregnancy. It develops dynamically, and, to avoid rejection of the fetus, there is no mixing of fetal and maternal blood; rather, the branched placental villi ‘bathe’ in blood supplied from the uterine arteries. Within the villi, the feto–placental vasculature also develops a complex branching structure in order to maximize exchange between the placental and maternal circulations. To understand the development of the placenta, we must translate functional information across spatial scales including the interaction between macro- and micro-scale haemodynamics and account for the effects of a dynamically and rapidly changing structure through the time course of pregnancy. Here, we present steps towards an anatomically based and multiscale approach to modelling the feto–placental circulation. We assess the effect of the location of cord insertion on feto–placental blood flow resistance and flow heterogeneity and show that, although cord insertion does not appear to directly influence feto–placental resistance, the heterogeneity of flow in the placenta is predicted to increase from a 19.4% coefficient of variation with central cord insertion to 23.3% when the cord is inserted 2 cm from the edge of the placenta. Model geometries with spheroidal and ellipsoidal shapes, but the same volume, showed no significant differences in flow resistance or heterogeneity, implying that normal asymmetry in shape does not affect placental efficiency. However, the size and number of small capillary vessels is predicted to have a large effect on feto–placental resistance and flow heterogeneity. Using this new model as an example, we highlight the importance of taking an integrated multi-disciplinary and multiscale approach to understand development of the placenta. PMID:25844150

  14. Multiscale modelling of the feto-placental vasculature.

    PubMed

    Clark, A R; Lin, M; Tawhai, M; Saghian, R; James, J L

    2015-04-06

    The placenta provides all the nutrients required for the fetus through pregnancy. It develops dynamically, and, to avoid rejection of the fetus, there is no mixing of fetal and maternal blood; rather, the branched placental villi 'bathe' in blood supplied from the uterine arteries. Within the villi, the feto-placental vasculature also develops a complex branching structure in order to maximize exchange between the placental and maternal circulations. To understand the development of the placenta, we must translate functional information across spatial scales including the interaction between macro- and micro-scale haemodynamics and account for the effects of a dynamically and rapidly changing structure through the time course of pregnancy. Here, we present steps towards an anatomically based and multiscale approach to modelling the feto-placental circulation. We assess the effect of the location of cord insertion on feto-placental blood flow resistance and flow heterogeneity and show that, although cord insertion does not appear to directly influence feto-placental resistance, the heterogeneity of flow in the placenta is predicted to increase from a 19.4% coefficient of variation with central cord insertion to 23.3% when the cord is inserted 2 cm from the edge of the placenta. Model geometries with spheroidal and ellipsoidal shapes, but the same volume, showed no significant differences in flow resistance or heterogeneity, implying that normal asymmetry in shape does not affect placental efficiency. However, the size and number of small capillary vessels is predicted to have a large effect on feto-placental resistance and flow heterogeneity. Using this new model as an example, we highlight the importance of taking an integrated multi-disciplinary and multiscale approach to understand development of the placenta.

  15. In Vivo Photoacoustic Imaging of Anterior Ocular Vasculature: A Random Sample Consensus Approach.

    PubMed

    Jeon, Seungwan; Song, Hyun Beom; Kim, Jaewoo; Lee, Byung Joo; Managuli, Ravi; Kim, Jin Hyoung; Kim, Jeong Hun; Kim, Chulhong

    2017-06-28

    Visualizing ocular vasculature is important in clinical ophthalmology because ocular circulation abnormalities are early signs of ocular diseases. Photoacoustic microscopy (PAM) images the ocular vasculature without using exogenous contrast agents, avoiding associated side effects. Moreover, 3D PAM images can be useful in understanding vessel-related eye disease. However, the complex structure of the multi-layered vessels still present challenges in evaluating ocular vasculature. In this study, we demonstrate a new method to evaluate blood circulation in the eye by combining in vivo PAM imaging and an ocular surface estimation method based on a machine learning algorithm: a random sample consensus algorithm. By using the developed estimation method, we were able to visualize the PA ocular vascular image intuitively and demonstrate layer-by-layer analysis of injured ocular vasculature. We believe that our method can provide more accurate evaluations of the eye circulation in ophthalmic applications.

  16. [(3) H]-L685,458 binding sites are abundant in multiple peripheral organs in rats: implications for safety assessment of putative γ-secretase targeting drugs.

    PubMed

    Yang, Zhi-Ying; Li, Jian-Ming; Xiao, Ling; Mou, Lin; Cai, Yan; Huang, He; Luo, Xue-Gang; Yan, Xiao-Xin

    2014-12-01

    γ-Secretase is a multimeric enzyme complex that carries out proteolytic processing to a variety of cellular proteins. It is currently explored as a therapeutic target for Alzheimer's disease (AD) and cancer. Mechanism-based toxicity needs to be thoroughly evaluated for γ-secretase inhibitory and/or modulatory drugs. This study comparatively assessed putative γ-secretase catalytic sites in rat peripheral tissues relative to brain and explored an effort of its pharmacological inhibition on hair regeneration. Using [(3) H]-labelled L685,458, a potent γ-secretase inhibitor, as probe, we found more abundant presence of γ-secretase binding sites in the liver, gastrointestinal tract, hair follicle, pituitary gland, ovary and testis, as compared to the brain. Local application of L658,458 delayed vibrissal regrowth following whisker removal. These results suggest that γ-secretase may execute important biological functions in many peripheral systems, as in the brain. The development of γ-secretase inhibitors/modulators for AD and cancer therapy should include close monitoring of toxicological panels for hepatic, gastrointestinal, endocrinal and reproductive functions.

  17. Daily expression of genes coding for neurotransmitters in central and peripheral tissues of redheaded bunting: Implication for circadian regulation of physiology in songbirds.

    PubMed

    Mishra, Ila; Singh, Devraj; Kumar, Vinod

    2016-01-01

    In birds, circadian control of tissue level communication is not well understood. The present study investigated this, by monitoring daily oscillation of genes coding for peptides (neuropeptide Y, NPY; vasoactive intestinal peptide, VIP; somatostatis, SST) and intermediary enzymes of amine and amino acid neurotransmitters (dopamine [tyrosine hydroxylase, TH]; glutamate [glutaminase, GLS; glutamate oxaloacetate transaminase 2, GOT2]; gamma amino butyric actid, GABA [glutamic acid decarboxylase 65, GAD65]) biosynthetic pathway, along with c-FOS as an activation marker, in different tissues of migratory redheaded buntings, Emberiza bruniceps. We cloned a partial sequence of these genes, and measured their mRNA expression in the 'central' clock (retina, hypothalamus) and peripheral (heart, stomach, gut, liver) tissues, collected at six times (ZT 2, 6, 11, 13, 18 and 23; ZT 0 = lights on) from birds (n = 4/ ZT) in the 12 h:12 h light-dark cycle. There were daily mRNA oscillations of all genes, although with a tissue-specific expression pattern as well as with the differential phase relationships in genes within and between tissues. These results support a conserved tissue level circadian regulation of genes coding for peptide, amine and amino acid neurotransmitters, and substantiate the expression and plausible role of neurotransmitters in the peripheral tissues. We suggest a tissue-specific contribution of neurotransmitters in the circadian regulation of physiology and behaviour in a seasonal migratory species, the redheaded bunting.

  18. Current status of high on-treatment platelet reactivity in patients with coronary or peripheral arterial disease: Mechanisms, evaluation and clinical implications

    PubMed Central

    Spiliopoulos, Stavros; Pastromas, Georgios

    2015-01-01

    Antiplatelet therapy with aspirin or clopidogrel or both is the standard care for patients with proven coronary or peripheral arterial disease, especially those undergoing endovascular revascularization procedures. However, despite the administration of the antiplatelet regiments, some patients still experience recurrent cardiovascular ischemic events. So far, it is well documented by several studies that in vitro response of platelets may be extremely variable. Poor antiplatelet effect of clopidogrel or high on-treatment platelet reactivity (HTPR) is under investigation by numerous recent studies. This review article focuses on methods used for the ex vivo evaluation of HTPR, as well as on the possible underlying mechanisms and the clinical consequences of this entity. Alternative therapeutic options and future directions are also addressed. PMID:26730297

  19. Peripheral Retinal Vascular Patterns in Patients with Rhegmatogenous Retinal Detachment in Taiwan

    PubMed Central

    Chen, San-Ni; Hwang, Jiunn-Feng; Wu, Wen-Chuan

    2016-01-01

    This is an observational study of fluorescein angiography (FA) in consecutive patients with rhegmatogenous retinal detachment (RRD) in Changhua Christian Hospital to investigate the peripheral retinal vascular patterns in those patients. All patients had their age, sex, axial length (AXL), and refraction status (RF) recorded. According to the findings in FA of the peripheral retina, the eyes were divided into 4 groups: in group 1, there was a ramified pattern of peripheral retinal vasculature with gradual tapering; in group 2, there was an abrupt ending of peripheral vasculature with peripheral non-perfusion; in group 3, there was a curving route of peripheral vasculature forming vascular arcades or anastomosis; and in group 4, the same as in group 3, but with one or more wedge-shaped avascular notches. Comparisons of age, sex, AXL, and RF, association of breaks with lattice degeneration and retinal non-perfusion, surgical procedures utilized, and mean numbers of operations were made among the four groups. Of the 73 eyes studied, there were 13 eyes (17.8%) in group 1, 3 eyes (4.1%) in group 2, 40 eyes (54.8%) in group 3 and 17 eyes (23.3%) in group 4. Significant differences in age, AXL and RF, and association of retinal breaks to non-perfusion were noted among the four groups. Patients in group 1 had older ages, while younger ages were noted in groups 3 and 4. Eyes in group 1 had the shortest average AXL and were least myopic in contrast to the eyes in groups 3 and 4. Association of retinal breaks and retinal non-perfusion was significantly higher in groups 2, 3 and 4 than in group 1. In conclusion, peripheral vascular anomalies are common in cases with RRD. Patients with peripheral non-perfusion tend to be younger, with longer axial length and have the breaks associated with retinal non-perfusion. PMID:26909812

  20. Specific mediator inhibition by the NO donors SNP and NCX 2057 in the peripheral lung: implications for allergen-induced bronchoconstriction

    PubMed Central

    Larsson, Anna-Karin; Bäck, Magnus; Lundberg, Jon O; Dahlén, Sven-Erik

    2009-01-01

    Background The aim of this study was to examine potential therapeutic effect of the two NO donors NCX 2057 (3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid) 4-(nitrooxy)butyl ester) and SNP (sodium nitroprusside) on the early allergic airway response in the peripheral lung. Methods The experiments were performed in guinea pig lung parenchyma (GPLP) derived from ovalbumin (OVA) sensitized guinea pigs. The effects of NCX 2057 and SNP were evaluated by contractile responses and mediator release during OVA challenge. The generation of nitrite and nitrate was assessed by chemiluminescence. Statistical analysis was evaluated by ANOVA. Results Cumulatively increasing concentrations of OVA (1–10,000 ng/ml) induced concentration-dependent contractions of the GPLP that were reduced by NCX 2057 (100 μM, p < 0.001) and SNP (100 μM, p < 0.05). Antigen-induced eicosanoid release was decreased by NCX 2057 (100 μM, p < 0.001) but not by SNP (100 μM), whereas the release of histamine was reduced by SNP (100 μM, p < 0.001) but not by NCX 2057 (100 μM). In addition, NCX 2057 (0.1–100 μM), but not SNP (0.1–100 μM), relaxed leukotriene D4 (10 nM) precontracted GPLP (p < 0.01). The guanylyl cyclase inhibitor ODQ had no effect on the NCX 2057 mediated relaxation. SNP released significantly less nitrite than NCX 2057. Conclusion Although both SNP and NCX 2057 reduced the release of pro-inflammatory mediators, their profiles were distinctly different. Furthermore, NCX 2057 also induced smooth muscle dilation in the GPLP. The findings point to specific anti-inflammatory effects of different NO donors in the peripheral lung tissue. PMID:19493362

  1. Effects of simulated neural mobilization on fluid movement in cadaveric peripheral nerve sections: implications for the treatment of neuropathic pain and dysfunction

    PubMed Central

    Roger James, C.; Apte, Gail; Brown, Cynthia; Sizer, Phillip S.; Brismée, Jean-Michel; Smith, Michael P.

    2015-01-01

    Background and purpose Neural mobilization techniques are used clinically to treat neuropathic pain and dysfunction. While selected studies report efficacy of these techniques, the mechanisms of benefit are speculative. The purpose of this study was to evaluate the effects of in vitro simulated stretch/relax neural mobilization cycles on fluid dispersion within sections of unembalmed cadaveric peripheral nerve tissue. Methods Bilateral sciatic nerve sections were harvested from six cadavers. Matched pairs of nerve sections were secured in a tissue tester and injected with a plasma/Toluidine Blue dye solution. Once the initial dye spread stabilized, the experimental nerve sections underwent 25 stretch/relaxation cycles (e.g. simulated neural mobilization) produced by a mechanical tissue tester. Post-test dye spread measurements were compared to pre-test measurements as well as control findings (no simulated mobilization). Data were analyzed using paired t-tests. Results Individual dye spread measurements were reliable [ICC(3,1) = 0·99]. The post-test intraneural fluid movement (dye spread) in the experimental section increased significantly with simulated neural mobilization compared to pre-test measurements (3·2±2·1 mm; P = 0·015) and control measurements (3·3±2·7 mm; P = 0·013). Conclusion Repetitive simulated neural mobilization, incorporating stretch/relax cycles, of excised cadaveric peripheral nerve tissue produced an increase in intraneural fluid dispersion. Neural mobilization may alter nerve tissue environment, promoting improved function and nerve health, by dispersing tissue fluid and diminishing intraneural swelling and/or pressure. PMID:26917940

  2. Percentage of Peripheral CD19+CD24hiCD38hi Regulatory B Cells in Neonatal Sepsis Patients and Its Functional Implication.

    PubMed

    Pan, Xiao; Ji, Zuoquan; Xue, Jiang

    2016-07-07

    BACKGROUND As a major cause of mortality in neonates, neonatal sepsis is often accompanied by immune dysfunctions, which are frequently caused by dysregulated T cell sub-populations. The role of regulatory B cells in neonatal sepsis, however, remains unknown. Therefore, this study investigated the percentage and functional variation of CD19+CD24hiCD38hi regulatory B cells in peripheral blood of neonatal sepsis patients in an attempt to elucidate the role of these regulatory B cells in pathogenesis of sepsis. MATERIAL AND METHODS Flow cytometry was used to quantify the percentage of CD19+CD24hiCD38hi regulatory B cells from peripheral blood samples. The correlation between B cell percentage and C reactive protein (CRP) level was analyzed. Secretion level of interleukin-10 (IL-10) and effects on the proliferation of naïve CD4+ T cells were further analyzed. RESULTS The percentage of CD19+CD24hiCD38hi regulatory B cells in neonatal sepsis patients was significantly higher compared to healthy controls (p<0.05), and was positively correlated with serum CRP level. The percentage of IL-10+ CD19+CD24hiCD38hi regulatory B cells was also higher in sepsis patients, and also had more potent inhibition on naïve CD4+ T cells (p<0.01). CONCLUSIONS The elevation of CD19+CD24hiCD38hi regulatory B cells in neonatal sepsis can inhibit body immune function and thus may participate in the pathogenesis of sepsis.

  3. Effects of simulated neural mobilization on fluid movement in cadaveric peripheral nerve sections: implications for the treatment of neuropathic pain and dysfunction.

    PubMed

    Gilbert, Kerry K; Roger James, C; Apte, Gail; Brown, Cynthia; Sizer, Phillip S; Brismée, Jean-Michel; Smith, Michael P

    2015-09-01

    Neural mobilization techniques are used clinically to treat neuropathic pain and dysfunction. While selected studies report efficacy of these techniques, the mechanisms of benefit are speculative. The purpose of this study was to evaluate the effects of in vitro simulated stretch/relax neural mobilization cycles on fluid dispersion within sections of unembalmed cadaveric peripheral nerve tissue. Bilateral sciatic nerve sections were harvested from six cadavers. Matched pairs of nerve sections were secured in a tissue tester and injected with a plasma/Toluidine Blue dye solution. Once the initial dye spread stabilized, the experimental nerve sections underwent 25 stretch/relaxation cycles (e.g. simulated neural mobilization) produced by a mechanical tissue tester. Post-test dye spread measurements were compared to pre-test measurements as well as control findings (no simulated mobilization). Data were analyzed using paired t-tests. Individual dye spread measurements were reliable [ICC(3,1) = 0·99]. The post-test intraneural fluid movement (dye spread) in the experimental section increased significantly with simulated neural mobilization compared to pre-test measurements (3·2±2·1 mm; P = 0·015) and control measurements (3·3±2·7 mm; P = 0·013). Repetitive simulated neural mobilization, incorporating stretch/relax cycles, of excised cadaveric peripheral nerve tissue produced an increase in intraneural fluid dispersion. Neural mobilization may alter nerve tissue environment, promoting improved function and nerve health, by dispersing tissue fluid and diminishing intraneural swelling and/or pressure.

  4. Retinal vessel caliber and peripheral neuropathy in diabetic participants.

    PubMed

    Sabanayagam, Charumathi; Tai, E Shyong; Lee, Jeannette; Lim, Su Chi; Wong, Tien Yin

    2010-05-01

    Retinal vascular caliber changes predict diabetic microvascular complications such as retinopathy, and nephropathy. However, the association between retinal vasculature and peripheral neuropathy is not well studied. We evaluated the association between retinal vascular caliber and peripheral neuropathy in a multi-ethnic Asian population with diabetes (n = 423) in Singapore. Retinal arteriolar and venular caliber was measured from digital retinal photographs and summarized as central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent. Peripheral neuropathy was defined from neurothesiometer or monofilament sensory testing. Larger CRAE was positively associated with peripheral neuropathy independent of age, sex, ethnicity, current smoking, alcohol consumption, body mass index, total cholesterol, systolic blood pressure, and duration of diabetes. The multivariable odds ratio (OR) [95% confidence interval (CI)] of peripheral neuropathy was 2.81 (1.38-5.73) comparing highest vs. lower three quartiles of CRAE. This association was consistently present in analyses stratified by age, sex and ethnicity. Retinal venular caliber was not associated with peripheral neuropathy. These data suggest that larger retinal arteriolar diameters are associated with peripheral neuropathy independent of major risk factors.

  5. In vivo transcriptional targeting into the retinal vasculature using recombinant baculovirus carrying the human flt-1 promoter

    PubMed Central

    Luz-Madrigal, Agustín; Clapp, Carmen; Aranda, Jorge; Vaca, Luis

    2007-01-01

    Background Endothelial cells are a target for gene therapy because they are implicated in a number of vascular diseases. Recombinant baculovirus have emerged as novel gene delivery vectors. However, there is no information available concerning the use of endothelial-specific promoters in the context of the baculovirus genome. In the present study, we have generated a recombinant baculovirus containing the human flt-1 promoter (BacFLT-GFP) driving the expression of the green fluorescent protein. Transcriptional gene targeting was analyzed in vitro in different mammalian cell lines and in vivo in adult rat retinal vasculature. Results BacFLT-GFP evoked the highest levels of expression in the endothelial cell line BUVEC-E6E7-1, similar to those reached by recombinant baculovirus carrying the CMV promoter (112% relative to BacCMV-GFP, n = 4). Interestingly, BacFLT-GFP directed high levels of expression in rat glioma C6 and in human glioblastoma CH235 cells (34.78% and 47.86% relative to BacCMV-GFP, respectively). Histone deacetylase inhibitors such as butyrate or trichostatin A enhanced the transcriptional activity of both BacCMV-GFP and BacFLT-GFP. Thus, in this study histone deacetylation appears to be a central mechanism for the silencing of baculovirus, independently of the promoter utilized. In vivo transcriptional targeting was demonstrated in adult rat retinal vasculature by intravitreal delivery of BacFLT-GFP and immunohistochemical staining with von Willebrand factor (vWF). Analysis by fluorescence microscopy and deconvolved three-dimensional confocal microscopy of retinal whole mounts obtained after 3 days of baculovirus injection showed that most GFP-expressing cells localized to the inner limiting membrane (ILM) and ganglion cell layer (GCL) and colocalize with vWF (70%, n = 10) in blood vessels, confirming the endothelial phenotype of the transduced cells. Conclusion Taken together, our results indicate that the restricted expression in endothelial cells

  6. Reevaluating and Refining Peripherality.

    ERIC Educational Resources Information Center

    Thomas, Erik R.

    The idea that vowel nuclei in many northern European languages can be divided into peripheral and non-peripheral categories is discussed. Peripheral vowels are those located at the edge of the vowel envelope, and non-peripheral nuclei are those located on the inside. This assertion has not received as much scrutiny as it should. There are at least…

  7. Direct interactions of androgenic/anabolic steroids with the peripheral benzodiazepine receptor in rat brain: implications for the psychological and physiological manifestations of androgenic/anabolic steroid abuse.

    PubMed

    Masonis, A E; McCarthy, M P

    1996-08-01

    The peripheral benzodiazepine receptor (PBR) is a mitochondrial protein involved in regulating steroid synthesis and transport. We report here the effects of androgenic/anabolic steroids (AAS) on the binding of the PBR-specific ligand [3H] PK11195 to male rat brain cortical synaptoneurosomes. Two synthetic AAS, stanozolol and 17beta-testosterone cypionate (17beta-cyp), significantly inhibited 1 nM [3H] PK11195 binding at concentrations greater than 5 and 25 microM, respectively. Stanozolol was the most effective inhibitor, reducing [3H] PK11195 binding by up to 75%, compared to only 40% inhibition by 17beta-cyp, at 50 microM AAS concentration. Two other AAS, 17alpha-methyltestosterone and nortestosterone decanoate, were incapable of inhibiting [3H] PK11195 binding at concentrations up to 50 microM. On the basis of Scatchard/Rosenthal analysis, [3H] PK11195 binds to two classes of binding sites, and the inhibition of [3H] PK11195 binding by stanozolol appears to be allosteric, primarily reducing binding to the higher affinity [3H] PK11195 binding site. These results, in combination with earlier studies indicating the direct effects of AAS on the function of additional central nervous system receptor complexes, suggest that the behavioral and psychological effects of AAS result from the interactions of AAS with multiple regulatory systems in the brain.

  8. Disruption of miR-29 Leads to Aberrant Differentiation of Smooth Muscle Cells Selectively Associated with Distal Lung Vasculature.

    PubMed

    Cushing, Leah; Costinean, Stefan; Xu, Wei; Jiang, Zhihua; Madden, Lindsey; Kuang, Pingping; Huang, Jingshu; Weisman, Alexandra; Hata, Akiko; Croce, Carlo M; Lü, Jining

    2015-05-01

    Differentiation of lung vascular smooth muscle cells (vSMCs) is tightly regulated during development or in response to challenges in a vessel specific manner. Aberrant vSMCs specifically associated with distal pulmonary arteries have been implicated in the pathogenesis of respiratory diseases, such as pulmonary arterial hypertension (PAH), a progressive and fatal disease, with no effective treatment. Therefore, it is highly relevant to understand the underlying mechanisms of lung vSMC differentiation. miRNAs are known to play critical roles in vSMC maturation and function of systemic vessels; however, little is known regarding the role of miRNAs in lung vSMCs. Here, we report that miR-29 family members are the most abundant miRNAs in adult mouse lungs. Moreover, high levels of miR-29 expression are selectively associated with vSMCs of distal vessels in both mouse and human lungs. Furthermore, we have shown that disruption of miR-29 in vivo leads to immature/synthetic vSMC phenotype specifically associated with distal lung vasculature, at least partially due to the derepression of KLF4, components of the PDGF pathway and ECM-related genes associated with synthetic phenotype. Moreover, we found that expression of FBXO32 in vSMCs is significantly upregulated in the distal vasculature of miR-29 null lungs. This indicates a potential important role of miR-29 in smooth muscle cell function by regulating FBXO32 and SMC protein degradation. These results are strongly supported by findings of a cell autonomous role of endogenous miR-29 in promoting SMC differentiation in vitro. Together, our findings suggested a vessel specific role of miR-29 in vSMC differentiation and function by targeting several key negative regulators.

  9. Disruption of miR-29 Leads to Aberrant Differentiation of Smooth Muscle Cells Selectively Associated with Distal Lung Vasculature

    PubMed Central

    Xu, Wei; Jiang, Zhihua; Madden, Lindsey; Kuang, Pingping; Huang, Jingshu; Weisman, Alexandra; Hata, Akiko; Croce, Carlo M.; Lü, Jining

    2015-01-01

    Differentiation of lung vascular smooth muscle cells (vSMCs) is tightly regulated during development or in response to challenges in a vessel specific manner. Aberrant vSMCs specifically associated with distal pulmonary arteries have been implicated in the pathogenesis of respiratory diseases, such as pulmonary arterial hypertension (PAH), a progressive and fatal disease, with no effective treatment. Therefore, it is highly relevant to understand the underlying mechanisms of lung vSMC differentiation. miRNAs are known to play critical roles in vSMC maturation and function of systemic vessels; however, little is known regarding the role of miRNAs in lung vSMCs. Here, we report that miR-29 family members are the most abundant miRNAs in adult mouse lungs. Moreover, high levels of miR-29 expression are selectively associated with vSMCs of distal vessels in both mouse and human lungs. Furthermore, we have shown that disruption of miR-29 in vivo leads to immature/synthetic vSMC phenotype specifically associated with distal lung vasculature, at least partially due to the derepression of KLF4, components of the PDGF pathway and ECM-related genes associated with synthetic phenotype. Moreover, we found that expression of FBXO32 in vSMCs is significantly upregulated in the distal vasculature of miR-29 null lungs. This indicates a potential important role of miR-29 in smooth muscle cell function by regulating FBXO32 and SMC protein degradation. These results are strongly supported by findings of a cell autonomous role of endogenous miR-29 in promoting SMC differentiation in vitro. Together, our findings suggested a vessel specific role of miR-29 in vSMC differentiation and function by targeting several key negative regulators. PMID:26020233

  10. ADAM12 is expressed in the tumour vasculature and mediates ectodomain shedding of several membrane-anchored endothelial proteins.

    PubMed

    Fröhlich, Camilla; Klitgaard, Marie; Noer, Julie B; Kotzsch, Alexander; Nehammer, Camilla; Kronqvist, Pauliina; Berthelsen, Jens; Blobel, Carl; Kveiborg, Marie; Albrechtsen, Reidar; Wewer, Ulla M

    2013-05-15

    ADAM (a disintegrin and metalloproteinase) 12 is a metalloprotease implicated in cancer progression. ADAM12 can activate membrane-anchored proteins, such as sonic hedgehog, Delta-like 1 and certain epidermal growth factor receptor ligands, through a process called ectodomain shedding. We screened several membrane-anchored proteins to further dissect the substrate profile of ADAM12-mediated ectodomain shedding, and found shedding of five previously unreported substrates [Kitl1, VE-cadherin (vascular endothelial cadherin), Flk-1 (fetal liver kinase 1), Tie-2, and VCAM-1 (vascular cell adhesion molecule 1)], of which the latter four are specifically expressed by endothelial cells. We also observed that ADAM12 expression was increased in the tumour vasculature of infiltrating ductal carcinoma of the human breast as compared with little to no expression in normal breast tissue vasculature, suggesting a role for ADAM12 in tumour vessels. These results prompted us to further evaluate ADAM12-mediated shedding of two endothelial cell proteins, VE-cadherin and Tie-2. Endogenous ADAM12 expression was very low in cultured endothelial cells, but was significantly increased by cytokine stimulation. In parallel, the shed form of VE-cadherin was elevated in such cytokine-stimulated endothelial cells, and ADAM12 siRNA (small interfering RNA) knockdown reduced cytokine-induced shedding of VE-cadherin. In conclusion, the results of the present study demonstrate a role for ADAM12 in ectodomain shedding of several membrane-anchored endothelial proteins. We speculate that this process may have importance in tumour neovascularization or/and tumour cell extravasation.

  11. CLARITY reveals dynamics of ovarian follicular architecture and vasculature in three-dimensions

    PubMed Central

    Feng, Yi; Cui, Peng; Lu, Xiaowei; Hsueh, Brian; Möller Billig, Fredrik; Zarnescu Yanez, Livia; Tomer, Raju; Boerboom, Derek; Carmeliet, Peter; Deisseroth, Karl; Hsueh, Aaron J. W.

    2017-01-01

    Optimal distribution of heterogeneous organelles and cell types within an organ is essential for physiological processes. Unique for the ovary, hormonally regulated folliculogenesis, ovulation, luteal formation/regression and associated vasculature changes lead to tissue remodeling during each reproductive cycle. Using the CLARITY approach and marker immunostaining, we identified individual follicles and corpora lutea in intact ovaries. Monitoring lifetime changes in follicle populations showed age-dependent decreases in total follicles and percentages of advanced follicles. Follicle development from primordial to preovulatory stage was characterized by 3 × 105-fold increases in volume, decreases in roundness, and decreased clustering of same stage follicles. Construction of follicle-vasculature relationship maps indicated age- and gonadotropin-dependent increases in vasculature and branching surrounding follicles. Heterozygous mutant mice with deletion of hypoxia-response element in the vascular endothelial growth factor A (VEGFA) promoter showed defective ovarian vasculature and decreased ovulatory responses. Unilateral intrabursal injection of axitinib, an inhibitor of VEGF receptors, retarded neo-angiogenesis that was associated with defective ovulation in treated ovaries. Our approach uncovers unique features of ovarian architecture and essential roles of vasculature in organizing follicles to allow future studies on normal and diseased human ovaries. Similar approaches could also reveal roles of neo-angiogenesis during embryonic development and tumorigenesis. PMID:28333125

  12. Computer Simulations of the Tumor Vasculature: Applications to Interstitial Fluid Flow, Drug Delivery, and Oxygen Supply.

    PubMed

    Welter, Michael; Rieger, Heiko

    2016-01-01

    Tumor vasculature, the blood vessel network supplying a growing tumor with nutrients such as oxygen or glucose, is in many respects different from the hierarchically organized arterio-venous blood vessel network in normal tissues. Angiogenesis (the formation of new blood vessels), vessel cooption (the integration of existing blood vessels into the tumor vasculature), and vessel regression remodel the healthy vascular network into a tumor-specific vasculature. Integrative models, based on detailed experimental data and physical laws, implement, in silico, the complex interplay of molecular pathways, cell proliferation, migration, and death, tissue microenvironment, mechanical and hydrodynamic forces, and the fine structure of the host tissue vasculature. With the help of computer simulations high-precision information about blood flow patterns, interstitial fluid flow, drug distribution, oxygen and nutrient distribution can be obtained and a plethora of therapeutic protocols can be tested before clinical trials. This chapter provides an overview over the current status of computer simulations of vascular remodeling during tumor growth including interstitial fluid flow, drug delivery, and oxygen supply within the tumor. The model predictions are compared with experimental and clinical data and a number of longstanding physiological paradigms about tumor vasculature and intratumoral solute transport are critically scrutinized.

  13. Trapping and dynamic manipulation with magnetomotive photoacoustic imaging of targeted microspheres mimicking metastatic cancer cells trafficking in the vasculature

    NASA Astrophysics Data System (ADS)

    Wei, Chenwei; Xia, Jinjun; Pelivanov, Ivan; Hu, Xiaoge; Gao, Xiaohu; O'Donnell, Matthew

    2012-02-01

    Trapping and manipulation of micro-scale objects mimicking metastatic cancer cells in a flow field have been demonstrated with magnetomotive photoacoustic (mmPA) imaging. Coupled contrast agents combining gold nanorods (15 nm × 50 nm; absorption peak around 730 nm) with 15 nm diameter magnetic nanospheres were targeted to 10 μm polystyrene beads recirculating in a 1.6 mm diameter tube mimicking a human peripheral vessel. Targeted objects were then trapped by an external magnetic field produced by a dual magnet system consisting of two disc magnets separated by 6 cm to form a polarizing field (0.04 Tesla in the tube region) to magnetize the magnetic contrast agents, and a custom designed cone magnet array with a high magnetic field gradient (about 0.044 Tesla/mm in the tube region) producing a strong trapping force to magnetized contrast agents. Results show that polystyrene beads linked to nanocomposites can be trapped at flow rates up to 12 ml/min. It is shown that unwanted background in a photoacoustic image can be significantly suppressed by changing the position of the cone magnet array with respect to the tube, thus creating coherent movement of the trapped objects. This study makes mmPA imaging very promising for differential visualization of metastatic cells trafficking in the vasculature.

  14. The high affinity peripheral benzodiazepine receptor ligand DAA1106 binds specifically to microglia in a rat model of traumatic brain injury: implications for PET imaging

    PubMed Central

    Venneti, Sriram; Wagner, Amy K.; Wang, Guoji; Slagel, Susan L.; Chen, Xiangbai; Lopresti, Brian J.; Mathis, Chester A.; Wiley., Clayton A.

    2007-01-01

    Traumatic brain injury (TBI) is a significant cause of mortality, morbidity, and disability. Microglial activation is commonly observed in response to neuronal injury which, when prolonged, is thought to be detrimental to neuronal survival. Activated microglia can be labeled using PK11195, a ligand that bind the peripheral benzodiazepine receptor (PBR), receptors which are highly expressed in activated microglia and sparse in the resting brain. We compared the binding properties of two PBR ligands PK11195 and DAA1106 in rats using the controlled cortical impact (CCI) model of experimental TBI. While both ligands showed relative increases with specific binding in the cortex ipsilateral to injury compared to the contralateral side, [3H]DAA1106 showed higher binding affinity compared with [3H](R)-PK11195. Combined immunohistochemistry and autoradiography in brain tissues near the injury site showed that [3H]DAA1106 binding co-registered with activated microglia more than astrocytes. Further, increased [3H]DAA1106 specific binding positively correlated with degree of microglial activation, and to a lesser degree with reactive astrocytosis. Finally, in vivo administration of each ligand in rats with TBI showed greater retention of [11C]DAA1106 compared to [11C](R)-PK11195 at the site of the contusion as assessed by ex vivo autoradiography. These results in a rat model of TBI indicate that [11C]DAA1106 binds with higher affinity to microglia when compared with PK11195, suggesting that [11C]DAA1106 may represent a better ligand than [11C](R)-PK11195 for in vivo PET imaging of activated microglia in TBI. PMID:17658516

  15. Kinetics and functional implications of Th1 and Th2 cytokine production following activation of peripheral blood mononuclear cells in primary culture.

    PubMed

    McHugh, S; Deighton, J; Rifkin, I; Ewan, P

    1996-06-01

    The importance of cytokine production in some disease processes is now widely recognized. To investigate temporal relationships between cytokines, we stimulated peripheral blood mononuclear cells (PBMC) in vitro using the T cell mitogen phytohemagglutinin (PHA) and various antigens chosen to induce predominantly Th1 (streptokinase: streptodornase or purified protein derivative) or Th2 (Dermatophagoides pteronyssinus, bee or wasp venom: allergens in sensitive subjects) responses. Cytokine production was measured by sensitive bioassays or enzyme-linked immunosorbent assays. Of the 30 subjects studied, 10 were normal and 20 individuals were allergic to either D. pteronyssinus (n = 10) or bee venom (n = 10) (examined before specific allergen immunotherapy). We examined the temporal profiles of a panel of cytokines produced in primary culture. In PHA-driven cultures, cytokines were found to be sequentially produced in the order interleukin (IL)-2, IL-4, IL-5, IL-3, interferon (IFN)-gamma, IL-10, IL-6, IL-12 and tumor necrosis factor (TNF)-alpha. The response to allergen in allergic patients was predominantly Th2 in nature, with the production of IL-4, IL-5, IL-6 and IL-10, but little or no IFN-gamma. IL-2, IL-3, TNF-alpha and IL-12 were also produced in low amounts. The response of both atopic and normal subjects to recall bacterial antigens was predominantly Th1, with high levels of IFN-gamma, IL-2 and TNF-alpha. The relevance of the order, amount and speed of production, characteristic kinetics (production, consumption, homeostatic regulation) and the cell source of the cytokines are discussed.

  16. Effects of eribulin, vincristine, paclitaxel and ixabepilone on fast axonal transport and kinesin-1 driven microtubule gliding: Implications for chemotherapy-induced peripheral neuropathy

    PubMed Central

    LaPointe, Nichole E.; Morfini, Gerardo; Brady, Scott T.; Feinstein, Stuart C.; Wilson, Leslie; Jordan, Mary Ann

    2014-01-01

    Chemotherapy-induced peripheral neuropathy (CIPN) is a serious, painful and dose-limiting side effect of cancer drugs that target microtubules. The mechanisms underlying the neuronal damage are unknown, but may include disruption of fast axonal transport, an essential microtubule-based process that moves cellular components over long distances between neuronal cell bodies and nerve terminals. This idea is supported by the “dying back” pattern of degeneration observed in CIPN, and by the selective vulnerability of sensory neurons bearing the longest axonal projections. In this study, we test the hypothesis that microtubule-targeting drugs disrupt fast axonal transport using vesicle motility assays in isolated squid axoplasm and a cell-free microtubule gliding assay with defined components. We compare four clinically-used drugs, eribulin, vincristine, paclitaxel and ixabepilone. Of these, eribulin is associated with a relatively low incidence of severe neuropathy, while vincristine has a relatively high incidence. In vesicle motility assays, we found that all four drugs inhibited anterograde (conventional kinesin-dependent) fast axonal transport, with the potency being vincristine = ixabepilone > paclitaxel = eribulin. Interestingly, eribulin and paclitaxel did not inhibit retrograde (cytoplasmic dynein-dependent) fast axonal transport, in contrast to vincristine and ixabepilone. Similarly, vincristine and ixabepilone both exerted significant inhibitory effects in an in vitro microtubule gliding assay consisting of recombinant kinesin (kinesin-1) and microtubules composed of purified bovine brain tubulin, whereas paclitaxel and eribulin had negligible effects. Our results suggest that (i) inhibition of microtubule-based fast axonal transport may be a significant contributor to neurotoxicity induced by microtubule-targeting drugs, and (ii) that individual microtubule-targeting drugs affect fast axonal transport through different mechanisms. PMID:23711742

  17. The deep accumulation of 10Be at Utsira, southwestern Norway: Implications for cosmogenic nuclide exposure dating in peripheral ice sheet landscapes

    NASA Astrophysics Data System (ADS)

    Briner, Jason P.; Goehring, Brent M.; Mangerud, Jan; Svendsen, John Inge

    2016-09-01

    Cosmogenic nuclide exposure dating is a widely used method for constraining past ice sheet histories. We scrutinize a recently published data set of cosmogenic 10Be data from erratic boulders in Norway used to constrain the deglaciation of the western Scandinavian Ice Sheet to 20 ka. Our model of the 10Be inventory in glacial surfaces leads us to conclude that the chronology may be afflicted by the deep subsurface accumulation of 10Be during long-lasting ice-free periods that resulted in 10Be ages >10% too old. We suggest that the majority of the dated erratic boulders contain a uniform level of inherited muon-produced 10Be and were derived from bedrock depths >2.5 m and most likely ~4 m. The implication of our finding is that for landscapes that experience long ice-free periods between brief maximum glacial phases, glacial erosion of >5 m is required to remove detectable traces of inherited 10Be.

  18. Label-free imaging of developing vasculature in zebrafish with phase variance optical coherence microscopy

    NASA Astrophysics Data System (ADS)

    Chen, Yu; Fingler, Jeff; Trinh, Le A.; Fraser, Scott E.

    2016-03-01

    A phase variance optical coherence microscope (pvOCM) has been created to visualize blood flow in the vasculature of zebrafish embryos, without using exogenous labels. The pvOCM imaging system has axial and lateral resolutions of 2 μm in tissue, and imaging depth of more than 100 μm. Imaging of 2-5 days post-fertilization zebrafish embryos identified the detailed structures of somites, spinal cord, gut and notochord based on intensity contrast. Visualization of the blood flow in the aorta, veins and intersegmental vessels was achieved with phase variance contrast. The pvOCM vasculature images were confirmed with corresponding fluorescence microscopy of a zebrafish transgene that labels the vasculature with green fluorescent protein. The pvOCM images also revealed functional information of the blood flow activities that is crucial for the study of vascular development.

  19. Anatomy and development of the cardiac lymphatic vasculature: Its role in injury and disease.

    PubMed

    Norman, Sophie; Riley, Paul R

    2016-04-01

    Lymphatic vessels are present throughout the entire body in all mammals and function to regulate tissue fluid balance, lipid transport and survey the immune system. Despite the presence of an extensive lymphatic plexus within the heart, until recently the importance of the cardiac lymphatic vasculature and its origins were unknown. Several studies have described the basic anatomy of the developing cardiac lymphatic vasculature and more recently the detailed development of the murine cardiac lymphatics has been documented, with important insight into their cellular sources during embryogenesis. In this review we initially describe the development of systemic lymphatic vasculature, to provide the background for a comparative description of the spatiotemporal development of the cardiac lymphatic vessels, including detail of both canonical, typically venous, and noncanonical (hemogenic endothelium) cellular sources. Subsequently, we address the response of the cardiac lymphatic network to myocardial infarction (heart attack) and the therapeutic potential of targeting cardiac lymphangiogenesis. © 2015 Wiley Periodicals, Inc.

  20. Vascular endothelial growth factor co-ordinates proper development of lung epithelium and vasculature.

    PubMed

    Zhao, Liqing; Wang, Ke; Ferrara, Napoleone; Vu, Thiennu H

    2005-07-01

    The vasculature forms an intrinsic functional component of the lung and its development must be tightly regulated and coordinated with lung epithelial morphogenesis. Vascular endothelial growth factor (VEGF) and its receptors are highly expressed in a complementary pattern in the lungs during embryonic development. VEGF is expressed by epithelium and the receptors in the surrounding mesenchyme. To determine the function of VEGF in lung formation, we inhibited its activity using a soluble receptor in lung renal capsule grafts. Inhibition of VEGF results in inhibition of vascular development and significant alteration in epithelial development. Epithelial proliferation is inhibited, sacculation is impaired, and the epithelium undergoes apoptosis. Interestingly, when VEGF is attenuated, epithelial differentiation still proceeds, as shown by acquisition of both proximal and distal markers. These data show that VEGF co-ordinates epithelial and vascular development. It is required for the development of the lung vasculature and the vasculature is necessary for epithelial proliferation and morphogenesis, but not for cell differentiation.

  1. Endoplasmic Reticulum Stress and Nox-Mediated Reactive Oxygen Species Signaling in the Peripheral Vasculature: Potential Role in Hypertension

    PubMed Central

    Nabeebaccus, Adam A.; Shah, Ajay M.; Camargo, Livia L.; Filho, Sidney V.; Lopes, Lucia R.

    2014-01-01

    Abstract Significance: Reactive oxygen species (ROS) are produced during normal endoplasmic reticulum (ER) metabolism. There is accumulating evidence showing that under stress conditions such as ER stress, ROS production is increased via enzymes of the NADPH oxidase (Nox) family, especially via the Nox2 and Nox4 isoforms, which are involved in the regulation of blood pressure. Hypertension is a major contributor to cardiovascular and renal disease, and it has a complex pathophysiology involving the heart, kidney, brain, vessels, and immune system. ER stress activates the unfolded protein response (UPR) signaling pathway that has prosurvival and proapoptotic components. Recent Advances: Here, we summarize the evidence regarding the association of Nox enzymes and ER stress, and its potential contribution in the setting of hypertension, including the role of other conditions that can lead to hypertension (e.g., insulin resistance and diabetes). Critical Issues: A better understanding of this association is currently of great interest, as it will provide further insights into the cellular mechanisms that can drive the ER stress-induced adaptive versus maladaptive pathways linked to hypertension and other cardiovascular conditions. More needs to be learnt about the precise signaling regulation of Nox(es) and ER stress in the cardiovascular system. Future Directions: The development of specific approaches that target individual Nox isoforms and the UPR signaling pathway may be important for the achievement of therapeutic efficacy in hypertension. Antioxid. Redox Signal. 20, 121–134. PMID:23472786

  2. Mechanics and Function of the Pulmonary Vasculature: Implications for Pulmonary Vascular Disease and Right Ventricular Function

    PubMed Central

    Lammers, Steven; Scott, Devon; Hunter, Kendall; Tan, Wei; Shandas, Robin; Stenmark, Kurt R.

    2012-01-01

    The relationship between cardiac function and the afterload against which the heart muscle must work to circulate blood throughout the pulmonary circulation is defined by a complex interaction between many coupled system parameters. These parameters range broadly and incorporate system effects originating primarily from three distinct locations: input power from the heart, hydraulic impedance from the large conduit pulmonary arteries, and hydraulic resistance from the more distal microcirculation. These organ systems are not independent, but rather, form a coupled system in which a change to any individual parameter affects all other system parameters. The result is a highly nonlinear system which requires not only detailed study of each specific component and the effect of disease on their specific function, but also requires study of the interconnected relationship between the microcirculation, the conduit arteries, and the heart in response to age and disease. Here, we investigate systems-level changes associated with pulmonary hypertensive disease progression in an effort to better understand this coupled relationship. PMID:23487595

  3. Current views on the function of the lymphatic vasculature in health and disease

    PubMed Central

    Wang, Yingdi; Oliver, Guillermo

    2010-01-01

    The lymphatic vascular system is essential for lipid absorption, fluid homeostasis, and immune surveillance. Until recently, lymphatic vessel dysfunction had been associated with symptomatic pathologic conditions such as lymphedema. Work in the last few years had led to a better understanding of the functional roles of this vascular system in health and disease. Furthermore, recent work has also unraveled additional functional roles of the lymphatic vasculature in fat metabolism, obesity, inflammation, and the regulation of salt storage in hypertension. In this review, we summarize the functional roles of the lymphatic vasculature in health and disease. PMID:20889712

  4. Septo-optic dysplasia associated with congenital persistent fetal vasculature, retinal detachment, and gastroschisis.

    PubMed

    Jordan, Michael A; Montezuma, Sandra R

    2015-01-01

    The purpose of this study was to report the association of septo-optic dysplasia, persistent fetal vasculature, retinal detachment, and gastroschisis in a preterm neonate. This is a case report. A female preterm neonate was found to have septo-optic dysplasia, with optic nerve hypoplasia, tripartite splitting of the vessels at the optic nerve, an ectopic pituitary gland, and absence of the septum pellucidum associated with persistent fetal vasculature, a retinal detachment, and gastroschisis. Septo-optic dysplasia may also be associated with other ophthalmic findings and other developmental malformations as the authors report in this case. Follow-up should consist of a multidisciplinary approach with radiologic and endocrinology consultation.

  5. Alterations in the neural circuits from peripheral afferents to the spinal cord: possible implications for diabetic polyneuropathy in streptozotocin-induced type 1 diabetic rats

    PubMed Central

    Kou, Zhen-Zhen; Li, Chun-Yu; Hu, Jia-Chen; Yin, Jun-Bin; Zhang, Dong-Liang; Liao, Yong-Hui; Wu, Zhen-Yu; Ding, Tan; Qu, Juan; Li, Hui; Li, Yun-Qing

    2014-01-01

    Diabetic polyneuropathy (DPN) presents as a wide variety of sensorimotor symptoms and affects approximately 50% of diabetic patients. Changes in the neural circuits may occur in the early stages in diabetes and are implicated in the development of DPN. Therefore, we aimed to detect changes in the expression of isolectin B4 (IB4, the marker for nonpeptidergic unmyelinated fibers and their cell bodies) and calcitonin gene-related peptide (CGRP, the marker for peptidergic fibers and their cell bodies) in the dorsal root ganglion (DRG) and spinal cord of streptozotocin (STZ)-induced type 1 diabetic rats showing alterations in sensory and motor function. We also used cholera toxin B subunit (CTB) to show the morphological changes of the myelinated fibers and motor neurons. STZ-induced diabetic rats exhibited hyperglycemia, decreased body weight gain, mechanical allodynia and impaired locomotor activity. In the DRG and spinal dorsal horn, IB4-labeled structures decreased, but both CGRP immunostaining and CTB labeling increased from day 14 to day 28 in diabetic rats. In spinal ventral horn, CTB labeling decreased in motor neurons in diabetic rats. Treatment with intrathecal injection of insulin at the early stages of DPN could alleviate mechanical allodynia and impaired locomotor activity in diabetic rats. The results suggest that the alterations of the neural circuits between spinal nerve and spinal cord via the DRG and ventral root might be involved in DPN. PMID:24523675

  6. Peripheral Nerve Disorders

    MedlinePlus

    ... Like static on a telephone line, peripheral nerve disorders distort or interrupt the messages between the brain ... are more than 100 kinds of peripheral nerve disorders. They can affect one nerve or many nerves. ...

  7. Peripheral artery bypass - leg

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/007394.htm Peripheral artery bypass - leg To use the sharing features on this page, please enable JavaScript. Peripheral artery bypass is surgery to reroute the blood supply ...

  8. Peripheral arterial line (image)

    MedlinePlus

    A peripheral arterial line is a small, short plastic catheter placed through the skin into an artery of the arm or leg. The purpose of a peripheral arterial line is to allow continuous monitoring of blood pressure ...

  9. Peripheral Color Demo.

    PubMed

    Tyler, Christopher W

    2015-12-01

    A set of structured demonstrations of the vividness of peripheral color vision is provided by arrays of multicolored disks scaled with eccentricity. These demonstrations are designed to correct the widespread misconception that peripheral color vision is weak or nonexistent.

  10. Interaction of isoflavones and endophyte-infected tall fescue seed extract on vasoactivity of bovine mesenteric vasculature

    USDA-ARS?s Scientific Manuscript database

    It was hypothesized that isoflavones may attenuate ergot alkaloid-induced vasoconstriction and possibly alleviate diminished contractility of vasculature after exposure to ergot alkaloids. The objective of this study was to determine if prior incubation of bovine mesenteric vasculature with the isof...

  11. Novel surface targets and serum biomarkers from the ovarian cancer vasculature

    PubMed Central

    Hammond, Rachel; Kougioumtzidou, Eleni; Katsaros, Dionyssis; Buckanovich, Ron; Devarajan, Karthik; Sandaltzopoulos, Raphael; Godwin, Andrew K; Scholler, Nathalie

    2011-01-01

    The molecular phenotype of tumor vasculature is different from normal vasculature, offering new opportunities for diagnosis and therapy of cancer, but the identification of tumor-restricted targets remains a challenge. We investigated 13 tumor vascular markers (TVMs) from 50 candidates identified through expression profiling of ovarian cancer vascular cells and selected to be either transmembrane or secreted, and to be either absent or expressed at low levels in normal tissues while overexpressed in tumors, based on analysis of 1,110 normal and tumor tissues from publicly available Affymetrix microarray data. Tumor-specific expression of each TVM was confirmed at the protein level in tumor tissue and/or in serum. Among the 13 TVMs, 11 were expressed on tumor vascular endothelium; the remaining 2 TVMs were expressed by tumor leukocytes. Our results demonstrate that certain transmembrane TVMs such as ADAM12 and CDCP1 are selectively expressed in tumor vasculature and represent promising targets for vascular imaging or anti-vascular therapy of epithelial ovarian cancer, while secreted or shed molecules such as TNFRSF21/DR6 can function as serum biomarkers. We have identified novel tumor-specific vasculature markers which appear promising for cancer serum diagnostics, molecular imaging and/or therapeutic targeting applications and warrant further clinical development. PMID:21617380

  12. Cited2 is required for the proper formation of the hyaloid vasculature and for lens morphogenesis

    PubMed Central

    Chen, Yu; Doughman, Yong-qiu; Gu, Shi; Jarrell, Andrew; Aota, Shin-ichi; Cvekl, Ales; Watanabe, Michiko; Dunwoodie, Sally L.; Johnson, Randall S.; van Heyningen, Veronica; Kleinjan, Dirk A.; Beebe, David C.; Yang, Yu-Chung

    2009-01-01

    Cited2 is a transcriptional modulator with pivotal roles in different biological processes. Cited2-deficient mouse embryos manifested two major defects in the developing eye. An abnormal corneal-lenticular stalk was characteristic of Cited2−/− developing eyes, a feature reminiscent of Peters’ anomaly, which can be rescued by increased Pax6 gene dosage in Cited2−/− embryonic eyes. In addition, the hyaloid vascular system showed hyaloid hypercellularity consisting of aberrant vasculature, which might be correlated with increased VEGF expression in the lens. Deletion of Hif1a (which encodes HIF-1α) in Cited2−/− lens specifically eliminated the excessive accumulation of cellular mass and aberrant vasculature in the developing vitreous without affecting the corneal-lenticular stalk phenotype. These in vivo data demonstrate for the first time dual functions for Cited2: one upstream of, or together with, Pax6 in lens morphogenesis; and another in the normal formation of the hyaloid vasculature through its negative modulation of HIF-1 signaling. Taken together, our study provides novel mechanistic revelation for lens morphogenesis and hyaloid vasculature formation and hence might offer new insights into the etiology of Peters’ anomaly and ocular hypervascularity. PMID:18653562

  13. TISSUE-SPECIFIC VENOUS EXPRESSION OF THE EPH FAMILY RECEPTOR EPHB1 IN THE SKIN VASCULATURE

    PubMed Central

    Li, Wenling; Mukouyama, Yoh-suke

    2013-01-01

    Background The major arteries and veins are formed early during development. The molecular tools to identify arterial and venous endothelial cells improve our understanding of arterial-venous differentiation and branching morphogenesis. Compared to arterial differentiation, relatively little is known about what controls venous development, due to a lack of definitive molecular markers for venous endothelial cells. Results Here we report that the antibody against EphB1, an EphB class receptor, makes it possible to establish a reliable whole-mount immunohistochemical analysis of venous identity with greater resolution than previously possible in embryonic and adult skin vasculature models. EphB1 expression is restricted to the entire venous vasculature throughout embryonic development to adulthood, whereas the previously established venous marker EphB4 is also detectable in lymphatic vasculature. This venous-restricted expression of EphB1 is established after the vascular remodeling of the primary capillary plexus has occurred. Compared to its venous-specific expression in the skin, however, EphB1 is not restricted to the venous vasculature in yolk sac, trunk and lung. Conclusions These studies introduce EphB1 as a new venous-restricted marker in a tissue-specific and time-dependent manner. PMID:23649798

  14. Pregnane X receptor regulates drug metabolism and transport in the vasculature and protects from oxidative stress

    PubMed Central

    Swales, Karen E.; Moore, Rick; Truss, Nicola J.; Tucker, Arthur; Warner, Timothy D.; Negishi, Masahiko; Bishop-Bailey, David

    2012-01-01

    Aims Circulating endogenous, dietary, and foreign chemicals can contribute to vascular dysfunction. The mechanism by which the vasculature protects itself from these chemicals is unknown. This study investigates whether the pregnane X receptor (PXR), the major transcriptional regulator of hepatic drug metabolism and transport that responds to such xenobiotics, mediates vascular protection by co-ordinating a defence gene programme in the vasculature. Methods and results PXR was detected in primary human and rat aortic endothelial and smooth muscle cells (SMC) and blood vessels including the human and rat aorta. Metabolic PXR target genes cytochrome P450 3A, 2B, 2C, and glutathione S-transferase mRNA and activity were induced by PXR ligands in rodent and human vascular cells and absent in the aortas from PXR-null mice stimulated in vivo or in rat aortic SMC expressing dominant-negative PXR. Activation of aortic PXR by classical agonists had several protective effects: increased xenobiotic metabolism demonstrated by bioactivation of the pro-drug clopidogrel, which reduced adenosine diphosphate-induced platelet aggregation; increased expression of multidrug resistance protein 1, mediating chemical efflux from the vasculature; and protection from reactive oxygen species-mediated cell death. Conclusion PXR co-ordinately up-regulates drug metabolism, transport, and antioxidant genes to protect the vasculature from endogenous and exogenous insults, thus representing a novel gatekeeper for vascular defence. PMID:22166712

  15. A New Presentation and Exploration of Human Cerebral Vasculature Correlated with Surface and Sectional Neuroanatomy

    ERIC Educational Resources Information Center

    Nowinski, Wieslaw L.; Thirunavuukarasuu, Arumugam; Volkau, Ihar; Marchenko, Yevgen; Aminah, Bivi; Gelas, Arnaud; Huang, Su; Lee, Looi Chow; Liu, Jimin; Ng, Ting Ting; Nowinska, Natalia G.; Qian, Guoyu Yu; Puspitasari, Fiftarina; Runge, Val M.

    2009-01-01

    The increasing complexity of human body models enabled by advances in diagnostic imaging, computing, and growing knowledge calls for the development of a new generation of systems for intelligent exploration of these models. Here, we introduce a novel paradigm for the exploration of digital body models illustrating cerebral vasculature. It enables…

  16. Multiscale imaging and computational modeling of blood flow in the tumor vasculature.

    PubMed

    Kim, Eugene; Stamatelos, Spyros; Cebulla, Jana; Bhujwalla, Zaver M; Popel, Aleksander S; Pathak, Arvind P

    2012-11-01

    The evolution in our understanding of tumor angiogenesis has been the result of pioneering imaging and computational modeling studies spanning the endothelial cell, microvasculature and tissue levels. Many of these primary data on the tumor vasculature are in the form of images from pre-clinical tumor models that provide a wealth of qualitative and quantitative information in many dimensions and across different spatial scales. However, until recently, the visualization of changes in the tumor vasculature across spatial scales remained a challenge due to a lack of techniques for integrating micro- and macroscopic imaging data. Furthermore, the paucity of three-dimensional (3-D) tumor vascular data in conjunction with the challenges in obtaining such data from patients presents a serious hurdle for the development and validation of predictive, multiscale computational models of tumor angiogenesis. In this review, we discuss the development of multiscale models of tumor angiogenesis, new imaging techniques capable of reproducing the 3-D tumor vascular architecture with high fidelity, and the emergence of "image-based models" of tumor blood flow and molecular transport. Collectively, these developments are helping us gain a fundamental understanding of the cellular and molecular regulation of tumor angiogenesis that will benefit the development of new cancer therapies. Eventually, we expect this exciting integration of multiscale imaging and mathematical modeling to have widespread application beyond the tumor vasculature to other diseases involving a pathological vasculature, such as stroke and spinal cord injury.

  17. Multiscale Imaging and Computational Modeling of Blood Flow in the Tumor Vasculature

    PubMed Central

    Kim, Eugene; Stamatelos, Spyros; Cebulla, Jana; Bhujwalla, Zaver M.; Popel, Aleksander S.; Pathak, Arvind P.

    2013-01-01

    The evolution in our understanding of tumor angiogenesis has been the result of pioneering imaging and computational modeling studies spanning the endothelial cell, microvasculature and tissue levels. Many of these primary data on the tumor vasculature are in the form of images from pre-clinical tumor models that provide a wealth of qualitative and quantitative information in many dimensions and across different spatial scales. However, until recently, the visualization of changes in the tumor vasculature across spatial scales remained a challenge due to a lack of techniques for integrating micro- and macroscopic imaging data. Furthermore, the paucity of three-dimensional (3-D) tumor vascular data in conjunction with the challenges in obtaining such data from patients presents a serious hurdle for the development and validation of predictive, multiscale computational models of tumor angiogenesis. In this review, we discuss the development of multiscale models of tumor angiogenesis, new imaging techniques capable of reproducing the 3-D tumor vascular architecture with high fidelity, and the emergence of “image-based models”of tumor blood flow and molecular transport. Collectively, these developments are helping us gain a fundamental understanding of the cellular and molecular regulation of tumor angiogenesis that will benefit the development of new cancer therapies. Eventually, we expect this exciting integration of multiscale imaging and mathematical modeling to have widespread application beyond the tumor vasculature to other diseases involving a pathological vasculature, such as stroke and spinal cord injury. PMID:22565817

  18. Posterior tunica vasculosa lentis and "brittle star" of persistent fetal vasculature.

    PubMed

    Pellegrini, Marco; Shields, Carol L; Arepalli, Sruthi; Shields, Jerry A

    2014-11-19

    A 17-month-old girl referred for a suspected ciliary body medulloepithelioma was found to have persistent fetal vasculature. Fluorescein angiography showed perfused hyaloid artery posterior tunica vasculosa lentis with brittle star appearance and nonperfused anterior pupillary membrane. Ultrasound biomicroscopy confirmed absence of iris or ciliary body solid tumor.

  19. A New Presentation and Exploration of Human Cerebral Vasculature Correlated with Surface and Sectional Neuroanatomy

    ERIC Educational Resources Information Center

    Nowinski, Wieslaw L.; Thirunavuukarasuu, Arumugam; Volkau, Ihar; Marchenko, Yevgen; Aminah, Bivi; Gelas, Arnaud; Huang, Su; Lee, Looi Chow; Liu, Jimin; Ng, Ting Ting; Nowinska, Natalia G.; Qian, Guoyu Yu; Puspitasari, Fiftarina; Runge, Val M.

    2009-01-01

    The increasing complexity of human body models enabled by advances in diagnostic imaging, computing, and growing knowledge calls for the development of a new generation of systems for intelligent exploration of these models. Here, we introduce a novel paradigm for the exploration of digital body models illustrating cerebral vasculature. It enables…

  20. Floral vasculature and its variation for carpellary supply in Anthurium (Araceae, Alismatales)

    PubMed Central

    Temponi, Lívia G.; Coan, Alessandra I.

    2017-01-01

    Introduction and Aims Anthurium is the largest genus of Araceae, with 950 species distributed in the neotropics. Despite the great diversity of the genus, the knowledge of its floral vasculature is based on observations in only two species, viz. A. denudatum and A. lhotzkyanum, with remarkable variation in vascular carpellary supply: carpels are either vascularized by ventral bundles alone or by reduced dorsal bundles in addition to the ventral ones. Our main objective is to test this peculiar variation through a detailed anatomical study of the floral vasculature in taxa belonging to some sections of Anthurium designated as monophyletic groups in recent phylogenies. Methods We compare the floral vasculature of 20 neotropical species belonging to distinct sections of Anthurium, using both light and confocal laser scanning microscopies. Results The number and position of vascular bundles are constant within the tepals and stamens, regardless of the species and sections studied. However, the gynoecium vasculature exhibits variation between species belonging to the same or different sections. Our results reveal two patterns of vasculature: carpels vascularized by synlateral bundles alone (Pattern A) and carpels vascularized by both dorsal and synlateral bundles (Pattern B). Pattern A is shared by the majority of species studied here and corroborates the previous data in the literature. Pattern B occurs in three species: A. affine (Anthurium sect. Pachyneurium series Pachyneurium), A. obtusum and A. scandens (Anthurium sect. Tetraspermium), described here for the first time for the genus. Conclusions The variation in the supply to the carpels in Anthurium is corroborated here. However, our results in addition to those from the available literature suggest the existence of three patterns (A, B and C) of carpellary vasculature. Based on the recent phylogeny of Anthurium it is possible to notice that the three patterns of carpellary vasculature occur in representatives of

  1. New insights into insulin action and resistance in the vasculature

    PubMed Central

    Manrique, Camila; Lastra, Guido; Sowers, James R.

    2014-01-01

    Two-thirds of adults in the United States are overweight or obese, and another 26 million have type 2 diabetes. Decreased insulin sensitivity in cardiovascular tissue is an underlying abnormality in these individuals. Insulin metabolic signaling increases endothelial cell nitric oxide production. Impaired vascular insulin sensitivity is an early defect leading to impaired vascular relaxation. In overweight and obese persons, as well as in those with hypertension, systemic and vascular insulin resistance often occurs in conjunction with activation of the cardiovascular tissue renin–angiotensin–aldosterone system (RAAS). Activated angiotensin II type 1 receptor and mineralocorticoid receptor signaling promote the development of vascular insulin resistance and impaired endothelial nitric oxide–mediated relaxation. Research in this area has implicated excessive serine phosphorylation and proteasomal degradation of the docking protein insulin receptor substrate and enhanced signaling through hybrid insulin/insulin-like growth factor (IGF-1) receptor as important mechanisms underlying RAAS impediment of downstream vascular insulin metabolic signaling. This review will present recent evidence supporting the notion that RAAS signaling represents a potential pathway for the development of vascular insulin resistance and impaired endothelial-mediated vasodilation. PMID:24650277

  2. Cone beam CT tumor vasculature dynamic study (Murine model)

    NASA Astrophysics Data System (ADS)

    Yang, Dong; Ning, Ruola; Conover, David; Ricardo, Betancourt; Liu, Shaohua

    2008-03-01

    Tumor angiogenesis is the process by which new blood vessels are formed from the existing vessels in a tumor to promote tumor growth. Tumor angiogenesis has important implications in the diagnosis and treatment of various solid tumors. Flat panel detector based cone beam CT opens up a new way for detection of tumors, and tumor angiogenesis associated with functional CBCT has the potential to provide more information than traditional functional CT due to more overall coverage during the same scanning period and the reconstruction being isotropic resulting in a more accurate 3D volume intensity measurement. A functional study was conducted by using CBCT to determine the degree of the enhancement within the tumor after injecting the contrast agent intravenously. For typical doses of contrast material, the amount of enhancement is proportional to the concentration of this material within the region of interest. A series of images obtained at one location over time allows generation of time-attenuation data from which a number of semi-quantitative parameters, such as enhancement rate, can be determined. An in vivo mice study with and without mammo tumor was conducted on our prototype CBCT system, and half scan scheme is used to determine the time-intensity curve within the VOI of the mouse. The CBCT has an x-ray tube, a gantry with slip ring technology, and a 40×30 cm Varian Paxscan 4030CB real time FPD.

  3. Anti-angiogenic nanotherapy via active targeting systems to tumors and adipose tissue vasculature.

    PubMed

    Sakurai, Yu; Kajimoto, Kazuaki; Harashima, Hideyoshi

    2015-09-01

    Sophisticated drug delivery systems (DDS) are required for delivering drugs, especially macromolecules such as nucleic acids or proteins, to their sites of action. Therefore it is a prerequisite that future DDS are designed to selectively target a tissue. In this review, we focus on systems that actively target the vasculature in tumors or adipose tissues. For targeting tumor vasculatur, a new strategy referred to as dual-targeting is proposed that uses a combination of a receptor specific ligand and a cell penetrating peptide, which can induce the synergistic enhancement of tissue selectivity under in vivo conditions. A novel pH-sensitive cationic lipid was designed to enhance the endosomal release of encapsulated compounds such as siRNA as well as to improve the stability in blood circulation after intravenous administration. A cyclic RGD peptide is used as an active targeting ligand. For targeting adipose vasculature, prohibitin, which is expressed on the surface of adipose endothelial cells, was targeted with KGGRAKD peptides on the surface of PEGylated nanoparticles. Prohibitin targeted nanoparticles (PTNP) encapsulating Cytochrome c (CytC) can selectively target adipose vasculature by optimizing the lengths of the PEG linkers and can deliver CytC to adipose endothelial cells. PTNP can successfully induce anti-obese effects as well as apoptosis by delivering CytC to the cytosol in endothelial cells. Unexpectedly, the EPR (enhanced permeability and retention) effect, which is usually observed in tumor tissue, was also observed in the adipose vasculature, especially in obese mice, where PEGylated nanoparticles can pass through the endothelial barriers in adipose tissue. We believe that these achievements in active targeting will allow a greatly expanded use of DDS for nanomedicines.

  4. CAVAREV—an open platform for evaluating 3D and 4D cardiac vasculature reconstruction

    NASA Astrophysics Data System (ADS)

    Rohkohl, Christopher; Lauritsch, Günter; Keil, Andreas; Hornegger, Joachim

    2010-05-01

    The 3D reconstruction of cardiac vasculature, e.g. the coronary arteries, using C-arm CT (rotational angiography) is an active and challenging field of research. There are numerous publications on different reconstruction techniques. However, there is still a lack of comparability of achieved results for several reasons: foremost, datasets used in publications are not open to public and thus experiments are not reproducible by other researchers. Further, the results highly depend on the vasculature motion, i.e. cardiac and breathing motion patterns which are also not comparable across publications. We aim to close this gap by providing an open platform, called Cavarev (CArdiac VAsculature Reconstruction EValuation). It features two simulated dynamic projection datasets based on the 4D XCAT phantom with contrasted coronary arteries which was derived from patient data. In the first dataset, the vasculature undergoes a continuous periodic motion. The second dataset contains aperiodic heart motion by including additional breathing motion. The geometry calibration and acquisition protocol were obtained from a real-world C-arm system. For qualitative evaluation of the reconstruction results, the correlation of the morphology is used. Two segmentation-based quality measures are introduced which allow us to assess the 3D and 4D reconstruction quality. They are based on the spatial overlap of the vasculature reconstruction with the ground truth. The measures enable a comprehensive analysis and comparison of reconstruction results independent from the utilized reconstruction algorithm. An online platform (www.cavarev.com) is provided where the datasets can be downloaded, researchers can manage and publish algorithm results and download a reference C++ and Matlab implementation.

  5. Mesenteric Vasculature-guided Small Bowel Segmentation on 3D CT

    PubMed Central

    Zhang, Weidong; Liu, Jiamin; Yao, Jianhua; Louie, Adeline; Nguyen, Tan B.; Wank, Stephen; Nowinski, Wieslaw L.; Summers, Ronald M.

    2014-01-01

    Due to its importance and possible applications in visualization, tumor detection and pre-operative planning, automatic small bowel segmentation is essential for computer-aided diagnosis of small bowel pathology. However, segmenting the small bowel directly on CT scans is very difficult because of the low image contrast on CT scans and high tortuosity of the small bowel and its close proximity to other abdominal organs. Motivated by the intensity characteristics of abdominal CT images, the anatomic relationship between the mesenteric vasculature and the small bowel, and potential usefulness of the mesenteric vasculature for establishing the path of the small bowel, we propose a novel mesenteric vasculature map-guided method for small bowel segmentation on high-resolution CT angiography scans. The major mesenteric arteries are first segmented using a vessel tracing method based on multi-linear subspace vessel model and Bayesian inference. Second, multi-view, multi-scale vesselness enhancement filters are used to segment small vessels, and vessels directly or indirectly connecting to the superior mesenteric artery are classified as mesenteric vessels. Third, a mesenteric vasculature map is built by linking vessel bifurcation points, and the small bowel is segmented by employing the mesenteric vessel map and fuzzy connectness. The method was evaluated on 11 abdominal CT scans of patients suspected of having carcinoid tumors with manually labeled reference standard. The result, 82.5% volume overlap accuracy compared with the reference standard, shows it is feasible to segment the small bowel on CT scans using the mesenteric vasculature as a roadmap. PMID:23807437

  6. Flt-1 haploinsufficiency ameliorates muscular dystrophy phenotype by developmentally increased vasculature in mdx mice

    PubMed Central

    Verma, Mayank; Asakura, Yoko; Hirai, Hiroyuki; Watanabe, Shuichi; Tastad, Christopher; Fong, Guo-Hua; Ema, Masatsugu; Call, Jarrod A.; Lowe, Dawn A.; Asakura, Atsushi

    2010-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disease caused by mutations in the gene coding for the protein dystrophin. Recent work demonstrates that dystrophin is also found in the vasculature and its absence results in vascular deficiency and abnormal blood flow. This induces a state of ischemia further aggravating the muscular dystrophy pathogenesis. For an effective form of therapy of DMD, both the muscle and the vasculature need to be addressed. To reveal the developmental relationship between muscular dystrophy and vasculature, mdx mice, an animal model for DMD, were crossed with Flt-1 gene knockout mice to create a model with increased vasculature. Flt-1 is a decoy receptor for vascular endothelial growth factor, and therefore both homozygous (Flt-1−/−) and heterozygous (Flt-1+/−) Flt-1 gene knockout mice display increased endothelial cell proliferation and vascular density during embryogenesis. Here, we show that Flt-1+/− and mdx:Flt-1+/− adult mice also display a developmentally increased vascular density in skeletal muscle compared with the wild-type and mdx mice, respectively. The mdx:Flt-1+/− mice show improved muscle histology compared with the mdx mice with decreased fibrosis, calcification and membrane permeability. Functionally, the mdx:Flt-1+/− mice have an increase in muscle blood flow and force production, compared with the mdx mice. Consequently, the mdx:utrophin−/−:Flt-1+/− mice display improved muscle histology and significantly higher survival rates compared with the mdx:utrophin−/− mice, which show more severe muscle phenotypes than the mdx mice. These data suggest that increasing the vasculature in DMD may ameliorate the histological and functional phenotypes associated with this disease. PMID:20705734

  7. Optical imaging of the chorioretinal vasculature in the living human eye.

    PubMed

    Kim, Dae Yu; Fingler, Jeff; Zawadzki, Robert J; Park, Susanna S; Morse, Lawrence S; Schwartz, Daniel M; Fraser, Scott E; Werner, John S

    2013-08-27

    Detailed visualization of microvascular changes in the human retina is clinically limited by the capabilities of angiography imaging, a 2D fundus photograph that requires an intravenous injection of fluorescent dye. Whereas current angiography methods enable visualization of some retinal capillary detail, they do not adequately reveal the choriocapillaris or other microvascular features beneath the retina. We have developed a noninvasive microvascular imaging technique called phase-variance optical coherence tomography (pvOCT), which identifies vasculature three dimensionally through analysis of data acquired with OCT systems. The pvOCT imaging method is not only capable of generating capillary perfusion maps for the retina, but it can also use the 3D capabilities to segment the data in depth to isolate vasculature in different layers of the retina and choroid. This paper demonstrates some of the capabilities of pvOCT imaging of the anterior layers of choroidal vasculature of a healthy normal eye as well as of eyes with geographic atrophy (GA) secondary to age-related macular degeneration. The pvOCT data presented permit digital segmentation to produce 2D depth-resolved images of the retinal vasculature, the choriocapillaris, and the vessels in Sattler's and Haller's layers. Comparisons are presented between en face projections of pvOCT data within the superficial choroid and clinical angiography images for regions of GA. Abnormalities and vascular dropout observed within the choriocapillaris for pvOCT are compared with regional GA progression. The capability of pvOCT imaging of the microvasculature of the choriocapillaris and the anterior choroidal vasculature has the potential to become a unique tool to evaluate therapies and understand the underlying mechanisms of age-related macular degeneration progression.

  8. Peripheral Neuropathy and Agent Orange

    MedlinePlus

    ... ZIP code here Enter ZIP code here Peripheral Neuropathy and Agent Orange VA presumes Veterans' early-onset ... percent disabling by VA's rating regulations. About peripheral neuropathy Peripheral neuropathy is a condition of the peripheral ...

  9. Advances in understanding the peripheral circadian clocks.

    PubMed

    Richards, Jacob; Gumz, Michelle L

    2012-09-01

    In the past decade, it has become increasingly evident that the circadian clock system plays an important role in many physiological processes. The circadian clock can be divided into 2 parts: the central clock, residing in the suprachiasmatic nucleus of the hypothalamus, which receives light cues, and the peripheral clocks that reside in various tissues throughout the body. The peripheral clocks play an integral and unique role in each of their respective tissues, driving the circadian expression of specific genes involved in a variety of physiological functions. The goal of this review is to provide an introduction to and overview of the peripheral clocks, including potential mechanisms, targets, and implications for disease states. The peripheral clocks include the cardiovascular, metabolic, endocrine, immune, and reproductive systems.

  10. Peripheral visual changes and spatial attention.

    PubMed

    Lambert, A; Spencer, M; Hockey, R

    1991-04-01

    Three experiments are reported investigating the attentional effects of peripheral visual changes. In agreement with previous work, experiment 1 demonstrated facilitatory and inhibitory effects of a peripheral visual change on the latency of peripheral target detection. However, after a few minutes practice the facilitatory effect disappeared entirely. The inhibitory effect, though slightly reduced in later blocks, remained significant. Hence, the two effects are dissociable and not inter-dependent as argued by Maylor (1985). In experiments 2 and 3 the perceptual salience of the peripheral cue was manipulated. With a low energy, barely noticeable cue there was no reduction in either facilitation or inhibition as a function of practice. In contrast, the attentional effects of cues higher in energy tended to diminish with practice. Theoretical implications of these data are discussed.

  11. Peripheral Nerve Injury: Stem Cell Therapy and Peripheral Nerve Transfer

    PubMed Central

    Sullivan, Robert; Dailey, Travis; Duncan, Kelsey; Abel, Naomi; Borlongan, Cesario V.

    2016-01-01

    Peripheral nerve injury can lead to great morbidity in those afflicted, ranging from sensory loss, motor loss, chronic pain, or a combination of deficits. Over time, research has investigated neuronal molecular mechanisms implicated in nerve damage, classified nerve injury, and developed surgical techniques for treatment. Despite these advancements, full functional recovery remains less than ideal. In this review, we discuss historical aspects of peripheral nerve injury and introduce nerve transfer as a therapeutic option, as well as an adjunct therapy to transplantation of Schwann cells and their stem cell derivatives for repair of the damaged nerve. This review furthermore, will provide an elaborated discussion on the sources of Schwann cells, including sites to harvest their progenitor and stem cell lines. This reflects the accessibility to an additional, concurrent treatment approach with nerve transfers that, predicated on related research, may increase the efficacy of the current approach. We then discuss the experimental and clinical investigations of both Schwann cells and nerve transfer that are underway. Lastly, we provide the necessary consideration that these two lines of therapeutic approaches should not be exclusive, but conversely, should be pursued as a combined modality given their mutual role in peripheral nerve regeneration. PMID:27983642

  12. Three-dimensional flow patterns in the feto-placental vasculature system of the mouse placenta.

    PubMed

    Shannon, Alexander T; Mirbod, Parisa

    2017-05-01

    In this study, three-dimensional (3D) blood flow of the feto-placental vasculature system of the mouse placenta was investigated using computational fluid dynamics (CFD) methods and finite element analysis. Micro-computerized tomography (micro-CT) images were used to acquire the 3D geometry of the feto-placental vasculature system, and image-processing software has been used to calculate the 3D morphology of the placenta. The flow was analyzed numerically and compared to the experimental data received from the same model. The numerical and experimental results agree well. Experimentally measured time dependent blood velocity data, available in the literature, was used as the inlet boundary condition to represent the fetal blood pulsatile flow. Velocity profiles and pressure distributions are investigated during different phases of the unsteady flow. The results clearly illustrate the important role of the vasculature structure (e.g., diameter and curvature) in the fetal hemodynamics, which to our knowledge has not been examined previously. The data also show that, at each bifurcation, the blood flow velocity decreases significantly in the transition from the parent vessel (i.e., umbilical artery) to the daughter vessels because of the higher total cross-sectional area of the daughter vessels compared to the parent vessel. It can also be observed that pressure drop at the umbilical artery and pressure drop across the arterial trees obtained in this study agree well with the physiological data reported in the literature. Moreover, the velocity profiles after each bifurcation are symmetric. Finally, from the results no secondary flow has been observed in the vasculature system. This study provides a foundation in understanding and modeling the complex structure of the feto-placental vasculature system and serves as a first step towards developing new concepts for computational analysis of the feto-placental vasculature systems of both human and mouse to better

  13. Dark Signals in the Choroidal Vasculature on Optical Coherence Tomography Angiography: An Artefact or Not?

    PubMed Central

    Wang, Hailin

    2017-01-01

    Optical coherence tomography angiography (OCTA) based on mathematical processing of sequentially acquired structural OCT images has been applied widely in both retinal and choroidal research and may have advantages over traditional angiography. Images obtained by OCTA are rendered under the assumption that the only moving entity in the retina is blood flow. Optical phenomena and image processing algorithms may create imaging artefacts. Therefore, OCTA images require careful interpretation. This review discusses the dark signals seen in the choroidal vasculature on OCTA using multiple factor analysis. For accurate and comprehensive interpretation of the choroidal vasculature, we recommend simultaneous consideration of the laser light penetration depth and masking effect of retinal pigment epithelium, the orientation of vessels in relation to the scanning lasers and blood flow, the range of regional detectable velocity of blood flow, atrophic tissues in the periphery, and absorption of superior vessels on the scanning laser. PMID:28607772

  14. In Vivo Tumor Vasculature Targeting of CuS@MSN Based Theranostic Nanomedicine

    PubMed Central

    2015-01-01

    Actively targeted theranostic nanomedicine may be the key for future personalized cancer management. Although numerous types of theranostic nanoparticles have been developed in the past decade for cancer treatment, challenges still exist in the engineering of biocompatible theranostic nanoparticles with highly specific in vivo tumor targeting capabilities. Here, we report the design, synthesis, surface engineering, and in vivo active vasculature targeting of a new category of theranostic nanoparticle for future cancer management. Water-soluble photothermally sensitive copper sulfide nanoparticles were encapsulated in biocompatible mesoporous silica shells, followed by multistep surface engineering to form the final theranostic nanoparticles. Systematic in vitro targeting, an in vivo long-term toxicity study, photothermal ablation evaluation, in vivo vasculature targeted imaging, biodistribution and histology studies were performed to fully explore the potential of as-developed new theranostic nanoparticles. PMID:25843647

  15. Functionalized Hollow Mesoporous Silica Nanoparticles for Tumor Vasculature Targeting and PET Image-Guided Drug Delivery

    PubMed Central

    Chakravarty, Rubel; Goel, Shreya; Hong, Hao; Chen, Feng; Valdovinos, Hector F.; Hernandez, Reinier; Barnhart, Todd E.; Cai, Weibo

    2014-01-01

    Aim Development of multifunctional and well-dispersed hollow mesoporous silica nanoparticles (HMSNs) for tumor vasculature targeted drug delivery and positron emission tomography (PET) imaging. Materials and Methods Amine functionalized HMSNs (150–250 nm) were conjugated with a macrocyclic chelator, NOTA, PEGylated and loaded with anti-angiogenesis drug, Sunitinib. Cyclo(Arg-Gly-Asp-D-Tyr-Lys) (cRGDyK) peptide was attached to the nanoconjugate and radiolabeled with 64Cu for PET imaging. Results 64Cu-NOTA-HMSN-PEG-cRGDyK exhibited integrin specific uptake both in vitro and in vivo. PET results indicated ~ 8 %ID/g uptake of targeted nanoconjugates in U87MG tumors, which correlated well with ex vivo and histological analyses. Enhanced tumor targeted delivery of sunitinib was also observed. Conclusions We successfully developed tumor vasculature targeted HMSNs for PET imaging and image guided drug delivery. PMID:25955122

  16. Long-term Effects of Epoprostenol on the Pulmonary Vasculature in Idiopathic Pulmonary Arterial Hypertension

    PubMed Central

    Pogoriler, Jennifer; Husain, Aliya N.; Toth, Peter T.; Gomberg-Maitland, Mardi; Archer, Stephen L.

    2010-01-01

    The current treatment of pulmonary arterial hypertension (PAH) uses vasodilator drugs. Although they improve symptoms associated with PAH, their chronic effects on the pulmonary vasculature and the right ventricle (RV) in humans remain unknown. We report the autopsy findings from a patient with idiopathic PAH treated with epoprostenol successfully for 18 years. The patient died of colon cancer. The pulmonary vasculature surprisingly showed extensive changes of a proliferative vasculopathy. Immunohistochemical studies confirmed ongoing cellular proliferation. Studies of the RV demonstrated concentric hypertrophy with seemingly preserved contractility. The myocardium shifted to glycolytic metabolism. Although the long-term use of epoprostenol contributed to the patient’s increased survival, it did not prevent progression of the underlying vascular disease. Remarkably, the RV was able to sustain a normal cardiac output in the face of advanced vascular pathology. The mechanisms by which the RV adapts to chronic PAH need further study. PMID:21051399

  17. A model for gas and nutrient exchange in the chorionic vasculature system of the mouse placenta

    NASA Astrophysics Data System (ADS)

    Mirbod, Parisa; Sled, John

    2015-11-01

    The aim of this study is to develop an analytical model for the oxygen and nutrient transport from the umbilical cord to the small villous capillaries. The nutrient and carbon dioxide removal from the fetal cotyledons in the mouse placental system has also been considered. This model describes the mass transfer between the fetal and the maternal red blood cells in the chorionic arterial vasculature system. The model reveals the detail fetal vasculature system and its geometry and the precise mechanisms of mass transfer through the placenta. The dimensions of the villous capillaries, the total length of the villous trees, the total villi surface area, and the total resistance to mass transport in the fetal villous trees has also been defined. This is the first effort to explain the reason why there are at least 7 lobules in the mouse placenta from the fluid dynamics point of view.

  18. Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature.

    PubMed

    Srinivasan, R Sathish; Dillard, Miriam E; Lagutin, Oleg V; Lin, Fu-Jung; Tsai, Sophia; Tsai, Ming-Jer; Samokhvalov, Igor M; Oliver, Guillermo

    2007-10-01

    The origin of the mammalian lymphatic vasculature has been debated for more than 100 years. Whether lymphatic endothelial cells have a single or dual, venous or mesenchymal origin remains controversial. To resolve this debate, we performed Cre/loxP-based lineage-tracing studies using mouse strains expressing Cre recombinase under the control of the Tie2, Runx1, or Prox1 promoter elements. These studies, together with the analysis of Runx1-mutant embryos lacking definitive hematopoiesis, conclusively determined that from venous-derived lymph sacs, lymphatic endothelial cells sprouted, proliferated, and migrated to give rise to the entire lymphatic vasculature, and that hematopoietic cells did not contribute to the developing lymph sacs. We conclude that the mammalian lymphatic system has a solely venous origin.

  19. Peptides as targeting probes against tumor vasculature for diagnosis and drug delivery

    PubMed Central

    2012-01-01

    Tumor vasculature expresses a distinct set of molecule signatures on the endothelial cell surface different from the resting blood vessels of other organs and tissues in the body. This makes them an attractive target for cancer therapy and molecular imaging. The current technology using the in vivo phage display biopanning allows us to quickly isolate and identify peptides potentially homing to various tumor blood vessels. Tumor-homing peptides in conjugation with chemotherapeutic drugs or imaging contrast have been extensively tested in various preclinical and clinical studies. These tumor-homing peptides have valuable potential as targeting probes for tumor molecular imaging and drug delivery. In this review, we summarize the recent advances about the applications of tumor-homing peptides selected by in vivo phage display library screening against tumor vasculature. We also introduce the characteristics of the latest discovered tumor-penetrating peptides in their potential clinical applications. PMID:23046982

  20. The biomechanical properties of an epithelial tissue determine the location of its vasculature

    PubMed Central

    Kragl, Martin; Schubert, Rajib; Karsjens, Haiko; Otter, Silke; Bartosinska, Barbara; Jeruschke, Kay; Weiss, Jürgen; Chen, Chunguang; Alsteens, David; Kuss, Oliver; Speier, Stephan; Eberhard, Daniel; Müller, Daniel J.; Lammert, Eckhard

    2016-01-01

    An important question is how growing tissues establish a blood vessel network. Here we study vascular network formation in pancreatic islets, endocrine tissues derived from pancreatic epithelium. We find that depletion of integrin-linked kinase (ILK) in the pancreatic epithelial cells of mice results in glucose intolerance due to a loss of the intra-islet vasculature. In turn, blood vessels accumulate at the islet periphery. Neither alterations in endothelial cell proliferation, apoptosis, morphology, Vegfa expression and VEGF-A secretion nor ‘empty sleeves' of vascular basement membrane are found. Instead, biophysical experiments reveal that the biomechanical properties of pancreatic islet cells, such as their actomyosin-mediated cortex tension and adhesive forces to endothelial cells, are significantly changed. These results suggest that a sorting event is driving the segregation of endothelial and epithelial cells and indicate that the epithelial biomechanical properties determine whether the blood vasculature invades or envelops a growing epithelial tissue. PMID:27995929

  1. A vasculature-associated niche for undifferentiated spermatogonia in the mouse testis.

    PubMed

    Yoshida, Shosei; Sukeno, Mamiko; Nabeshima, Yo-Ichi

    2007-09-21

    Mammalian spermatogenesis produces numerous sperm for a long period based on a highly potent stem cell system, which relies on a special microenvironment, or niche, that has not yet been identified. In this study, using time-lapse imaging of green fluorescent protein-labeled undifferentiated spermatogonia (A(undiff)) and three-dimensional reconstitution, we revealed a biased localization of A(undiff) to the vascular network and accompanying Leydig and other interstitial cells, in intact testes. Differentiating spermatogonia left these niche regions and dispersed throughout the basal compartment of the seminiferous epithelium. Moreover, rearrangement of A(undiff) accompanied the vasculature alteration. We propose that the mammalian germline niche is established as a consequence of vasculature pattern formation. This is different from what is observed in Drosophila or Caenorhabditis elegans, which display developmentally specified niche structures within polarized gonads.

  2. Peptides as targeting probes against tumor vasculature for diagnosis and drug delivery.

    PubMed

    Li, Zhi Jie; Cho, Chi Hin

    2012-09-19

    Tumor vasculature expresses a distinct set of molecule signatures on the endothelial cell surface different from the resting blood vessels of other organs and tissues in the body. This makes them an attractive target for cancer therapy and molecular imaging. The current technology using the in vivo phage display biopanning allows us to quickly isolate and identify peptides potentially homing to various tumor blood vessels. Tumor-homing peptides in conjugation with chemotherapeutic drugs or imaging contrast have been extensively tested in various preclinical and clinical studies. These tumor-homing peptides have valuable potential as targeting probes for tumor molecular imaging and drug delivery. In this review, we summarize the recent advances about the applications of tumor-homing peptides selected by in vivo phage display library screening against tumor vasculature. We also introduce the characteristics of the latest discovered tumor-penetrating peptides in their potential clinical applications.

  3. Sensitivity of CFD based hemodynamic results in rabbit aneurysm models to idealizations in surrounding vasculature.

    PubMed

    Zeng, Zijing; Kallmes, David F; Durka, Michael J; Ding, Yonghong; Lewis, Debra; Kadirvel, Ramanathan; Robertson, Anne M

    2010-09-01

    Computational fluid dynamics (CFD) studies provide a valuable tool for evaluating the role of hemodynamics in vascular diseases such as cerebral aneurysms and atherosclerosis. However, such models necessarily only include isolated segments of the vasculature. In this work, we evaluate the influence of geometric approximations in vascular anatomy on hemodynamics in elastase induced saccular aneurysms in rabbits. One representative high aspect ratio (AR-height/neck width) aneurysm and one low AR aneurysm were created at the origin of the right common carotid artery in two New Zealand white rabbits. Three-dimensional (3D) reconstructions of the aneurysm and surrounding arteries were created using 3D rotational angiographic data. Five models with varying extents of neighboring vasculature were created for both the high and low AR cases. A reference model included the aneurysm sac, left common carotid artery (LCCA), aortic arch, and downstream trifurcation/quadrification. Three-dimensional, pulsatile CFD studies were performed and streamlines, wall shear stress (WSS), oscillatory shear index, and cross sectional velocity were compared between the models. The influence of the vascular domain on intra-aneurysmal hemodynamics varied between the low and high AR cases. For the high AR case, even a simple model including only the aneurysm, a small section of neighboring vasculature, and simple extensions captured the main features of the steamline and WSS distribution predicted by the reference model. However, the WSS distribution in the low AR case was more strongly influenced by the extent of vasculature. In particular, it was necessary to include the downstream quadrification and upstream LCCA to obtain good predictions of WSS. The findings in this work demonstrate the accuracy of CFD results can be compromised if insufficient neighboring vessels are included in studies of hemodynamics in elastase induced rabbit aneurysms. Consideration of aspect ratio, hemodynamic

  4. c-Kit Receptor Signaling Regulates Islet Vasculature, β-Cell Survival, and Function In Vivo.

    PubMed

    Feng, Zhi-Chao; Popell, Alex; Li, Jinming; Silverstein, Jenna; Oakie, Amanda; Yee, Siu-Pok; Wang, Rennian

    2015-11-01

    The receptor tyrosine kinase c-Kit plays an integral role in maintaining β-cell mass and function. Although c-Kit receptor signaling promotes angiogenesis in multiple cell types, its role in islet vasculature is unknown. This study examines the effects of c-Kit-mediated vascular endothelial growth factor isoform A (VEGF-A) and islet vascularization on β-cell function and survival using in vitro cell culture and in vivo mouse models. In cultured INS-1 cells and primary islets, c-Kit regulates VEGF-A expression via the Akt/mammalian target of rapamycin (mTOR) signaling pathway. Juvenile mice with mutated c-Kit (c-Kit(Wv/+)) showed impaired islet vasculature and β-cell dysfunction, while restoring c-Kit expression in β-cells of c-Kit(Wv/+) mice rescued islet vascular defects through modulation of the Akt/mTOR/VEGF-A pathway, indicating that c-Kit signaling in β-cells is a required regulator for maintaining normal islet vasculature. Furthermore, β-cell-specific c-Kit overexpression (c-KitβTg) in aged mice showed significantly increased islet vasculature and β-cell function, but, when exposed to a long-term high-fat diet, c-Kit signaling in c-KitβTg mice induced substantial vascular remodeling, which resulted in increased islet inflammatory responses and β-cell apoptosis. These results suggest that c-Kit-mediated VEGF-A action in β-cells plays a pivotal role in maintaining islet vascularization and function.

  5. Morphologic Response of the Pulmonary Vasculature to Endoscopic Lung Volume Reduction

    PubMed Central

    Rahaghi, Farbod N.; Come, Carolyn E.; Ross, James C.; Harmouche, Rola; Diaz, Alejandro A.; Estépar, Raul San José; Washko, George R.

    2015-01-01

    Introduction: Endoscopic lung volume reduction has been used to reduce lung hyperinflation in selected patients with severe emphysema. Little is known about the effect of this procedure on the intraparenchymal pulmonary vasculature. In this study we used computed tomography (CT)- based vascular reconstruction to quantify the effect of the procedure on the pulmonary vasculature. Methods: Intraparenchymal vasculature was reconstructed and quantified in 12 patients with CT scans at baseline and 12 weeks following bilateral introduction of sealants in the upper lobes. The volume of each lung and each lobe was measured, and the vascular volume profile was calculated for both lower lobes. The detected vasculature was further labeled manually as arterial or venous in the right lower lobe. Results: There was an increase in the volume of the lower lobes (3.14L to 3.25L, p=0.0005). There was an increase in BV5, defined as the volume of blood vessels with cross sectional area of less than 5mm2, (53.2ml to 57.9ml, p=0.03). This was found to be correlated with the increase in lower lobe volumes (R=0.65, p=0.02). The changes appear to be symmetric for veins and arteries with a correlation coefficient of 0.87 and a slope of near identity. Conclusion: In the individuals studied, there was an increase, from baseline, in BV5 in the lower lobes that correlated with the change in the volume of the lower lobes. The change appeared to be symmetric for both arteries and veins. The study illustrates the use of intraparenchymal pulmonary vascular reconstruction to study morphologic changes in response to interventions. PMID:26587564

  6. βA3/A1-crystallin and persistent fetal vasculature (PFV) disease of the eye☆

    PubMed Central

    Zigler, J. Samuel; Valapala, Mallika; Shang, Peng; Hose, Stacey; Goldberg, Morton F.; Sinha, Debasish

    2015-01-01

    Background Persistent fetal vasculature (PFV) is a human disease in which the fetal vasculature of the eye fails to regress normally. The fetal, or hyaloid, vasculature nourishes the lens and retina during ocular development, subsequently regressing after formation of the retinal vessels. PFV causes serious congenital pathologies and is responsible for as much as 5% of blindness in the United States. Scope of review The causes of PFV are poorly understood, however there are a number of animal models in which aspects of the disease are present. One such model results from mutation or elimination of the gene (Cryba1) encoding βA3/A1-crystallin. In this review we focus on the possible mechanisms whereby loss of functional βA3/A1-crystallin might lead to PFV. Major conclusions Cryba1 is abundantly expressed in the lens, but is also expressed in certain other ocular cells, including astrocytes. In animal models lacking βA3/A1-crystallin, astrocyte numbers are increased and they migrate abnormally from the retina to ensheath the persistent hyaloid artery. Evidence is presented that the absence of functional βA3/A1-crystallin causes failure of the normal acidification of endolysosomal compartments in the astrocytes, leading to impairment of certain critical signaling pathways, including mTOR and Notch/STAT3. General significance The findings suggest that impaired endolysosomal signaling in ocular astrocytes can cause PFV disease, by adversely affecting the vascular remodeling processes essential to ocular development, including regression of the fetal vasculature. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease. PMID:26022148

  7. Quantitative in vivo optical tomography of cancer progression & vasculature development in adult zebrafish

    PubMed Central

    Kumar, Sunil; Lockwood, Nicola; Ramel, Marie-Christine; Correia, Teresa; Ellis, Matthew; Alexandrov, Yuriy; Andrews, Natalie; Patel, Rachel; Bugeon, Laurence; Dallman, Margaret J.; Brandner, Sebastian; Arridge, Simon; Katan, Matilda; McGinty, James; Frankel, Paul; French, Paul M.W.

    2016-01-01

    We describe a novel approach to study tumour progression and vasculature development in vivo via global 3-D fluorescence imaging of live non-pigmented adult zebrafish utilising angularly multiplexed optical projection tomography with compressive sensing (CS-OPT). This “mesoscopic” imaging method bridges a gap between established ~μm resolution 3-D fluorescence microscopy techniques and ~mm-resolved whole body planar imaging and diffuse tomography. Implementing angular multiplexing with CS-OPT, we demonstrate the in vivo global imaging of an inducible fluorescently labelled genetic model of liver cancer in adult non-pigmented zebrafish that also present fluorescently labelled vasculature. In this disease model, addition of a chemical inducer (doxycycline) drives expression of eGFP tagged oncogenic K-RASV12 in the liver of immune competent animals. We show that our novel in vivo global imaging methodology enables non-invasive quantitative imaging of the development of tumour and vasculature throughout the progression of the disease, which we have validated against established methods of pathology including immunohistochemistry. We have also demonstrated its potential for longitudinal imaging through a study of vascular development in the same zebrafish from early embryo to adulthood. We believe that this instrument, together with its associated analysis and data management tools, constitute a new platform for in vivo cancer studies and drug discovery in zebrafish disease models. PMID:27259259

  8. Adaptive Image Enhancement for Tracing 3D Morphologies of Neurons and Brain Vasculatures.

    PubMed

    Zhou, Zhi; Sorensen, Staci; Zeng, Hongkui; Hawrylycz, Michael; Peng, Hanchuan

    2015-04-01

    It is important to digitally reconstruct the 3D morphology of neurons and brain vasculatures. A number of previous methods have been proposed to automate the reconstruction process. However, in many cases, noise and low signal contrast with respect to the image background still hamper our ability to use automation methods directly. Here, we propose an adaptive image enhancement method specifically designed to improve the signal-to-noise ratio of several types of individual neurons and brain vasculature images. Our method is based on detecting the salient features of fibrous structures, e.g. the axon and dendrites combined with adaptive estimation of the optimal context windows where such saliency would be detected. We tested this method for a range of brain image datasets and imaging modalities, including bright-field, confocal and multiphoton fluorescent images of neurons, and magnetic resonance angiograms. Applying our adaptive enhancement to these datasets led to improved accuracy and speed in automated tracing of complicated morphology of neurons and vasculatures.

  9. Endocrine vasculatures are preferable targets of an antitumor ineffective low dose of anti-VEGF therapy

    PubMed Central

    Zhang, Yin; Yang, Yunlong; Hosaka, Kayoko; Huang, Guichun; Zang, Jingwu; Chen, Fang; Zhang, Yun; Samani, Nilesh J.; Cao, Yihai

    2016-01-01

    Anti-VEGF–based antiangiogenic drugs are designed to block tumor angiogenesis for treatment of cancer patients. However, anti-VEGF drugs produce off-tumor target effects on multiple tissues and organs and cause broad adverse effects. Here, we show that vasculatures in endocrine organs were more sensitive to anti-VEGF treatment than tumor vasculatures. In thyroid, adrenal glands, and pancreatic islets, systemic treatment with low doses of an anti-VEGF neutralizing antibody caused marked vascular regression, whereas tumor vessels remained unaffected. Additionally, a low dose of VEGF blockade significantly inhibited the formation of thyroid vascular fenestrae, leaving tumor vascular structures unchanged. Along with vascular structural changes, the low dose of VEGF blockade inhibited vascular perfusion and permeability in thyroid, but not in tumors. Prolonged treatment with the low-dose VEGF blockade caused hypertension and significantly decreased circulating levels of thyroid hormone free-T3 and -T4, leading to functional impairment of thyroid. These findings show that the fenestrated microvasculatures in endocrine organs are more sensitive than tumor vasculatures in response to systemic anti-VEGF drugs. Thus, our data support the notion that clinically nonbeneficial treatments with anti-VEGF drugs could potentially cause adverse effects. PMID:27035988

  10. Visualization of vasculature using a hand-held photoacoustic probe: phantom and in vivo validation

    NASA Astrophysics Data System (ADS)

    Heres, H. Maarten; Arabul, Mustafa Umit; Rutten, Marcel C. M.; Van de Vosse, Frans N.; Lopata, Richard G. P.

    2017-04-01

    Assessment of microvasculature and tissue perfusion can provide diagnostic information on local or systemic diseases. Photoacoustic (PA) imaging has strong clinical potential because of its sensitivity to hemoglobin. We used a hand-held PA probe with integrated diode lasers and examined its feasibility and validity in the detection of increasing blood volume and (sub) dermal vascularization. Blood volume detection was tested in custom-made perfusion phantoms. Results showed that an increase of blood volume in a physiological range of 1.3% to 5.4% could be detected. The results were validated with power Doppler sonography. Using a motorized scanning setup, areas of the skin were imaged at relatively short scanning times (<10 s/cm2) with PA. Three-dimensional visualization of these structures was achieved by combining the consecutively acquired cross-sectional images. Images revealed the epidermis and submillimeter vasculature up to depth of 5 mm. The geometries of imaged vasculature were validated with segmentation of the vasculature in high-frequency ultrasound imaging. This study proves the feasibility of PA imaging in its current implementation for the detection of perfusion-related parameters in skin and subdermal tissue and underlines its potential as a diagnostic tool in vascular or dermal pathologies.

  11. Quantitative in vivo optical tomography of cancer progression & vasculature development in adult zebrafish.

    PubMed

    Kumar, Sunil; Lockwood, Nicola; Ramel, Marie-Christine; Correia, Teresa; Ellis, Matthew; Alexandrov, Yuriy; Andrews, Natalie; Patel, Rachel; Bugeon, Laurence; Dallman, Margaret J; Brandner, Sebastian; Arridge, Simon; Katan, Matilda; McGinty, James; Frankel, Paul; French, Paul M W

    2016-07-12

    We describe a novel approach to study tumour progression and vasculature development in vivo via global 3-D fluorescence imaging of live non-pigmented adult zebrafish utilising angularly multiplexed optical projection tomography with compressive sensing (CS-OPT). This "mesoscopic" imaging method bridges a gap between established ~μm resolution 3-D fluorescence microscopy techniques and ~mm-resolved whole body planar imaging and diffuse tomography. Implementing angular multiplexing with CS-OPT, we demonstrate the in vivo global imaging of an inducible fluorescently labelled genetic model of liver cancer in adult non-pigmented zebrafish that also present fluorescently labelled vasculature. In this disease model, addition of a chemical inducer (doxycycline) drives expression of eGFP tagged oncogenic K-RASV12 in the liver of immune competent animals. We show that our novel in vivo global imaging methodology enables non-invasive quantitative imaging of the development of tumour and vasculature throughout the progression of the disease, which we have validated against established methods of pathology including immunohistochemistry. We have also demonstrated its potential for longitudinal imaging through a study of vascular development in the same zebrafish from early embryo to adulthood. We believe that this instrument, together with its associated analysis and data management tools, constitute a new platform for in vivo cancer studies and drug discovery in zebrafish disease models.

  12. In vivo preclinical photoacoustic imaging of tumor vasculature development and therapy.

    PubMed

    Laufer, Jan; Johnson, Peter; Zhang, Edward; Treeby, Bradley; Cox, Ben; Pedley, Barbara; Beard, Paul

    2012-05-01

    The use of a novel all-optical photoacoustic scanner for imaging the development of tumor vasculature and its response to a therapeutic vascular disrupting agent is described. The scanner employs a Fabry-Perot polymer film ultrasound sensor for mapping the photoacoustic waves and an image reconstruction algorithm based upon attenuation-compensated acoustic time reversal. The system was used to noninvasively image human colorectal tumor xenografts implanted subcutaneously in mice. Label-free three-dimensional in vivo images of whole tumors to depths of almost 10 mm with sub-100-micron spatial resolution were acquired in a longitudinal manner. This enabled the development of tumor-related vascular features, such as vessel tortuosity, feeding vessel recruitment, and necrosis to be visualized over time. The system was also used to study the temporal evolution of the response of the tumor vasculature following the administration of a therapeutic vascular disrupting agent (OXi4503). This revealed the well-known destruction and recovery phases associated with this agent. These studies illustrate the broader potential of this technology as an imaging tool for the preclinical and clinical study of tumors and other pathologies characterized by changes in the vasculature.

  13. The association between retinal vasculature changes and stroke: a literature review and Meta-analysis

    PubMed Central

    Wu, Hui-Qun; Wu, Huan; Shi, Li-Li; Yu, Li-Yuan; Wang, Li-Yuan; Chen, Ya-Lan; Geng, Jin-Song; Shi, Jian; Jiang, Kui; Dong, Jian-Cheng

    2017-01-01

    AIM To determine the association between retinal vasculature changes and stroke. METHODS MEDLINE and EMBASE were searched for relevant human studies to September 2015 that investigated the association between retinal vasculature changes and the prevalence or incidence of stroke; the studies were independently examined for their qualities. Data on clinical characteristics and calculated summary odds ratios (ORs) were extracted for associations between retinal microvascular abnormalities and stroke, including stroke subtypes where possible, and adjusted for key variables. RESULTS Nine cases were included in the study comprising 20 659 patients, 1178 of whom were stroke patients. The retinal microvascular morphological markers used were hemorrhage, microaneurysm, vessel caliber, arteriovenous nicking, and fractal dimension. OR of retinal arteriole narrowing and retinal arteriovenous nicking and stroke was 1.42 and 1.91, respectively, indicating that a small-caliber retinal arteriole and retinal arteriovenous nicking were associated with stroke. OR of retinal hemorrhage and retinal microaneurysm and stroke was 3.21 and 3.83, respectively, indicating that retinal microvascular lesions were highly associated with stroke. Results also showed that retinal fractal dimension reduction was associated with stroke (OR: 2.28 for arteriole network, OR: 1.80 for venular network). CONCLUSION Retinal vasculature changes have a specific relationship to stroke, which is promising evidence for the prediction of stroke using computerized retinal vessel analysis. PMID:28149786

  14. Revisiting tumor angiogenesis: vessel co-option, vessel remodeling, and cancer cell-derived vasculature formation.

    PubMed

    Qian, Chao-Nan; Tan, Min-Han; Yang, Jun-Ping; Cao, Yun

    2016-01-08

    Tumor growth and metastasis depend on the establishment of tumor vasculature to provide oxygen, nutrients, and other essential factors. The well-known vascular endothelial growth factor (VEGF) signaling is crucial for sprouting angiogenesis as well as recruitment of circulating progenitor endothelial cells to tumor vasculature, which has become therapeutic targets in clinical practice. However, the survival benefits gained from targeting VEGF signaling have been very limited, with the inevitable development of treatment resistance. In this article, we discuss the most recent findings and understanding on how solid tumors evade VEGF-targeted therapy, with a special focus on vessel co-option, vessel remodeling, and tumor cell-derived vasculature establishment. Vessel co-option may occur in tumors independently of sprouting angiogenesis, and sprouting angiogenesis is not always required for tumor growth. The differences between vessel-like structure and tubule-like structure formed by tumor cells are also introduced. The exploration of the underlying mechanisms of these alternative angiogenic approaches would not only widen our knowledge of tumor angiogenesis but also provide novel therapeutic targets for better controlling cancer growth and metastasis.

  15. Targeted drug delivery to tumor vasculature by a carbohydrate mimetic peptide

    PubMed Central

    Hatakeyama, Shingo; Sugihara, Kazuhiro; Shibata, Toshiaki K.; Nakayama, Jun; Akama, Tomoya O.; Tamura, Naoaki; Wong, Shuk-Man; Bobkov, Andrey A.; Takano, Yutaka; Ohyama, Chikara; Fukuda, Minoru; Fukuda, Michiko N.

    2011-01-01

    Although numerous carbohydrates play significant roles in mammalian cells, carbohydrate-based drug discovery has not been explored due to the technical difficulty of chemically synthesizing complex carbohydrate structures. Previously, we identified a series of carbohydrate mimetic peptides and found that a 7-mer peptide, designated I-peptide, inhibits hematogenous carbohydrate-dependent cancer cell colonization. During analysis of the endothelial surface receptor for I-peptide, we found that I-peptide bound to annexin 1 (Anxa1). Because Anxa1 is a highly specific tumor vasculature surface marker, we hypothesized that an I-peptide-like peptide could target anticancer drugs to the tumor vasculature. This study identifies IFLLWQR peptide, designated IF7, as homing to tumors. When synthetic IF7 peptide was conjugated to fluorescent Alexa 488 (A488) and injected intravenously into tumor-bearing mice, IF7-A488 targeted tumors within minutes. IF7 conjugated to the potent anticancer drug SN-38 and injected intravenously into nude mice carrying human colon HCT116 tumors efficiently suppressed tumor growth at low dosages with no apparent side effects. These results suggest that IF7 serves as an efficient drug delivery vehicle by targeting Anxa1 expressed on the surface of tumor vasculature. Given its extremely specific tumor-targeting activity, IF7 may represent a clinically relevant vehicle for anticancer drugs. PMID:22114188

  16. Tissue Myeloid Progenitors Differentiate into Pericytes through TGF-β Signaling in Developing Skin Vasculature.

    PubMed

    Yamazaki, Tomoko; Nalbandian, Ani; Uchida, Yutaka; Li, Wenling; Arnold, Thomas D; Kubota, Yoshiaki; Yamamoto, Seiji; Ema, Masatsugu; Mukouyama, Yoh-Suke

    2017-03-21

    Mural cells (pericytes and vascular smooth muscle cells) are essential for the regulation of vascular networks and maintenance of vascular integrity, but their origins are diverse in different tissues and not known in the organs that arise from the ectoderm, such as skin. Here, we show that tissue-localized myeloid progenitors contribute to pericyte development in embryonic skin vasculature. A series of in vivo fate-mapping experiments indicates that tissue myeloid progenitors differentiate into pericytes. Furthermore, depletion of tissue myeloid cells and their progenitors in PU.1 (also known as Spi1) mutants results in defective pericyte development. Fluorescence-activated cell sorting (FACS)-isolated myeloid cells and their progenitors from embryonic skin differentiate into pericytes in culture. At the molecular level, transforming growth factor-β (TGF-β) induces pericyte differentiation in culture. Furthermore, type 2 TGF-β receptor (Tgfbr2) mutants exhibit deficient pericyte development in skin vasculature. Combined, these data suggest that pericytes differentiate from tissue myeloid progenitors in the skin vasculature through TGF-β signaling.

  17. Bim is Responsible for the Inherent Sensitivity of the Developing Retinal Vasculature to Hyperoxia

    PubMed Central

    Wang, Shoujian; Park, SunYoung; Fei, Ping; Sorenson, Christine M.

    2010-01-01

    Apoptosis plays an important role in development and remodeling of vasculature during organogenesis. Coordinated branching and remodeling of the retinal vascular tree is essential for normal retinal function. Bcl-2 family members, such as bim can not only influence apoptosis, but also cell adhesive and migratory properties essential during vascular development. Here we examined the impact of bim deficiency on postnatal retinal vascularization, as well as retinal neovascularization during oxygen-induced ischemic retinopathy (OIR) and laser-induced choroidal neovascularization. Loss of bim expression was associated with increased retinal vascular density in mature animals. This was mainly attributed to increased numbers of pericytes and endothelial cells. However, the initial spread of the superficial layer of retinal vasculature and, the appearance and density of the tip cells were similar in bim +/+ and bim -/- mice. In addition, hyaloid vessel regression was attenuated in the absence of bim. Furthermore, in the absence of bim retinal vessel obliteration and neovascularization did not occur during OIR. Instead, normal inner retinal vascularization proceeded independent of changes in oxygen levels. In contrast, choroidal neovascularization occurred equally well in bim +/+ and bim -/- mice. Together our data suggest bim expression may be responsible for the inherent sensitivity of the developing retinal vasculature to changes in oxygen levels, and promotes vessel obliteration in response to hyperoxia. PMID:21047504

  18. Assessment of variability in cerebral vasculature for neuro-anatomical surgery planning in rodent brain

    NASA Astrophysics Data System (ADS)

    Rangarajan, J. R.; Van Kuyck, K.; Himmelreich, U.; Nuttin, B.; Maes, F.; Suetens, P.

    2011-03-01

    Clinical and pre-clinical studies show that deep brain stimulation (DBS) of targeted brain regions by neurosurgical techniques ameliorate psychiatric disorder such as anorexia nervosa. Neurosurgical interventions in preclinical rodent brain are mostly accomplished manually with a 2D atlas. Considering both the large number of animals subjected to stereotactic surgical experiments and the associated imaging cost, feasibility of sophisticated pre-operative imaging based surgical path planning and/or robotic guidance is limited. Here, we spatially normalize vasculature information and assess the intra-strain variability in cerebral vasculature for a neurosurgery planning. By co-registering and subsequently building a probabilistic vasculature template in a standard space, we evaluate the risk of a user defined electrode trajectory damaging a blood vessel on its path. The use of such a method may not only be confined to DBS therapy in small animals, but also could be readily applicable to a wide range of stereotactic small animal surgeries like targeted injection of contrast agents and cell labeling applications.

  19. Peripheral neuropathy in diabetes.

    PubMed

    Majumder, A; Chatterjee, S; Maji, D

    2013-06-01

    Peripheral neuropathy is common complication of diabetes. The prevalence of peripheral neuropathy among diabetic patients on the basis of loss of vibration sensation had been studied. Detailed clinical history of each patient including age, gender, duration of diabetes, foot ulcer and biothesiometry was recorded in 211 diabetic patients between 20 and 80 years of age. It was observed that all patients under 30 years age (n = 8) felt vibration below 15 volts (no risk zone); 77% (24 out of 31) of the patients in the age group of 30-39 years were in the no risk zone, and 23% (n = 7) had mild peripheral neuropathy. Sixty per cent of the patients between 40 and 50 years (n = 44) were in the no risk zone, while 32% (n = 24) had mild peripheral neuropathy, 5% (n = 4) had moderate neuropathy and 3% (n = 2) had severe peripheral neuropathy. Amongst patients above 50 years of age, 31% (n = 31) were in no risk zone, 34% (n = 34) had mild peripheral neuropathy, 22% (n = 20) had moderate peripheral neuropathy and 13% (n = 13) had severe peripheral neuropathy. Of the patients with diabetes for less than 5 years, 58% had no neuropathy, and only 3% had severe neuropathy. Of the patients with diabetes for 5 to 15 years, 50% had no neuropathy, 30% had mild, and 10% had severe peripheral neuropathy. When patients with diabetes for over 15 years were studied, only 6% had no neuropathy and 19% had severe peripheral neuropathy. The study re-establishes that the severity of peripheral neuropathy increases with age and vibration perception decreses progressively with increased duration of diabetes. Vibration perception threshold testing helps to identify the high risk subjects who require special counselling and education to protect their feet.

  20. Peripheral ameloblastic fibroma.

    PubMed

    Darling, M R; Daley, T D

    2006-03-01

    Peripheral ameloblastic fibroma is an exceedingly rare lesion. Only three reports could be found, two of which appeared in the Japanese literature. Here, we report a case of peripheral ameloblastic fibroma occurring in a 5-year-old girl. The diagnosis was made after careful microscopic examination, to exclude other lesions. The lesion was excised and has not recurred 1 year after removal.

  1. Gold nanoparticle induced vasculature damage in radiotherapy: Comparing protons, megavoltage photons, and kilovoltage photons.

    PubMed

    Lin, Yuting; Paganetti, Harald; McMahon, Stephen J; Schuemann, Jan

    2015-10-01

    The purpose of this work is to investigate the radiosensitizing effect of gold nanoparticle (GNP) induced vasculature damage for proton, megavoltage (MV) photon, and kilovoltage (kV) photon irradiation. Monte Carlo simulations were carried out using tool for particle simulation (TOPAS) to obtain the spatial dose distribution in close proximity up to 20 μm from the GNPs. The spatial dose distribution from GNPs was used as an input to calculate the dose deposited to the blood vessels. GNP induced vasculature damage was evaluated for three particle sources (a clinical spread out Bragg peak proton beam, a 6 MV photon beam, and two kV photon beams). For each particle source, various depths in tissue, GNP sizes (2, 10, and 20 nm diameter), and vessel diameters (8, 14, and 20 μm) were investigated. Two GNP distributions in lumen were considered, either homogeneously distributed in the vessel or attached to the inner wall of the vessel. Doses of 30 Gy and 2 Gy were considered, representing typical in vivo enhancement studies and conventional clinical fractionation, respectively. These simulations showed that for 20 Au-mg/g GNP blood concentration homogeneously distributed in the vessel, the additional dose at the inner vascular wall encircling the lumen was 43% of the prescribed dose at the depth of treatment for the 250 kVp photon source, 1% for the 6 MV photon source, and 0.1% for the proton beam. For kV photons, GNPs caused 15% more dose in the vascular wall for 150 kVp source than for 250 kVp. For 6 MV photons, GNPs caused 0.2% more dose in the vascular wall at 20 cm depth in water as compared to at depth of maximum dose (Dmax). For proton therapy, GNPs caused the same dose in the vascular wall for all depths across the spread out Bragg peak with 12.7 cm range and 7 cm modulation. For the same weight of GNPs in the vessel, 2 nm diameter GNPs caused three times more damage to the vessel than 20 nm diameter GNPs. When the GNPs were attached to the inner vascular wall

  2. Gold nanoparticle induced vasculature damage in radiotherapy: Comparing protons, megavoltage photons, and kilovoltage photons

    PubMed Central

    Lin, Yuting; Paganetti, Harald; McMahon, Stephen J.; Schuemann, Jan

    2015-01-01

    Purpose: The purpose of this work is to investigate the radiosensitizing effect of gold nanoparticle (GNP) induced vasculature damage for proton, megavoltage (MV) photon, and kilovoltage (kV) photon irradiation. Methods: Monte Carlo simulations were carried out using tool for particle simulation (TOPAS) to obtain the spatial dose distribution in close proximity up to 20 μm from the GNPs. The spatial dose distribution from GNPs was used as an input to calculate the dose deposited to the blood vessels. GNP induced vasculature damage was evaluated for three particle sources (a clinical spread out Bragg peak proton beam, a 6 MV photon beam, and two kV photon beams). For each particle source, various depths in tissue, GNP sizes (2, 10, and 20 nm diameter), and vessel diameters (8, 14, and 20 μm) were investigated. Two GNP distributions in lumen were considered, either homogeneously distributed in the vessel or attached to the inner wall of the vessel. Doses of 30 Gy and 2 Gy were considered, representing typical in vivo enhancement studies and conventional clinical fractionation, respectively. Results: These simulations showed that for 20 Au-mg/g GNP blood concentration homogeneously distributed in the vessel, the additional dose at the inner vascular wall encircling the lumen was 43% of the prescribed dose at the depth of treatment for the 250 kVp photon source, 1% for the 6 MV photon source, and 0.1% for the proton beam. For kV photons, GNPs caused 15% more dose in the vascular wall for 150 kVp source than for 250 kVp. For 6 MV photons, GNPs caused 0.2% more dose in the vascular wall at 20 cm depth in water as compared to at depth of maximum dose (Dmax). For proton therapy, GNPs caused the same dose in the vascular wall for all depths across the spread out Bragg peak with 12.7 cm range and 7 cm modulation. For the same weight of GNPs in the vessel, 2 nm diameter GNPs caused three times more damage to the vessel than 20 nm diameter GNPs. When the GNPs were attached

  3. Gold nanoparticle induced vasculature damage in radiotherapy: Comparing protons, megavoltage photons, and kilovoltage photons

    SciTech Connect

    Lin, Yuting Paganetti, Harald; Schuemann, Jan; McMahon, Stephen J.

    2015-10-15

    Purpose: The purpose of this work is to investigate the radiosensitizing effect of gold nanoparticle (GNP) induced vasculature damage for proton, megavoltage (MV) photon, and kilovoltage (kV) photon irradiation. Methods: Monte Carlo simulations were carried out using tool for particle simulation (TOPAS) to obtain the spatial dose distribution in close proximity up to 20 μm from the GNPs. The spatial dose distribution from GNPs was used as an input to calculate the dose deposited to the blood vessels. GNP induced vasculature damage was evaluated for three particle sources (a clinical spread out Bragg peak proton beam, a 6 MV photon beam, and two kV photon beams). For each particle source, various depths in tissue, GNP sizes (2, 10, and 20 nm diameter), and vessel diameters (8, 14, and 20 μm) were investigated. Two GNP distributions in lumen were considered, either homogeneously distributed in the vessel or attached to the inner wall of the vessel. Doses of 30 Gy and 2 Gy were considered, representing typical in vivo enhancement studies and conventional clinical fractionation, respectively. Results: These simulations showed that for 20 Au-mg/g GNP blood concentration homogeneously distributed in the vessel, the additional dose at the inner vascular wall encircling the lumen was 43% of the prescribed dose at the depth of treatment for the 250 kVp photon source, 1% for the 6 MV photon source, and 0.1% for the proton beam. For kV photons, GNPs caused 15% more dose in the vascular wall for 150 kVp source than for 250 kVp. For 6 MV photons, GNPs caused 0.2% more dose in the vascular wall at 20 cm depth in water as compared to at depth of maximum dose (Dmax). For proton therapy, GNPs caused the same dose in the vascular wall for all depths across the spread out Bragg peak with 12.7 cm range and 7 cm modulation. For the same weight of GNPs in the vessel, 2 nm diameter GNPs caused three times more damage to the vessel than 20 nm diameter GNPs. When the GNPs were attached

  4. Vascular Endothelial Growth Factor Receptor-2 Promotes the Development of the Lymphatic Vasculature

    PubMed Central

    Dellinger, Michael T.; Meadows, Stryder M.; Wynne, Katherine; Cleaver, Ondine; Brekken, Rolf A.

    2013-01-01

    Vascular endothelial growth factor receptor 2 (VEGFR2) is highly expressed by lymphatic endothelial cells and has been shown to stimulate lymphangiogenesis in adult mice. However, the role VEGFR2 serves in the development of the lymphatic vascular system has not been defined. Here we use the Cre-lox system to show that the proper development of the lymphatic vasculature requires VEGFR2 expression by lymphatic endothelium. We show that Lyve-1wt/Cre;Vegfr2flox/flox mice possess significantly fewer dermal lymphatic vessels than Vegfr2flox/flox mice. Although Lyve-1wt/Cre;Vegfr2flox/flox mice exhibit lymphatic hypoplasia, the lymphatic network is functional and contains all of the key features of a normal lymphatic network (initial lymphatic vessels and valved collecting vessels surrounded by smooth muscle cells (SMCs)). We also show that Lyve-1Cre mice display robust Cre activity in macrophages and in blood vessels in the yolk sac, liver and lung. This activity dramatically impairs the development of blood vessels in these tissues in Lyve-1wt/Cre;Vegfr2flox/flox embryos, most of which die after embryonic day14.5. Lastly, we show that inactivation of Vegfr2 in the myeloid lineage does not affect the development of the lymphatic vasculature. Therefore, the abnormal lymphatic phenotype of Lyve-1wt/Cre;Vegfr2flox/flox mice is due to the deletion of Vegfr2 in the lymphatic vasculature not macrophages. Together, this work demonstrates that VEGFR2 directly promotes the expansion of the lymphatic network and further defines the molecular mechanisms controlling the development of the lymphatic vascular system. PMID:24023956

  5. Maternal heme oxygenase 1 regulates placental vasculature development via angiogenic factors in mice.

    PubMed

    Zhao, Hui; Azuma, Junya; Kalish, Flora; Wong, Ronald J; Stevenson, David K

    2011-11-01

    The placental vasculature is critical for nutrient, gas, and waste exchange between the maternal and fetal systems. Its development depends on the proper expression and interaction of angiogenesis and associated growth factors. Heme oxygenase (HMOX), the enzyme for heme degradation, plays a role in angiogenesis and is highly expressed in the placenta. To evaluate the role of maternal HMOX1, the inducible HMOX isozyme, on placental vasculature formation, mice with a partial deficiency in Hmox1 (Hmox1(+/-)) were used. Three-dimensional images of placental vasculatures as well as spiral arteries from Hmox1(+/+) or Hmox1(+/-) placentas were created by vascular corrosion casting technique and imaged by micro-computerized tomography (microCT). The structures and morphologies of fetomaternal interfaces were observed by histological staining and the ultrastructure of uterine natural killer (uNK) cells, a major regulator in spiral artery remodeling, was analyzed by transmission electron microscopy. A group of growth factors and angiogenic factors from the decidua/mesometrial lymphoid aggregate of pregnancy (MLAp) as well as labyrinth regions were quantified using an angiogenesis PCR array kit and compared between Hmox1(+/+) or Hmox1(+/-) placentas. In conclusion, a partial deficiency of maternal Hmox1 resulted in the malformation of fetomaternal interface, insufficiency of spiral artery remodeling, and alteration of uNK cell differentiation and maturation. These changes were independent of the fetal genotype, but relied on the maternal HMOX1 level, which determined the balance of expression levels of pro- and antiangiogenic factors in the decidua/MLAp region. These results implied that Hmox1 polymorphisms among the human population might contribute to some unexplained cases of pregnancy disorders, such as fetal growth retardation and preeclampsia.

  6. Vascular endothelial growth factor receptor-2 promotes the development of the lymphatic vasculature.

    PubMed

    Dellinger, Michael T; Meadows, Stryder M; Wynne, Katherine; Cleaver, Ondine; Brekken, Rolf A

    2013-01-01

    Vascular endothelial growth factor receptor 2 (VEGFR2) is highly expressed by lymphatic endothelial cells and has been shown to stimulate lymphangiogenesis in adult mice. However, the role VEGFR2 serves in the development of the lymphatic vascular system has not been defined. Here we use the Cre-lox system to show that the proper development of the lymphatic vasculature requires VEGFR2 expression by lymphatic endothelium. We show that Lyve-1(wt/Cre);Vegfr2(flox/flox) mice possess significantly fewer dermal lymphatic vessels than Vegfr2(flox/flox) mice. Although Lyve-1(wt/Cre);Vegfr2(flox/flox) mice exhibit lymphatic hypoplasia, the lymphatic network is functional and contains all of the key features of a normal lymphatic network (initial lymphatic vessels and valved collecting vessels surrounded by smooth muscle cells (SMCs)). We also show that Lyve-1(Cre) mice display robust Cre activity in macrophages and in blood vessels in the yolk sac, liver and lung. This activity dramatically impairs the development of blood vessels in these tissues in Lyve-1(wt/Cre);Vegfr2(flox/flox) embryos, most of which die after embryonic day14.5. Lastly, we show that inactivation of Vegfr2 in the myeloid lineage does not affect the development of the lymphatic vasculature. Therefore, the abnormal lymphatic phenotype of Lyve-1(wt/Cre);Vegfr2(flox/flox) mice is due to the deletion of Vegfr2 in the lymphatic vasculature not macrophages. Together, this work demonstrates that VEGFR2 directly promotes the expansion of the lymphatic network and further defines the molecular mechanisms controlling the development of the lymphatic vascular system.

  7. Three-dimensional printed ultrasound and photoacoustic training phantoms for vasculature access (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Nikitichev, Daniil I.; Xia, Wenfeng; West, Simeon J.; Desjardins, Adrien E.; Ourselin, Sebastien; Vercauteren, Tom

    2017-03-01

    Ultrasound (US) imaging is widely used to guide vascular access procedures such as arterial and venous cannulation. As needle visualisation with US imaging can be very challenging, it is easy to misplace the needle in the patient and it can be life threating. Photoacoustic (PA) imaging is well suited to image medical needles and catheters that are commonly used for vascular access. To improve the success rate, a certain level of proficiency is required that can be gained through extensive practice on phantoms. Unfortunately, commercial training phantoms are expensive and custom-made phantoms usually do not replicate the anatomy very well. Thus, there is a great demand for more realistic and affordable ultrasound and photoacoustic imaging phantoms for vasculature access procedures training. Three-dimensional (3D) printing can help create models that replicate complex anatomical geometries. However, the available 3D printed materials do not possess realistic tissue properties. Alternatively, tissue-mimicking materials can be employed using casting and 3D printed moulds but this approach is limited to the creation of realistic outer shapes with no replication of complex internal structures. In this study, we developed a realistic vasculature access phantom using a combination of mineral oil based materials as background tissue and a non-toxic, water dissolvable filament material to create complex vascular structure using 3D printing. US and PA images of the phantoms comprising the complex vasculature network were acquired. The results show that 3D printing can facilitate the fabrication of anatomically realistic training phantoms, with designs that can be customized and shared electronically.

  8. Digital reconstruction and morphometric analysis of human brain arterial vasculature from magnetic resonance angiography

    PubMed Central

    Wright, Susan N.; Kochunov, Peter; Mut, Fernando; Bergamino, Maurizio; Brown, Kerry M.; Mazziotta, John C.; Toga, Arthur W.; Cebral, Juan R.; Ascoli, Giorgio A.

    2014-01-01

    Characterization of the complex branching architecture of cerebral arteries across a representative sample of the human population is important for diagnosing, analyzing, and predicting pathological states. Brain arterial vasculature can be visualized by magnetic resonance angiography (MRA). However, most MRA studies are limited to qualitative assessments, partial morphometric analyses, individual (or small numbers of) subjects, proprietary datasets, or combinations of the above limitations. Neuroinformatics tools, developed for neuronal arbor analysis, were used to quantify vascular morphology from 3 T time-of-flight MRA high-resolution (620 μm isotropic) images collected in 61 healthy volunteers (36/25 F/M, average age = 31.2 ± 10.7, range = 19–64 years). We present in-depth morphometric analyses of the global and local anatomical features of these arbors. The overall structure and size of the vasculature did not significantly differ across genders, ages, or hemispheres. The total length of the three major arterial trees stemming from the circle of Willis (from smallest to largest: the posterior, anterior, and middle cerebral arteries; or PCAs, ACAs, and MCAs, respectively) followed an approximate 1:2:4 proportion. Arterial size co-varied across individuals: subjects with one artery longer than average tended to have all other arteries also longer than average. There was no net right–left difference across the population in any of the individual arteries, but ACAs were more lateralized than MCAs. MCAs, ACAs, and PCAs had similar branch-level properties such as bifurcation angles. Throughout the arterial vasculature, there were considerable differences between branch types: bifurcating branches were significantly shorter and straighter than terminating branches. Furthermore, the length and meandering of bifurcating branches increased with age and with path distance from the circle of Willis. All reconstructions are freely distributed through a public

  9. Altered reactivity of resistance vasculature contributes to hypertension in elastin insufficiency

    PubMed Central

    Knutsen, Russell H.; Kozel, Beth A.; Dietrich, Hans H.; Blumer, Kendall J.; Mecham, Robert P.

    2014-01-01

    Elastin (Eln) insufficiency in mice and humans is associated with hypertension and altered structure and mechanical properties of large arteries. However, it is not known to what extent functional or structural changes in resistance arteries contribute to the elevated blood pressure that is characteristic of Eln insufficiency. Here, we investigated how Eln insufficiency affects the structure and function of the resistance vasculature. A functional profile of resistance vasculature in Eln+/− mice was generated by assessing small mesenteric artery (MA) contractile and vasodilatory responses to vasoactive agents. We found that Eln haploinsufficiency had a modest effect on phenylephrine-induced vasoconstriction, whereas ANG II-evoked vasoconstriction was markedly increased. Blockade of ANG II type 2 receptors with PD-123319 or modulation of Rho kinase activity with the inhibitor Y-27632 attenuated the augmented vasoconstriction, whereas acute Y-27632 administration normalized blood pressure in Eln+/− mice. Sodium nitroprusside- and isoproterenol-induced vasodilatation were normal, whereas ACh-induced vasodilatation was severely impaired in Eln+/− MAs. Histologically, the number of smooth muscle layers did not change in Eln+/− MAs; however, an additional discontinuous layer of Eln appeared between the smooth muscle layers that was absent in wild-type arteries. We conclude that high blood pressure arising from Eln insufficiency is due partly to permanent changes in vascular tone as a result of increased sensitivity of the resistance vasculature to circulating ANG II and to impaired vasodilatory mechanisms arising from endothelial dysfunction characterized by impaired endothelium-dependent vasodilatation. Eln insufficiency causes augmented ANG II-induced vasoconstriction in part through a novel mechanism that facilitates contraction evoked by ANG II type 2 receptors and altered G protein signaling. PMID:24414067

  10. WE-G-BRE-04: Gold Nanoparticle Induced Vasculature Damage for Proton Therapy: Monte Carlo Simulation

    SciTech Connect

    Lin, Y; Paganetti, H; Schuemann, J

    2014-06-15

    Purpose: The aim of this work is to investigate the gold nanoparticle (GNP) induced vasculature damage in a proton beam. We compared the results using a clinical proton beam, 6MV photon beam and two kilovoltage photon beams. Methods: Monte Carlo simulations were carried out using TOPAS (TOol for PArticle Simulation) to obtain the spatial dose distribution in close proximity to GNPs up to 20μm distance. The spatial dose distribution was used as an input to calculate the additional dose deposited to the blood vessels. For this study, GNP induced vasculature damage is evaluated for three particle sources (proton beam, MV photon beam and kV photon beam), various treatment depths for each particle source, various GNP uptakes and three different vessel diameters (8μm, 14μm and 20μm). Results: The result shows that for kV photon, GNPs induce more dose in the vessel wall for 150kVp photon source than 250kVp. For proton therapy, GNPs cause more dose in the vessel wall at shallower treatment depths. For 6MV photons, GNPs induce more dose in the vessel wall at deeper treatment depths. For the same GNP concentration and prescribed dose, the additional dose at the inner vessel wall is 30% more than the prescribed dose for the kVp photon source, 15% more for the proton source and only 2% more for the 6MV photon source. In addition, the dose from GNPs deceases sharper for proton therapy than kVp photon therapy as the distance from the vessel inner wall increases. Conclusion: We show in this study that GNPs can potentially be used to enhance radiation therapy by causing vasculature damage using clinical proton beams. The GNP induced damage for proton therapy is less than for the kVp photon source but significantly larger than for the clinical MV photon source.

  11. A geometric flow for segmenting vasculature in proton-density weighted MRI.

    PubMed

    Descoteaux, Maxime; Collins, D Louis; Siddiqi, Kaleem

    2008-08-01

    Modern neurosurgery takes advantage of magnetic resonance images (MRI) of a patient's cerebral anatomy and vasculature for planning before surgery and guidance during the procedure. Dual echo acquisitions are often performed that yield proton-density (PD) and T2-weighted images to evaluate edema near a tumor or lesion. In this paper we develop a novel geometric flow for segmenting vasculature in PD images, which can also be applied to the easier cases of MR angiography data or Gadolinium enhanced MRI. Obtaining vasculature from PD data is of clinical interest since the acquisition of such images is widespread, the scanning process is non-invasive, and the availability of vessel segmentation methods could obviate the need for an additional angiographic or contrast-based sequence during preoperative imaging. The key idea is to first apply Frangi's vesselness measure [Frangi, A., Niessen, W., Vincken, K.L., Viergever, M.A., 1998. Multiscale vessel enhancement filtering. In: International Conference on Medical Image Computing and Computer Assisted Intervention, vol. 1496 of Lecture Notes in Computer Science, pp. 130-137] to find putative centerlines of tubular structures along with their estimated radii. This measure is then distributed to create a vector field which allows the flux maximizing flow algorithm of Vasilevskiy and Siddiqi [Vasilevskiy, A., Siddiqi, K., 2002. Flux maximizing geometric flows. IEEE Transactions on Pattern Analysis and Machine Intelligence 24 (12), 1565-1578] to be applied to recover vessel boundaries. We carry out a qualitative validation of the approach on PD, MR angiography and Gadolinium enhanced MRI volumes and suggest a new way to visualize the segmentations in 2D with masked projections. We validate the approach quantitatively on a single-subject data set consisting of PD, phase contrast (PC) angiography and time of flight (TOF) angiography volumes, with an expert segmented version of the TOF volume viewed as the ground truth. We then

  12. Antitumor activity of an enzyme prodrug therapy targeted to the breast tumor vasculature.

    PubMed

    Van Rite, Brent D; Krais, John J; Cherry, Mohamad; Sikavitsas, Vassilios I; Kurkjian, Carla; Harrison, Roger G

    2013-10-01

    The L-methioninase-annexin V/selenomethionine enzyme prodrug system, designed to target the tumor vasculature and release the methylselenol anticancer drug in the tumor, was tested in mice with implanted MBA-MB-231 breast tumors. This therapy was able to cause a reduction in the size of the tumors during the treatment period. It was shown that L-methioninase-annexin V was uniformly bound at the blood vessel surface in the tumor and also that there was a substantial cutoff of blood flowing through the treated tumor, consistent with the therapy's design. This new approach for enzyme prodrug therapy of breast cancer appears promising.

  13. In vivo label-free three-dimensional imaging of zebrafish vasculature with optical projection tomography

    NASA Astrophysics Data System (ADS)

    Bassi, Andrea; Fieramonti, Luca; D'Andrea, Cosimo; Mione, Marina; Valentini, Gianluca

    2011-10-01

    We introduce flow optical projection tomography, an imaging technique capable of visualizing the vasculature of living specimens in 3-D. The method detects the movement of cells in the bloodstream and creates flow maps using a motion-analysis procedure. Then, flow maps obtained from projection taken at several angles are used to reconstruct sections of the circulatory system of the specimen. We therefore demonstrate an in vivo, 3-D optical imaging technique that, without the use of any labeling, is able to reconstruct and visualize the vascular network of transparent and weakly scattering living specimens.

  14. Peripheral Arterial Disease

    MedlinePlus

    Peripheral arterial disease (PAD) happens when there is a narrowing of the blood vessels outside of your heart. The cause of ... smoking. Other risk factors include older age and diseases like diabetes, high blood cholesterol, high blood pressure, ...

  15. [Peripheral ulcerative keratitis].

    PubMed

    Stamate, Alina-cristina; Avram, Corina Ioana; Malciolu, R; Oprea, S; Zemba, M

    2014-01-01

    Ulcerative keratitis is frequently associated with collagen vascular diseases and presents a predilection for peripheral corneal localization, due to the distinct morphologic and immunologic features of the limbal conjunctiva, which provides access for the circulating immune complexes to the peripheral cornea via the capillary network. Deposition of immune complexes in the terminal ends of limbal vessels initiates an immune-mediated vasculitis process, with inflammatory cells and mediators involvement by alteration of the vascular permeability. Peripheral ulcerative keratitis generally correlates with exacerbations of the background autoimmune systemic disease. Associated sceritis, specially the necrotizing form, is usually observed in severe cases, which may evolve in corneal perforation and loss of vision. Although the first-line of treatment in acute phases is represented by systemic administration of corticosteroids, immunosuppressive and cytotoxic agents are necessary for the treatment of peripheral ulcerative keratitis associated with systemic diseases.

  16. Transdermal optogenetic peripheral nerve stimulation

    NASA Astrophysics Data System (ADS)

    Maimon, Benjamin E.; Zorzos, Anthony N.; Bendell, Rhys; Harding, Alexander; Fahmi, Mina; Srinivasan, Shriya; Calvaresi, Peter; Herr, Hugh M.

    2017-06-01

    Objective: A fundamental limitation in both the scientific utility and clinical translation of peripheral nerve optogenetic technologies is the optical inaccessibility of the target nerve due to the significant scattering and absorption of light in biological tissues. To date, illuminating deep nerve targets has required implantable optical sources, including fiber-optic and LED-based systems, both of which have significant drawbacks. Approach: Here we report an alternative approach involving transdermal illumination. Utilizing an intramuscular injection of ultra-high concentration AAV6-hSyn-ChR2-EYFP in rats. Main results: We demonstrate transdermal stimulation of motor nerves at 4.4 mm and 1.9 mm depth with an incident laser power of 160 mW and 10 mW, respectively. Furthermore, we employ this technique to accurately control ankle position by modulating laser power or position on the skin surface. Significance: These results have the potential to enable future scientific optogenetic studies of pathologies implicated in the peripheral nervous system for awake, freely-moving animals, as well as a basis for future clinical studies.

  17. Peripheral Tissue Homing Receptor Control of Naïve, Effector, and Memory CD8 T Cell Localization in Lymphoid and Non-Lymphoid Tissues

    PubMed Central

    Brinkman, C. Colin; Peske, J. David; Engelhard, Victor Henry

    2013-01-01

    T cell activation induces homing receptors that bind ligands on peripheral tissue vasculature, programing movement to sites of infection and injury. There are three major types of CD8 effector T cells based on homing receptor expression, which arise in distinct lymphoid organs. Recent publications indicate that naïve, effector, and memory T cell migration is more complex than once thought; while many effectors enter peripheral tissues, some re-enter lymph nodes (LN), and contain central memory precursors. LN re-entry can depend on CD62L or peripheral tissue homing receptors. Memory T cells in LN tend to express the same homing receptors as their forebears, but often are CD62Lneg. Homing receptors also control CD8 T cell tumor entry. Tumor vasculature has low levels of many peripheral tissue homing receptor ligands, but portions of it resemble high endothelial venules (HEV), enabling naïve T cell entry, activation, and subsequent effector activity. This vasculature is associated with positive prognoses in humans, suggesting it may sustain ongoing anti-tumor responses. These findings reveal new roles for homing receptors expressed by naïve, effector, and memory CD8 T cells in controlling entry into lymphoid and non-lymphoid tissues. PMID:23966998

  18. Three-dimensional micro computed tomography analysis of the lung vasculature and differential adipose proteomics in the Sugen/hypoxia rat model of pulmonary arterial hypertension

    PubMed Central

    Verdelis, Kostas; Passineau, Michael J.; Faight, Erin M.; Zourelias, Lee; Wu, Changgong; Chong, Rong; Benza, Raymond L.

    2016-01-01

    Abstract Pulmonary arterial hypertension (PAH) is a rare disease characterized by significant vascular remodeling. The obesity epidemic has produced great interest in the relationship between small visceral adipose tissue depots producing localized inflammatory conditions, which may link metabolism, innate immunity, and vascular remodeling. This study used novel micro computed tomography (microCT) three-dimensional modeling to investigate the degree of remodeling of the lung vasculature and differential proteomics to determine small visceral adipose dysfunction in rats with severe PAH. Sprague-Dawley rats were subjected to a subcutaneous injection of vascular endothelial growth factor receptor blocker (Sugen 5416) with subsequent hypoxia exposure for 3 weeks (SU/hyp). At 12 weeks after hypoxia, microCT analysis showed a decrease in the ratio of vascular to total tissue volume within the SU/hyp group (mean ± standard deviation: 0.27 ± 0.066; P = 0.02) with increased vascular separation (0.37 ± 0.062 mm; P = 0.02) when compared with the control (0.34 ± 0.084 and 0.30 ± 0.072 mm). Differential proteomics detected an up-regulation of complement protein 3 (C3; SU/hyp∶control ratio = 2.86) and the adipose tissue–specific fatty acid binding protein-4 (FABP4, 2.66) in the heart adipose of the SU/hyp. Significant remodeling of the lung vasculature validates the efficacy of the SU/hyp rat for modeling human PAH. The upregulation of C3 and FABP4 within the heart adipose implicates small visceral adipose dysfunction. C3 has been associated with vascular stiffness, and FABP4 suppresses peroxisome proliferator–activated receptor, which is a major regulator of adipose function and known to be downregulated in PAH. These findings reveal that small visceral adipose tissue within the SU/hyp model provides mechanistic links for vascular remodeling and adipose dysfunction in the pathophysiology of PAH. PMID:28090302

  19. Resistance reconstructed estimation of total peripheral resistance from computationally derived cardiac output - biomed 2013.

    PubMed

    Hill, Labarron K; Sollers Iii, John J; Thayer, Julian F

    2013-01-01

    Efficient functioning of the peripheral vasculature is an essential component in healthy cardiovascular regulation. Alterations in this functioning have been linked to the etiology and pathophysiological course of cardiovascular disease (CVD), especially hypertension. Given its significant role in the maintenance of both healthy and pathological blood pressure, total peripheral resistance (TPR), an index of the vasoconstrictive and elastic properties of the peripheral vasculature, has received much attention in this regard. However, obtaining a reliable estimate of TPR remains a complex and costly endeavor, primarily due to the necessity for sophisticated instrumentation as well as associated limitations in deriving cardiac output (CO). We have previously described a simple estimation method for CO using only arterial blood pressure and heart rate (Hill et al, 2012). In the present study we extend this technique to the estimation of TPR using beat-to-beat blood pressure data from the same sample of 67 young (mean age = 20.04± 2.8), healthy men (n = 30) and women (n = 37). Estimated TPR (TPRest) was calculated from the computationally-derived estimate of CO and mean arterial pressure (MAP). Correlation between TPR obtained via the validated Model-Flow technique and TPRest was moderate (r =.73, p <. 000) and stronger in men (r =.78, p <. 000) compared to women (r =.66, p <. 001). These data further suggest that reconstructed measures of hemodynamic functioning may be validly and adequately estimated from limited data sources.

  20. A chronic window imaging device for the investigation of in vivo peripheral nerves.

    PubMed

    Brodnick, Sarah K; Hayat, Mohammed R; Kapur, Sahil; Richner, Thomas J; Nonte, Michael W; Eliceiri, Kevin W; Krugner-Higby, Lisa; Williams, Justin C; Poore, Samuel O

    2014-01-01

    Chronic imaging of the peripheral nervous system with contemporary techniques requires repetitive surgical procedures to reopen an area of interest in order to see underlying biological processes over time. The recurrence of surgical openings on an animal increases trauma, stress, and risk of infection. Such effects can greatly lessen the physiological relevance of any data recorded in this manner. In order to bypass repetitive surgery, a Peripheral Nerve Window (PNW) device has been created for chronic in vivo imaging purposes. Intravital imaging window devices have been used previously to image parts of the rodent model such as the brain, spinal cord, and mammary tissue, but currently have not been used in the peripheral nervous system because of lack of bone anchoring and access to deep nerve tissue. We demonstrate a novel surgical technique in a rat which transposes the sciatic nerve above the surrounding muscle tissue allowing the PNW access to an 8mm section of the nerve. Subsequent days of observation revealed increased vasculature development primarily around the nerve, showing that this preparation can be used to image nerve tissue and surrounding vasculature for up to one week post-implantation.

  1. Morphometric analysis of Passiflora leaves: the relationship between landmarks of the vasculature and elliptical Fourier descriptors of the blade

    PubMed Central

    2017-01-01

    Abstract Background: Leaf shape among Passiflora species is spectacularly diverse. Underlying this diversity in leaf shape are profound changes in the patterning of the primary vasculature and laminar outgrowth. Each of these aspects of leaf morphology—vasculature and blade—provides different insights into leaf patterning. Results: Here, we morphometrically analyze >3300 leaves from 40 different Passiflora species collected sequentially across the vine. Each leaf is measured in two different ways: using 1) 15 homologous Procrustes-adjusted landmarks of the vasculature, sinuses, and lobes; and 2) Elliptical Fourier Descriptors (EFDs), which quantify the outline of the leaf. The ability of landmarks, EFDs, and both datasets together are compared to determine their relative ability to predict species and node position within the vine. Pairwise correlation of x and y landmark coordinates and EFD harmonic coefficients reveals close associations between traits and insights into the relationship between vasculature and blade patterning. Conclusions: Landmarks, more reflective of the vasculature, and EFDs, more reflective of the blade contour, describe both similar and distinct features of leaf morphology. Landmarks and EFDs vary in ability to predict species identity and node position in the vine and exhibit a correlational structure (both within landmark or EFD traits and between the two data types) revealing constraints between vascular and blade patterning underlying natural variation in leaf morphology among Passiflora species. PMID:28369351

  2. Technical Note: Contrast free angiography of the pulmonary vasculature in live mice using a laboratory x-ray source

    PubMed Central

    Samarage, Chaminda R.; Carnibella, Richard; Preissner, Melissa; Jones, Heather D.; Pearson, James T.; Fouras, Andreas; Dubsky, Stephen

    2016-01-01

    Purpose: In vivo imaging of the pulmonary vasculature in small animals is difficult yet highly desirable in order to allow study of the effects of a host of dynamic biological processes such as hypoxic pulmonary vasoconstriction. Here the authors present an approach for the quantification of changes in the vasculature. Methods: A contrast free angiography technique is validated in silico through the use of computer-generated images and in vivo through microcomputed tomography (μCT) of live mice conducted using a laboratory-based x-ray source. Subsequent image processing on μCT data allowed for the quantification of the caliber of pulmonary vasculature without the need for external contrast agents. These measures were validated by comparing with quantitative contrast microangiography in the same mice. Results: Quantification of arterial diameters from the method proposed in this study is validated against laboratory-based x-ray contrast microangiography. The authors find that there is a high degree of correlation (R = 0.91) between measures from microangiography and their contrast free method. Conclusions: A technique for quantification of murine pulmonary vasculature without the need for contrast is presented. As such, this technique could be applied for longitudinal studies of animals to study changes to vasculature without the risk of premature death in sensitive mouse models of disease. This approach may also be of value in the clinical setting. PMID:27806595

  3. Fusion Guidance in Endovascular Peripheral Artery Interventions: A Feasibility Study

    SciTech Connect

    Sailer, Anna M. Haan, Michiel W. de Graaf, Rick de Zwam, Willem H. van; Schurink, Geert Willem H.; Nelemans, Patricia J.; Wildberger, Joachim E. Das, Marco

    2015-04-15

    PurposeThis study was designed to evaluate the feasibility of endovascular guidance by means of live fluoroscopy fusion with magnetic resonance angiography (MRA) and computed tomography angiography (CTA).MethodsFusion guidance was evaluated in 20 endovascular peripheral artery interventions in 17 patients. Fifteen patients had received preinterventional diagnostic MRA and two patients had undergone CTA. Time for fluoroscopy with MRA/CTA coregistration was recorded. Feasibility of fusion guidance was evaluated according to the following criteria: for every procedure the executing interventional radiologists recorded whether 3D road-mapping provided added value (yes vs. no) and whether PTA and/or stenting could be performed relying on the fusion road-map without need for diagnostic contrast-enhanced angiogram series (CEAS) (yes vs. no). Precision of the fusion road-map was evaluated by recording maximum differences between the position of the vasculature on the virtual CTA/MRA images and conventional angiography.ResultsAverage time needed for image coregistration was 5 ± 2 min. Three-dimensional road-map added value was experienced in 15 procedures in 12 patients. In half of the patients (8/17), intervention was performed relying on the fusion road-map only, without diagnostic CEAS. In two patients, MRA roadmap showed a false-positive lesion. Excluding three patients with inordinate movements, mean difference in position of vasculature on angiography and MRA/CTA road-map was 1.86 ± 0.95 mm, implying that approximately 95 % of differences were between 0 and 3.72 mm (2 ± 1.96 standard deviation).ConclusionsFluoroscopy with MRA/CTA fusion guidance for peripheral artery interventions is feasible. By reducing the number of CEAS, this technology may contribute to enhance procedural safety.

  4. Remodeling Tumor Vasculature to Enhance Delivery of Intermediate-Sized Nanoparticles.

    PubMed

    Jiang, Wen; Huang, Yuhui; An, Yi; Kim, Betty Y S

    2015-09-22

    Restoration of dysfunctional tumor vasculature can reestablish the pressure gradient between intravascular and interstitial space that is essential for transporting nanomedicines into solid tumors. Morphologic and functional normalization of tumor vessels improves tissue perfusion to facilitate intratumoral nanoparticle delivery. However, this remodeling process also reduces tumor vessel permeability, which can impair nanoparticle transport. Although nanoparticles sized below 10 nm maximally benefited from tumor vessel normalization therapy for enhanced nanomedicine delivery, the small particle size severely limits its applicability. Here, we show that intermediate-sized nanoparticles (20-40 nm) can also benefit from tumor vasculature remodeling. We demonstrate that a window of opportunity exists for a two-stage transport strategy of different nanoparticle sizes. Overall, tumor vessel remodeling enhances the transvascular delivery of intermediate-size nanoparticles of up to 40 nm. Once within the tumor matrix, however, smaller nanoparticles experience a significantly lesser degree of diffusional hindrance, resulting in a more homogeneous distribution within the tumor interstitium. These findings suggest that antiangiogenic therapy and nanoparticle design can be combined in a multistage fashion, with two sets of size-inclusion criteria, to achieve optimal nanomedicine delivery into solid tumors.

  5. Cosmos 1887: morphology, histochemistry, and vasculature of the growing rat tibia

    NASA Technical Reports Server (NTRS)

    Doty, S. B.; Morey-Holton, E. R.; Durnova, G. N.; Kaplansky, A. S.

    1990-01-01

    Light microscopy, electron microscopy, and enzyme histochemistry were used to study the effects of spaceflight on metaphyseal and cortical bone of the rat tibia. Cortical cross-sectional area and perimeter were not altered by a 12.5-day spaceflight in 3-month-old male rats. The endosteal osteoblast population and the vasculature near the periosteal surface in flight rats compared with ground controls showed more pronounced changes in cortical bone than in metaphyseal bone. The osteoblasts demonstrated greater numbers of transitional Golgi vesicles, possibly caused by a decreased cellular metabolic energy source, but no difference in the large Golgi saccules or the cell membrane-associated alkaline phosphatase activity. The periosteal vasculature in the diaphysis of flight rats often showed lipid accumulations within the lumen of the vessels, occasional degeneration of the vascular wall, and degeneration of osteocytes adjacent to vessels containing intraluminal deposits. These changes were not found in the metaphyseal region of flight animals. The focal vascular changes may be due to ischemia of bone or a developing fragility of the vessel walls as a result of spaceflight.

  6. Swept-source OCT Angiography of the Retinal Vasculature using Intensity Differentiation Based OMAG Algorithms

    PubMed Central

    Huang, Yanping; Zhang, Qinqin; Thorell, Mariana Rossi; An, Lin; Durbin, Mary; Laron, Michal; Sharma, Utkarsh; Gregori, Giovanni; Rosenfeld, Philip J.; Wang, Ruikang K

    2014-01-01

    Background and Objective To demonstrate the feasibility of using a 1050 nm swept-source OCT (SS-OCT) system to achieve noninvasive retinal vasculature imaging in human eyes. Materials and Methods Volumetric datasets were acquired using a ZEISS 1 µm SS-OCT prototype that operated at an A-line rate of 100 kHz. A scanning protocol designed to allow for motion contrast processing, referred to as OCT angiography or optical microangiography (OMAG), was used to scan ~3 mm × 3 mm area in the central macular region of the retina within ~4.5 seconds. Intensity differentiation based OMAG algorithm was used to extract 3-D retinal functional microvasculature information. Results Intensity signal differentiation generated capillary-level resolution en face OMAG images of the retina. The parafoveal capillaries were clearly visible, thereby allowing visualization of the foveal avascular zone (FAZ) in normal subjects. Conclusion The capability of OMAG to produce retinal vascular images was demonstrated using the ZEISS 1 µm SS-OCT prototype. This technique can potentially have clinical value for studying retinal vasculature abnormalities. PMID:25230403

  7. Biomimetic carriers mimicking leukocyte plasma membrane to increase tumor vasculature permeability

    PubMed Central

    Palomba, R.; Parodi, A.; Evangelopoulos, M.; Acciardo, S.; Corbo, C.; de Rosa, E.; Yazdi, I. K.; Scaria, S.; Molinaro, R.; Furman, N. E. Toledano; You, J.; Ferrari, M.; Salvatore, F.; Tasciotti, E.

    2016-01-01

    Recent advances in the field of nanomedicine have demonstrated that biomimicry can further improve targeting properties of current nanotechnologies while simultaneously enable carriers with a biological identity to better interact with the biological environment. Immune cells for example employ membrane proteins to target inflamed vasculature, locally increase vascular permeability, and extravasate across inflamed endothelium. Inspired by the physiology of immune cells, we recently developed a procedure to transfer leukocyte membranes onto nanoporous silicon particles (NPS), yielding Leukolike Vectors (LLV). LLV are composed of a surface coating containing multiple receptors that are critical in the cross-talk with the endothelium, mediating cellular accumulation in the tumor microenvironment while decreasing vascular barrier function. We previously demonstrated that lymphocyte function-associated antigen (LFA-1) transferred onto LLV was able to trigger the clustering of intercellular adhesion molecule 1 (ICAM-1) on endothelial cells. Herein, we provide a more comprehensive analysis of the working mechanism of LLV in vitro in activating this pathway and in vivo in enhancing vascular permeability. Our results suggest the biological activity of the leukocyte membrane can be retained upon transplant onto NPS and is critical in providing the particles with complex biological functions towards tumor vasculature. PMID:27703233

  8. Biomimetic carriers mimicking leukocyte plasma membrane to increase tumor vasculature permeability.

    PubMed

    Palomba, R; Parodi, A; Evangelopoulos, M; Acciardo, S; Corbo, C; de Rosa, E; Yazdi, I K; Scaria, S; Molinaro, R; Furman, N E Toledano; You, J; Ferrari, M; Salvatore, F; Tasciotti, E

    2016-10-05

    Recent advances in the field of nanomedicine have demonstrated that biomimicry can further improve targeting properties of current nanotechnologies while simultaneously enable carriers with a biological identity to better interact with the biological environment. Immune cells for example employ membrane proteins to target inflamed vasculature, locally increase vascular permeability, and extravasate across inflamed endothelium. Inspired by the physiology of immune cells, we recently developed a procedure to transfer leukocyte membranes onto nanoporous silicon particles (NPS), yielding Leukolike Vectors (LLV). LLV are composed of a surface coating containing multiple receptors that are critical in the cross-talk with the endothelium, mediating cellular accumulation in the tumor microenvironment while decreasing vascular barrier function. We previously demonstrated that lymphocyte function-associated antigen (LFA-1) transferred onto LLV was able to trigger the clustering of intercellular adhesion molecule 1 (ICAM-1) on endothelial cells. Herein, we provide a more comprehensive analysis of the working mechanism of LLV in vitro in activating this pathway and in vivo in enhancing vascular permeability. Our results suggest the biological activity of the leukocyte membrane can be retained upon transplant onto NPS and is critical in providing the particles with complex biological functions towards tumor vasculature.

  9. On the way to subcellular imaging of mechanotransduction in the developing vasculature

    NASA Astrophysics Data System (ADS)

    Larina, Irina V.; Wang, Yingxiao; Chien, Shu; Lane, Mary E.; Dickinson, Mary E.

    2007-05-01

    Endothelial cells that comprise vessels and line the heart are known to respond to mechanical forces imparted by fluid flow. It is also known that blood flow is required for vascular remodeling and that abnormal heart contractions lead to the failure of the vasculature to remodel properly. Although there is considerable evidence to indicate that flow is necessary, little is known about how mechanical signals are transduced in endothelial cells in the embryo. This project is focused on understanding the role mechanical forces play in the development of the cardiovascular system using recently generated FRET (Fluorescence Resonance Energy Transfer) reporter that can detect real-time Src-kinase activity in cells using fluorescence microscopy. Src kinase regulates integrin-cytoskeleton interactions that are essential for mechanotransduction, and its activity is upregulated in cultured endothelial cells exposed to flow. Experiments reported here were focused on testing potential feasibility of the proposed technique to sense Src changes in vivo. Successful implementation of this project will reveal previously unknown signaling events involved in the mechanism of vascular remodeling and their relation to the blood flow, thus providing a unique tool for in vivo sub-cellular imaging of mechanotransduction in the vasculature and other organs.

  10. Claudin-5 expression in the vasculature of the developing chick embryo.

    PubMed

    Collins, Michelle M; Baumholtz, Amanda I; Ryan, Aimee K

    2012-01-01

    The claudin family of proteins are integral components of tight junctions and are responsible for determining the ion specificity and permeability of paracellular transport within epithelial and endothelial cell layers. Studies in human, mouse, Xenopus, and zebrafish have shown that only a limited number of claudins are expressed in endothelial cells. Here, we report the expression pattern of Claudin-5 during chick development. Between HH stage 4 and 6 Claudin-5 expression was observed exclusively in extraembryonic tissue. Claudin-5 expression was not observed in the embryo until HH stage 8, coincident with the onset of embryonic vascularization. Claudin-5 expression was maintained in the developing vasculature in the embryonic and extraembryonic tissue throughout organogenesis (HH stage 19-35), including the vasculature of the ectoderm and of organs derived from the mesoderm and endoderm lineages. These data describe a conserved expression pattern for Claudin-5 in the endothelial tight junction barrier and is the first report of the onset of Claudin-5 expression in a vertebrate embryo.

  11. Vasculature segmentation using parallel multi-hypothesis template tracking on heterogeneous platforms

    NASA Astrophysics Data System (ADS)

    Zhang, Dong Ping; Howes, Lee

    2013-02-01

    We present a parallel multi-hypothesis template tracking algorithm on heterogeneous platforms using a layered dispatch programming model. The contributions of this work are: an architecture-specific optimised solution for vasculature structure enhancement, an approach to segment the vascular lumen network from volumetric CTA images and a layered dispatch programming model to free the developers from hand-crafting mappings to particularly constrained execution domains on high throughput architecture. This abstraction is demonstrated through a vasculature segmentation application and can also be applied in other real-world applications. Current GPGPU programming models define a grouping concept which may lead to poorly scoped lo­ cal/ shared memory regions and an inconvenient approach to projecting complicated iterations spaces. To improve on this situation, we propose a simpler and more flexible programming model that leads to easier computation projections and hence a more convenient mapping of the same algorithm to a wide range of architectures. We first present an optimised image enhancement solution step- by-step, then solve a separable nonlinear least squares problem using a parallel Levenberg-Marquardt algorithm for template matching, and perform the energy efficiency analysis and performance comparison on a variety of platforms, including multi-core CPUs, discrete GPUs and APUs. We propose and discuss the efficiency of a layered-dispatch programming abstraction for mapping algorithms onto heterogeneous architectures.

  12. Residual motion compensation in ECG-gated interventional cardiac vasculature reconstruction

    NASA Astrophysics Data System (ADS)

    Schwemmer, C.; Rohkohl, C.; Lauritsch, G.; Müller, K.; Hornegger, J.

    2013-06-01

    Three-dimensional reconstruction of cardiac vasculature from angiographic C-arm CT (rotational angiography) data is a major challenge. Motion artefacts corrupt image quality, reducing usability for diagnosis and guidance. Many state-of-the-art approaches depend on retrospective ECG-gating of projection data for image reconstruction. A trade-off has to be made regarding the size of the ECG-gating window. A large temporal window is desirable to avoid undersampling. However, residual motion will occur in a large window, causing motion artefacts. We present an algorithm to correct for residual motion. Our approach is based on a deformable 2D-2D registration between the forward projection of an initial, ECG-gated reconstruction, and the original projection data. The approach is fully automatic and does not require any complex segmentation of vasculature, or landmarks. The estimated motion is compensated for during the backprojection step of a subsequent reconstruction. We evaluated the method using the publicly available CAVAREV platform and on six human clinical datasets. We found a better visibility of structure, reduced motion artefacts, and increased sharpness of the vessels in the compensated reconstructions compared to the initial reconstructions. At the time of writing, our algorithm outperforms the leading result of the CAVAREV ranking list. For the clinical datasets, we found an average reduction of motion artefacts by 13 ± 6%. Vessel sharpness was improved by 25 ± 12% on average.

  13. Color Doppler analysis of female reproductive vasculature in Behçet's disease.

    PubMed

    Tezcan, M E; Temizkan, O; Ozderya, A; Melikoglu, M; Aydin, K; Sargin, M; Temizkan, S

    2015-12-30

    Behçet's disease (BD) may affect female reproductive vasculature. We aimed to evaluate Doppler sonographic characteristics of female reproductive vasculature and also ovarian volume, endometrial thickness (EMT) and antral follicle count of BD patients in comparison with a healthy control group. Seventeen premenopausal women aged between 18-45 years with BD, and a control group of 31 age- and body mass index-matched healthy women was included in the study. Uterine, spiral and intraovarian artery blood flow were examined by Doppler sonography in the late follicular phase. Resistance index, pulsatility index and systolic/diastolic ratio were recorded together with ovarian volume, EMT and antral follicle count. In particular this is a pilot study including the evaluation of the spiral and uterine arteries in BD. Doppler sonographic parameters, ovarian volume, EMT and antral follicle count of BD patients and healthy controls were not found to be statistically different. As a result of our analysis, we found similar Doppler sonographic features of both BD patients and the control group. Further studies conducted on a larger sample population with more aggressive BD symptoms may reveal the actual effect of BD on the female reproductive system.

  14. The role of vasculature in bone development, regeneration and proper systemic functioning.

    PubMed

    Filipowska, Joanna; Tomaszewski, Krzysztof A; Niedźwiedzki, Łukasz; Walocha, Jerzy A; Niedźwiedzki, Tadeusz

    2017-02-13

    Bone is a richly vascularized connective tissue. As the main source of oxygen, nutrients, hormones, neurotransmitters and growth factors delivered to the bone cells, vasculature is indispensable for appropriate bone development, regeneration and remodeling. Bone vasculature also orchestrates the process of hematopoiesis. Blood supply to the skeletal system is provided by the networks of arteries and arterioles, having distinct molecular characteristics and localizations within the bone structures. Blood vessels of the bone develop through the process of angiogenesis, taking place through different, bone-specific mechanisms. Impaired functioning of the bone blood vessels may be associated with the occurrence of some skeletal and systemic diseases, i.e., osteonecrosis, osteoporosis, atherosclerosis or diabetes mellitus. When a disease or trauma-related large bone defects appear, bone grafting or bone tissue engineering-based strategies are required. However, a successful bone regeneration in both approaches largely depends on a proper blood supply. In this paper, we review the most recent data on the functions, molecular characteristics and significance of the bone blood vessels, with a particular emphasis on the role of angiogenesis and blood vessel functioning in bone development and regeneration, as well as the consequences of its impairment in the course of different skeletal and systemic diseases.

  15. Temporal requirement of RPE-derived VEGF in the development of choroidal vasculature.

    PubMed

    Le, Yun-Zheng; Bai, Yanyan; Zhu, Meili; Zheng, Lixin

    2010-03-01

    Vascular endothelial growth factor (VEGF-A or VEGF) is a potent growth factor for the development of retinal and choroidal vasculatures. To define the temporal requirement of the retinal pigmented epithelium (RPE)-derived VEGF in choroidal vascular development, we generated conditional VEGF knockout mice using an inducible Cre/lox system. The loss of the RPE-derived VEGF was confirmed with immunoblotting and immunohistochemistry. Retinal function and structure were assessed with electroretinography and histology, respectively. Choroidal vascular density was analyzed with computer-assisted semi-quantitative assay using fluorescently labeled choroidal flat-mounts. Induction of RPE-specific VEGF disruption at embryonic day 10 (E10) or E13 for 2 days caused regulatable decreases in choroidal vascular density, photoreceptor function, and photoreceptor outer nuclear layer thickness. The loss of the RPE-produced VEGF after E15 did not cause detectable defects in choroidal vasculatures and photoreceptor function and morphology. These results suggest that the RPE-derived VEGF plays a critical role in choroidal vascular development during organogenesis before E15.

  16. The Cadaveric Perfusion and Angiography as a Teaching Tool: Imaging the Intracranial Vasculature in Cadavers

    PubMed Central

    Turkoglu, Erhan; Seckin, Hakan; Gurer, Bora; Ahmed, Azam; Uluc, Kutluay; Pulfer, Kari; Arat, Anıl; Niemann, David; Baskaya, Mustafa K.

    2014-01-01

    Background and Study Aim To enhance the visualization of the intracranial vasculature of cadavers under gross examination with a combination of imaging modalities. Material and Methods A total of 20 cadaver heads were used to test two different perfusion techniques. First, fixed cadaver heads were perfused with water; second, fresh cadavers were perfused with saline and 10% formalin. Subsequently, brains were removed and fixed. The compounds used were silicone rubber, silicone rubber mixed with powdered barium sulfate, and silicone rubber mixed with tantalum dioxide prepared by the first perfusion technique and gelatin mixed with liquid barium prepared with the second technique. Conventional X-ray imaging, computed tomography (CT), dynamic computed tomography (dCT), and postprocessing three-dimensional (3D) images were used to evaluate all the heads. Results Gelatinized barium was better visualized when compared with tantalum dioxide in conventional X-ray images. The blood vessels injected with either tantalum dioxide or gelatinized barium demonstrated a higher enhancement than the surrounding soft tissues with CT or dCT. The quality of the 3D reconstruction of the intracranial vasculature was significantly better in the CT images obtained from the gelatinized barium group. Conclusions Radiologic examinations of the heads injected with gelatinized barium facilitates the 3D understanding of cerebrovascular anatomy as an important tool for neuroanatomy training. PMID:25452903

  17. In vivo photoacoustic imaging of vasculature with a low-cost miniature light emitting diode excitation.

    PubMed

    Dai, Xianjin; Yang, Hao; Jiang, Huabei

    2017-04-01

    In this Letter, we present a photoacoustic imaging (PAI) system based on a low-cost high-power miniature light emitting diode (LED) that is capable of in vivo mapping vasculature networks in biological tissue. Overdriving with 200 ns pulses and operating at a repetition rate of 40 kHz, a 1.2 W 405 nm LED with a radiation area of 1000  μm×1000  μm and a size of 3.5  mm×3.5  mm was used to excite photoacoustic signals in tissue. Phantoms including black stripes, lead, and hair were used to validate the system in which a volumetric PAI image was obtained by scanning the transducer and the light beam in a two-dimensional x-y plane over the object. In vivo imaging of the vasculature of a mouse ear shows that LED-based PAI could have great potential for label-free biomedical imaging applications where the use of bulky and expensive pulsed lasers is impractical.

  18. Biomimetic carriers mimicking leukocyte plasma membrane to increase tumor vasculature permeability

    NASA Astrophysics Data System (ADS)

    Palomba, R.; Parodi, A.; Evangelopoulos, M.; Acciardo, S.; Corbo, C.; De Rosa, E.; Yazdi, I. K.; Scaria, S.; Molinaro, R.; Furman, N. E. Toledano; You, J.; Ferrari, M.; Salvatore, F.; Tasciotti, E.

    2016-10-01

    Recent advances in the field of nanomedicine have demonstrated that biomimicry can further improve targeting properties of current nanotechnologies while simultaneously enable carriers with a biological identity to better interact with the biological environment. Immune cells for example employ membrane proteins to target inflamed vasculature, locally increase vascular permeability, and extravasate across inflamed endothelium. Inspired by the physiology of immune cells, we recently developed a procedure to transfer leukocyte membranes onto nanoporous silicon particles (NPS), yielding Leukolike Vectors (LLV). LLV are composed of a surface coating containing multiple receptors that are critical in the cross-talk with the endothelium, mediating cellular accumulation in the tumor microenvironment while decreasing vascular barrier function. We previously demonstrated that lymphocyte function-associated antigen (LFA-1) transferred onto LLV was able to trigger the clustering of intercellular adhesion molecule 1 (ICAM-1) on endothelial cells. Herein, we provide a more comprehensive analysis of the working mechanism of LLV in vitro in activating this pathway and in vivo in enhancing vascular permeability. Our results suggest the biological activity of the leukocyte membrane can be retained upon transplant onto NPS and is critical in providing the particles with complex biological functions towards tumor vasculature.

  19. Cancer cells remodel themselves and vasculature to overcome the endothelial barrier.

    PubMed

    Shenoy, Anitha K; Lu, Jianrong

    2016-10-01

    Metastasis refers to the spread of cancer cells from a primary tumor to distant organs mostly via the bloodstream. During the metastatic process, cancer cells invade blood vessels to enter circulation, and later exit the vasculature at a distant site. Endothelial cells that line blood vessels normally serve as a barrier to the movement of cells into or out of the blood. It is thus critical to understand how metastatic cancer cells overcome the endothelial barrier. Epithelial cancer cells acquire increased motility and invasiveness through epithelial-to-mesenchymal transition (EMT), which enables them to move toward vasculature. Cancer cells also express a variety of adhesion molecules that allow them to attach to vascular endothelium. Finally, cancer cells secrete or induce growth factors and cytokines to actively prompt vascular hyperpermeability that compromises endothelial barrier function and facilitates transmigration of cancer cells through the vascular wall. Elucidation of the mechanisms underlying metastatic dissemination may help develop new anti-metastasis therapeutics. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  20. Variation in the position, relation and vasculature of left suprarenal gland: a case report.

    PubMed

    Oztürk, N C; Uzmansel, D; Kara, A; Oztürk, H

    2010-12-01

    A malposition of the left suprarenal gland with varied relations and vasculature was observed in a 50-year-old male cadaver during the routine dissection of the abdominal region. The gland was partly situated over the hilum of the left kidney. Its posterior surface was related to the left crus of the diaphragm and to the hilum of the left kidney extending some distance above on the medial margin of the kidney. Its anterior surface was totally covered by the body of the pancreas and the splenic artery and vein. There were only two suprarenal arteries. A left lateral branch of the aorta divided into three branches of which the middle and inferior branches entered the gland as seperate suprarenal arteries. There were the two suprarenal veins of the gland which were draining into the left renal vein. Such a malposition with varied relations and vasculature is of utmost importance from the surgical point of view because it can affect the orientation of the surgeon in laparoscopic adrenalectomy.

  1. Vasculature of a Medial Femoral Condyle Free Flap in Intact and Osteotomized Flaps.

    PubMed

    Rysz, Maciej; Grabczan, Wojciech; Mazurek, Maciej Jan; Krajewski, Romuald; Grzelecki, Dariusz; Ciszek, Bogdan

    2017-04-01

    A small size and difficulties with shaping a medial femoral condyle corticocancellous bone flap are factors limiting its use. The goal of this study was to evaluate range of vascular supply to a medial femoral condyle corticocancellous bone flap to determine whether harvesting of larger flaps and performing a flap osteotomy would compromise the vasculature of a flap's bone. Twenty-four limbs were dissected and medial femoral condyle corticocancellous bone flaps were harvested with skin paddles. Thirteen of 24 flaps had subperiosteal osteotomies simulating shaping a bone for reconstruction. A pedicle artery was perfused with red latex. Medial femoral condyle corticocancellous bone flap vascularization was evaluated by cutting the bone into 1-cm blocks and assessing the number of Haversian canals filled with red latex. Length of harvested flaps was 7 to 13 cm, thickness was 0.5 to 3 cm, and width was 1 to 3 cm. Pedicle length was between 3.5 and 9 cm (mean ± SD, 6.6 ± 1.6 cm). Red latex filled bone vessels at a distance of 6 to 11.5 cm from the distal end of a flap (8.2 ± 1.4 cm). Skin paddles were filled with latex in all cases. A medial femoral condyle corticocancellous bone flap had sufficient blood supply, allowing for harvesting flaps up to 11 cm long, and subperiosteal osteotomy did not compromise the vasculature of the flap's bone.

  2. Functional and structural evaluation of the vasculature of skin flaps after ischemia and reperfusion

    SciTech Connect

    Marzella, L.; Jesudass, R.R.; Manson, P.N.; Myers, R.A.; Bulkley, G.B.

    1988-05-01

    Free radicals and other toxic oxygen species play a role in the pathogenesis of ischemic organ damage. The abdominal skin flap has been used as a model to study the effects of superoxide dismutase on the survival of ischemic skin. We have evaluated the evolution of functional and structural injury to the vasculature after ischemic injury in superoxide dismutase-treated and control skin flaps. Ischemia was induced by creating abdominal skin flaps and occluding either the venous or both the venous and arterial blood supplies. Superoxide dismutase was administered immediately after the occlusion was released. At 1 hour of reflow, erythrocyte stasis, platelet deposition, neutrophil adherence, and injury to the endothelium of the large vessels and of the microvasculature were evident. The blood flow in the ischemic skin was only 3 percent of normal. Superoxide dismutase caused no change in the ultrastructure of the vasculature and a marginal decrease in vascular permeability in the ischemic skin at 1 hour of reflow. Increased fluorescent staining of the skin was evident after 24 hours of reflow in the superoxide dismutase-treated flaps. These findings indicate that injury to vascular endothelium by ischemia and reperfusion plays a role in the evolution of skin necrosis.

  3. Expression and activation of the farnesoid X receptor in the vasculature

    NASA Astrophysics Data System (ADS)

    Bishop-Bailey, David; Walsh, Desmond T.; Warner, Timothy D.

    2004-03-01

    The farnesoid X receptor/bile acid receptor (FXR) is a recently discovered member of the nuclear hormone superfamily. FXR ligands have been proposed as targets in cardiovascular disease, regulating cholesterol metabolism and bile acid transport and metabolism in the liver and gastrointestinal tract. When we used a human cardiovascular tissue array, we found that FXR is expressed in a variety of normal and pathological human tissue. Particularly high levels of FXR were found in the vasculature and in a number of different metastatic cancers, as well as the previously identified target tissues of the liver, small intestine, and kidney. In vitro, FXR is present in rat and human vascular smooth muscle cells. When treated with a range of FXR ligands, vascular smooth muscle cells undergo apoptosis in a manner that correlates with the ligands' ability to activate FXR. Furthermore, FXR activators induce mRNA for the FXR target genes, phospholipid transfer protein, and the small heterodimer partner. FXR therefore is a functional protein in the vasculature that may provide a direct target for the treatment of proliferative and dyslipidaemic diseases.

  4. Selective alpha-particle mediated depletion of tumor vasculature with vascular normalization.

    PubMed

    Singh Jaggi, Jaspreet; Henke, Erik; Seshan, Surya V; Kappel, Barry J; Chattopadhyay, Debjit; May, Chad; McDevitt, Michael R; Nolan, Daniel; Mittal, Vivek; Benezra, Robert; Scheinberg, David A

    2007-03-07

    Abnormal regulation of angiogenesis in tumors results in the formation of vessels that are necessary for tumor growth, but compromised in structure and function. Abnormal tumor vasculature impairs oxygen and drug delivery and results in radiotherapy and chemotherapy resistance, respectively. Alpha particles are extraordinarily potent, short-ranged radiations with geometry uniquely suitable for selectively killing neovasculature. Actinium-225 ((225)Ac)-E4G10, an alpha-emitting antibody construct reactive with the unengaged form of vascular endothelial cadherin, is capable of potent, selective killing of tumor neovascular endothelium and late endothelial progenitors in bone-marrow and blood. No specific normal-tissue uptake of E4G10 was seen by imaging or post-mortem biodistribution studies in mice. In a mouse-model of prostatic carcinoma, (225)Ac-E4G10 treatment resulted in inhibition of tumor growth, lower serum prostate specific antigen level and markedly prolonged survival, which was further enhanced by subsequent administration of paclitaxel. Immunohistochemistry revealed lower vessel density and enhanced tumor cell apoptosis in (225)Ac-E4G10 treated tumors. Additionally, the residual tumor vasculature appeared normalized as evident by enhanced pericyte coverage following (225)Ac-E4G10 therapy. However, no toxicity was observed in vascularized normal organs following (225)Ac-E4G10 therapy. The data suggest that alpha-particle immunotherapy to neovasculature, alone or in combination with sequential chemotherapy, is an effective approach to cancer therapy.

  5. A new presentation and exploration of human cerebral vasculature correlated with surface and sectional neuroanatomy.

    PubMed

    Nowinski, Wieslaw L; Thirunavuukarasuu, Arumugam; Volkau, Ihar; Marchenko, Yevgen; Aminah, Bivi; Gelas, Arnaud; Huang, Su; Lee, Looi Chow; Liu, Jimin; Ng, Ting Ting; Nowinska, Natalia G; Qian, Guoyu Yu; Puspitasari, Fiftarina; Runge, Val M

    2009-01-01

    The increasing complexity of human body models enabled by advances in diagnostic imaging, computing, and growing knowledge calls for the development of a new generation of systems for intelligent exploration of these models. Here, we introduce a novel paradigm for the exploration of digital body models illustrating cerebral vasculature. It enables dynamic scene compositing, real-time interaction combined with animation, correlation of 3D models with sectional images, quantification as well as 3D manipulation-independent labeling and knowledge-related meta labeling (with name, diameter, description, variants, and references). This novel exploration is incorporated into a 3D atlas of cerebral vasculature with arteries and veins along with the surrounding surface and sectional neuroanatomy derived from 3.0 Tesla scans. This exploration paradigm is useful in medical education, training, research, and clinical applications. It enables development of new generation systems for rapid and intelligent exploration of complicated digital body models in real time with dynamic scene compositing from highly parcellated 3D models, continuous navigation, and manipulation-independent labeling with multiple features.

  6. Residual motion compensation in ECG-gated interventional cardiac vasculature reconstruction.

    PubMed

    Schwemmer, C; Rohkohl, C; Lauritsch, G; Müller, K; Hornegger, J

    2013-06-07

    Three-dimensional reconstruction of cardiac vasculature from angiographic C-arm CT (rotational angiography) data is a major challenge. Motion artefacts corrupt image quality, reducing usability for diagnosis and guidance. Many state-of-the-art approaches depend on retrospective ECG-gating of projection data for image reconstruction. A trade-off has to be made regarding the size of the ECG-gating window. A large temporal window is desirable to avoid undersampling. However, residual motion will occur in a large window, causing motion artefacts. We present an algorithm to correct for residual motion. Our approach is based on a deformable 2D-2D registration between the forward projection of an initial, ECG-gated reconstruction, and the original projection data. The approach is fully automatic and does not require any complex segmentation of vasculature, or landmarks. The estimated motion is compensated for during the backprojection step of a subsequent reconstruction. We evaluated the method using the publicly available CAVAREV platform and on six human clinical datasets. We found a better visibility of structure, reduced motion artefacts, and increased sharpness of the vessels in the compensated reconstructions compared to the initial reconstructions. At the time of writing, our algorithm outperforms the leading result of the CAVAREV ranking list. For the clinical datasets, we found an average reduction of motion artefacts by 13 ± 6%. Vessel sharpness was improved by 25 ± 12% on average.

  7. The Effects of Zoledronic Acid in the Bone and Vasculature Support of Hematopoietic Stem Cell Niches

    PubMed Central

    Soki, Fabiana N.; Li, Xin; Berry, Janice; Koh, Amy; Sinder, Benjamin P.; Qian, Xu; Kozloff, Kenneth M.; Taichman, Russell S.; McCauley, Laurie K.

    2013-01-01

    Hematopoietic stem cells (HSC) are maintained in a tightly regulated bone microenvironment constituted by a rich milieu of cells. Bone cells such as osteoblasts are associated with niche maintenance as regulators of the endosteal microenvironment. Bone remodeling also plays a role in HSC mobilization although it is poorly defined. The effects of zoledronic acid (ZA), a potent bisphosphonate that inhibits bone resorption, were investigated on bone marrow cell populations focusing on HSCs, and the endosteal and vascular niches in bone. ZA treatment significantly increased bone volume and HSCs in both young and adult mice (4 week and 4 month old, respectively). ZA increased vessel numbers with no overall change in vascular volume in bones of young and had no effect on vasculature in adult mice. Since both young and adult mice had increased HSCs and bone mass with differing vasculature responses, this suggests that ZA indirectly supports HSCs via the osteoblastic niche and not the vascular niche. Additionally, gene expression in Lin- cells demonstrated increased expression of self-renewal-related genes Bmi1 and Ink4a suggesting a role of ZA in the modulation of cell commitment and differentiation toward a long-term self-renewing cell. Genes that support the osteoblastic niche, BMP2 and BMP6 were also augmented in ZA treated mice. In conclusion, ZA-induced HSC expansion occurs independent of the vascular niche via indirect modulation of the osteoblastic niche. PMID:22833499

  8. Cross-talk between adipose tissue and vasculature: role of adiponectin.

    PubMed

    Li, F Y L; Cheng, K K Y; Lam, K S L; Vanhoutte, P M; Xu, A

    2011-09-01

    Adipose tissue is a highly dynamic endocrine organ, secreting a number of bioactive substances (adipokines) regulating insulin sensitivity, energy metabolism and vascular homeostasis. Dysfunctional adipose tissue is a key mediator that links obesity with insulin resistance, hypertension and cardiovascular disease. Obese adipose tissue is characterized by adipocyte hypertrophy and infiltration of inflammatory macrophages and lymphocytes, leading to the augmented production of pro-inflammatory adipokines and vasoconstrictors that induce endothelial dysfunction and vascular inflammation through their paracrine and endocrine actions. By contrast, the secretion of adiponectin, an adipokine with insulin sensitizing and anti-inflammatory activities, is decreased in obesity and its related pathologies. Emerging evidence suggests that adiponectin is protective against vascular dysfunction induced by obesity and diabetes, through its multiple favourable effects on glucose and lipid metabolism as well as on vascular function. Adiponectin improves insulin sensitivity and metabolic profiles, thus reducing the classical risk factors for cardiovascular disease. Furthermore, adiponectin protects the vasculature through its pleiotropic actions on endothelial cells, endothelial progenitor cells, smooth muscle cells and macrophages. Data from both animal and human investigations demonstrate that adiponectin is an important component of the adipo-vascular axis that mediates the cross-talk between adipose tissue and vasculature. This review highlights recent work on the vascular protective activities of adiponectin and discusses the molecular pathways underlying the vascular actions of this adipokine. © 2010 The Authors. Acta Physiologica © 2010 Scandinavian Physiological Society.

  9. Segmentation of digitized histological sections for quantification of the muscularized vasculature in the mouse hind limb.

    PubMed

    Xu, Yiwen; Pickering, J Geoffrey; Nong, Zengxuan; Ward, Aaron D

    2017-04-01

    Immunohistochemical tissue staining enhances microvasculature characteristics, including the smooth muscle in the medial layer of the vessel walls that is responsible for regulation of blood flow. The vasculature can be imaged in a comprehensive fashion using whole-slide scanning. However, since each such image potentially contains hundreds of small vessels, manual vessel delineation and quantification is not practically feasible. In this work, we present a fully automatic segmentation and vasculature quantification algorithm for whole-slide images. We evaluated its performance on tissue samples drawn from the hind limbs of wild-type mice, stained for smooth muscle using 3,3'-Diaminobenzidine (DAB) immunostain. The algorithm was designed to be robust to vessel fragmentation due to staining irregularity, and artefactual staining of nonvessel objects. Colour deconvolution was used to isolate the DAB stain for detection of vessel wall fragments. Complete vessels were reconstructed from the fragments by joining endpoints of topological skeletons. Automatic measures of vessel density, perimeter, wall area and local wall thickness were taken. The segmentation algorithm was validated against manual measures, resulting in a Dice similarity coefficient of 89%. The relationships observed between these measures were as expected from a biological standpoint, providing further reinforcement of the accuracy of this system. This system provides a fully automated and accurate means of measuring the arteriolar and venular morphology of vascular smooth muscle.

  10. Mapping the Extracellular and Membrane Proteome Associated with the Vasculature and the Stroma in the Embryo*

    PubMed Central

    Soulet, Fabienne; Kilarski, Witold W.; Roux-Dalvai, Florence; Herbert, John M. J.; Sacewicz, Izabela; Mouton-Barbosa, Emmanuelle; Bicknell, Roy; Lalor, Patricia; Monsarrat, Bernard; Bikfalvi, Andreas

    2013-01-01

    In order to map the extracellular or membrane proteome associated with the vasculature and the stroma in an embryonic organism in vivo, we developed a biotinylation technique for chicken embryo and combined it with mass spectrometry and bioinformatic analysis. We also applied this procedure to implanted tumors growing on the chorioallantoic membrane or after the induction of granulation tissue. Membrane and extracellular matrix proteins were the most abundant components identified. Relative quantitative analysis revealed differential protein expression patterns in several tissues. Through a bioinformatic approach, we determined endothelial cell protein expression signatures, which allowed us to identify several proteins not yet reported to be associated with endothelial cells or the vasculature. This is the first study reported so far that applies in vivo biotinylation, in combination with robust label-free quantitative proteomics approaches and bioinformatic analysis, to an embryonic organism. It also provides the first description of the vascular and matrix proteome of the embryo that might constitute the starting point for further developments. PMID:23674615

  11. Eradication of Tumors through Simultaneous Ablation of CD276/B7-H3-Positive Tumor Cells and Tumor Vasculature.

    PubMed

    Seaman, Steven; Zhu, Zhongyu; Saha, Saurabh; Zhang, Xiaoyan M; Yang, Mi Young; Hilton, Mary Beth; Morris, Karen; Szot, Christopher; Morris, Holly; Swing, Deborah A; Tessarollo, Lino; Smith, Sean W; Degrado, Sylvia; Borkin, Dmitry; Jain, Nareshkumar; Scheiermann, Julia; Feng, Yang; Wang, Yanping; Li, Jinyu; Welsch, Dean; DeCrescenzo, Gary; Chaudhary, Amit; Zudaire, Enrique; Klarmann, Kimberly D; Keller, Jonathan R; Dimitrov, Dimiter S; St Croix, Brad

    2017-04-10

    Targeting the tumor vasculature with antibody-drug conjugates (ADCs) is a promising anti-cancer strategy that in order to be realized must overcome several obstacles, including identification of suitable targets and optimal warheads. Here, we demonstrate that the cell-surface protein CD276/B7-H3 is broadly overexpressed by multiple tumor types on both cancer cells and tumor-infiltrating blood vessels, making it a potentially ideal dual-compartment therapeutic target. In preclinical studies CD276 ADCs armed with a conventional MMAE warhead destroyed CD276-positive cancer cells, but were ineffective against tumor vasculature. In contrast, pyrrolobenzodiazepine-conjugated CD276 ADCs killed both cancer cells and tumor vasculature, eradicating large established tumors and metastases, and improving long-term overall survival. CD276-targeted dual-compartment ablation could aid in the development of highly selective broad-acting anti-cancer therapies. Published by Elsevier Inc.

  12. Central Versus Peripheral Cardiovascular Risk in Metabolic Syndrome

    PubMed Central

    Edgell, H.; Petrella, R. J.; Hodges, G. J.; Shoemaker, J. K.

    2012-01-01

    Individuals with metabolic syndrome (MetS; i.e., three of five of the following risk factors (RFs): elevated blood pressure, waist circumference, triglycerides, blood glucose, or reduced HDL) are thought to be prone to serious cardiovascular disease and there is debate as to whether the disease begins in the peripheral vasculature or centrally. This study investigates hemodynamics, cardiac function/morphology, and mechanical properties of the central (heart, carotid artery) or peripheral [total peripheral resistance (TPR), forearm vascular bed] vasculature in individuals without (1–2 RFs: n = 28), or with (≥3 RFs: n = 46) MetS. After adjustments for statin and blood pressure medication use, those with MetS had lower mitral valve E/A ratios (<3 RFs: 1.24 ± 0.07; ≥3 RFs: 1.01 ± 0.04; P = 0.025), and higher TPR index (<3 RFs: 48 ± 2 mmHg/L/min/m2; ≥3 RFs: 53 ± 2 mmHg/L/min/m2; P = 0.04). There were no differences in heart size, carotid artery measurements, cardiovagal baroreflex, pulse-wave velocity, stroke volume index, or cardiac output index due to MetS after adjustments for statin and blood pressure medication use. The use of statins was associated with increased inertia in the brachial vascular bed, increased HbA1c and decreased LDL cholesterol. The independent use of anti-hypertensive medication was associated with decreased predicted VO2max, triglycerides, diastolic blood pressure, interventricular septum thickness, calculated left ventricle mass, left ventricle posterior wall thickness, and left ventricle pre-ejection period, but increased carotid stiffness, HDL cholesterol, and heart rate. These data imply that both a central cardiac effect and a peripheral effect of vascular resistance are expressed in MetS. These data also indicate that variance in between-group responses due to pharmacological treatments are important factors to consider in studying cardiovascular changes in these individuals. PMID:22375126

  13. Peripheral nerve stimulation: definition.

    PubMed

    Abejón, David; Pérez-Cajaraville, Juan

    2011-01-01

    Recently, there has been a tremendous evolution in the field of neurostimulation, both from the technological point of view and from development of the new and different indications. In some areas, such as peripheral nerve stimulation, there has been a boom in recent years due to the variations in the surgical technique and the improved results documented by in multiple published papers. All this makes imperative the need to classify and define the different types of stimulation that are used today. The confusion arises when attempting to describe peripheral nerve stimulation and subcutaneous stimulation. Peripheral nerve stimulation, in its pure definition, involves implanting a lead on a nerve, with the aim to produce paresthesia along the entire trajectory of the stimulated nerve. Copyright © 2011 S. Karger AG, Basel.

  14. Etonogestrel implant migration to the vasculature, chest wall, and distant body sites: cases from a pharmacovigilance database.

    PubMed

    Kang, Sarah; Niak, Ali; Gada, Neha; Brinker, Allen; Jones, S Christopher

    2017-09-01

    To describe clinical outcomes of etonogestrel implant patients with migration to the vasculature, chest wall and other distant body sites spontaneously reported to the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. We performed a standardized Medical Dictionary for Regulatory Activities (MedDRA) query in the FAERS database (through November 15, 2015), with reports coded with one or more MedDRA preferred terms that indicate complications with device placement or migration of the device from the original site of insertion to the vasculature, chest wall and other distant body sites. We excluded any cases previously described in the medical literature. We identified 38 cases of pronounced etonogestrel implant migration. Migration locations included the lung/pulmonary artery (n=9), chest wall (n=1), vasculature at locations other than the lung/pulmonary artery (n=14) and extravascular migrations (n=14) to other body sites (e.g., the axilla and clavicle/neck line/shoulder). The majority of cases were asymptomatic and detected when the patient desired implant removal; however, seven cases reported symptoms such as pain, discomfort and dyspnea in association with implant migration. Three cases also describe pulmonary fibrosis and skin reactions as a result of implant migration to the vasculature, chest wall and other distant body sites. Sixteen cases reported surgical removal in an operating room setting. Our FAERS case series demonstrates etonogestrel implant migration to the vasculature, chest wall and other body sites distant from the site of original insertion. As noted by the sponsor in current prescribing information, a key determinant in the risk for etonogestrel contraceptive implant migration appears to be improper insertion technique. Although migration of etonogestrel implants to the vasculature is rare, awareness of migration and education on proper insertion technique may reduce the risk. Published by Elsevier Inc.

  15. Optimization of Peripheral Vascular Sizing with Conductance Guidewire: Theory and Experiment.

    PubMed

    Choi, Hyo Won; Berwick, Zachary C; Sulkin, Matthew S; Owens, Christopher D; Kassab, Ghassan S

    2017-01-01

    Although the clinical range of interventions for coronary arteries is about 2 to 5 mm, the range of diameters of peripheral vasculature is significantly larger (about 10 mm for human iliac artery). When the vessel diameter is increased, the spacing between excitation electrodes on a conductance sizing device must also increase to accommodate the greater range of vessel diameters. The increase in the excitation electrodes distance, however, causes higher parallel conductance or current losses outside of artery lumen. We have previously shown that the conductance catheter/guidewire excitation electrode distances affects the measurement accuracy for the peripheral artery lumen sizing. Here, we propose a simple solution that varies the detection electrode distances to compensate for parallel conductance losses. Computational models were constructed to simulate the conductance guidewire with various electrodes spacing combinations over a range of peripheral artery lumen diameters and surrounding tissue electrical conductivities. The results demonstrate that the measurement accuracy may be significantly improved by increased detection spacing. Specifically, an optimally configured detection/excitation spacing (i.e., 5-5-5 or an equidistant electrode interval with a detection-to-excitation spacing ratio of 0.3) was shown to accurately predict the lumen diameter (i.e., -10% < error < 10%) over a broad range of peripheral artery dimensions (4 mm < diameter < 10 mm). The computational results were substantiated with both ex-vivo and in-vivo measurements of peripheral arteries. The present results support the accuracy of the conductance technique for measurement of peripheral reference vessel diameter.

  16. Inherited peripheral neuropathies.

    PubMed

    Saporta, Mario A; Shy, Michael E

    2013-05-01

    Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral neuropathies in which the neuropathy is the sole or primary component of the disorder, as opposed to diseases in which the neuropathy is part of a more generalized neurologic or multisystem syndrome. Because of the great genetic heterogeneity of this condition, it can be challenging for the general neurologist to diagnose patients with specific types of CMT. This article reviews the biology of the inherited peripheral neuropathies, delineates major phenotypic features of the CMT subtypes, and suggest strategies for focusing genetic testing. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Inherited Peripheral Neuropathies

    PubMed Central

    Saporta, Mario A.; Shy, Michael E.

    2013-01-01

    SYNOPSIS Charcot Marie Tooth disease (CMT) is a heterogeneous group of inherited peripheral neuropathies in which the neuropathy is the sole or primary component of the disorder, as opposed to diseases in which the neuropathy is part of a more generalized neurological or multisystem syndrome. Due to the great genetic heterogeneity of this condition, it can be challenging for the general neurologist to diagnose patients with specific types of CMT. Here, we review the biology of the inherited peripheral neuropathies, delineate major phenotypic features of the CMT subtypes and suggest strategies for focusing genetic testing. PMID:23642725

  18. Analysis of Choroidal Morphology and Vasculature in Healthy Eyes Using Spectral-Domain Optical Coherence Tomography

    PubMed Central

    Branchini, Lauren A; Adhi, Mehreen; Regatieri, Caio V; Nandakumar, Namrata; Liu, Jonathan J; Laver, Nora; Fujimoto, James G; Duker, Jay S

    2013-01-01

    Objective To analyze the morphology and vasculature of the choroid in healthy eyes using spectral-domain optical coherence tomography (SD-OCT). Design Cross-sectional retrospective review. Participants Forty-two healthy subjects (42 eyes), with no ocular disease who underwent high-definition scanning with Cirrus HD-OCT at the New England Eye Center, Boston, Massachusetts between November 2009 and September 2010. Methods The SD-OCT images were evaluated for morphological features of the choroid, including the shape of the choroid-scleral border, location of the thickest point of choroid and regions of focal choroidal thinning. Total choroidal thickness and large choroidal vessel layer thickness were measured by two independent observers experienced in analyzing OCT images using the Cirrus linear measurement tool at the fovea, 750μm nasal and temporal to the fovea. Custom software was used to calculate the ratio of choroidal stroma to the choroidal vessel lumen. Main Outcome Measures Qualitative assessment of the choroidal morphology, quantitative analysis of choroidal vasculature and use of a novel automated software to determine the ratio of choroidal stromal area to the area of choroidal vessel lumen. Results The 42 subjects had a mean age of 51.6 years. All subjects (100%) had a “bowl” or convex shape to the choroid-sclera junction and the thickest point of the choroid was under the fovea in 88.0% of the subjects. The mean choroidal thickness was 256.8±75.8μm, thickness of the large choroidal vessel layer was 204.3±65.9μm and that of medium choroidal vessel layer/choriocapillaris layer was 52.9±20.6μm beneath the fovea. The ratio of large choroidal vessel layer thickness to the total choroidal thickness beneath the fovea was 0.7±0.06. The software generated ratio of choroidal stromal area to the choroidal vessel lumen area to be 0.27±0.08, suggesting that choroidal vessel lumen forms a greater proportion of the choroid than choroidal stroma in

  19. Dose reduction in CT urography and vasculature phantom studies using model-based iterative reconstruction.

    PubMed

    Page, Leland; Wei, Wei; Kundra, Vikas; Rong, John

    2016-11-08

    To evaluate the feasibility of radiation dose reduction using model-based iterative reconstruction (MBIR) for evaluating the ureters and vasculature in a phantom, a tissue-equivalent CT dose phantom was scanned using a 64-channel CT scan-ner. Tubes of varying diameters filled with different dilutions of a contrast agent, simulating ureters or vessels, were inserted into the center of the phantom. Each combination was scanned using an existing renal protocol at 140 kVp or 120 kVp, yielding a display volumetric CT dose index (CTDIvol) of 24 mGy. The scans were repeated using reduced scan techniques to achieve lower radiation doses down to 0.8 mGy. The images were reconstructed using filtered back-projection (FBP) and model-based iterative reconstruction (MBIR). The noise and contrast-to-noise ratio (CNR) was measured for each contrast object. Comparisons between the two reconstruction methods at different dose levels were evaluated using a factorial design. At each CTDIvol the measured image noise was lower using MBIR compared to FBP (p < 0.0001). At low doses, the percent change in measured image noise between FBP and MBIR was larger. For the 12 mm object simulating a ureter or large vessel with an HU of 600, the measured CNR using MBIR at a CTDIvol of 1.7 mGy was greater than the CNR of FBP at a CTIDvol of 24 mGy (p < 0.0001). For the 5 mm object simulating a medium-sized vessel with a HU of 250, the mea-sured CNR using MBIR at a CTDIvol of 1.7 mGy was equivalent to that of FBP at a CTDIvol of 24 mGy. For the 2 mm, 100 HU object simulating a small vessel, the measured CNR using MBIR at a CTDIvol of 1.7 mGy was equivalent to that of FBP at a CTDIvol of 24 mGy. Low-dose (3.6 mGy) CT imaging of vasculature and ureter phantoms using MBIR results in similar noise and CNR compared to FBP at approximately one-sixth the dose. This suggests that, using MBIR, a one milliSievert exam of the ureters and vasculature may be clinically possible whilst still maintaining adequate

  20. Neuropathic Pain: Central vs. Peripheral Mechanisms.

    PubMed

    Meacham, Kathleen; Shepherd, Andrew; Mohapatra, Durga P; Haroutounian, Simon

    2017-06-01

    Our goal is to examine the processes-both central and peripheral-that underlie the development of peripherally-induced neuropathic pain (pNP) and to highlight recent evidence for mechanisms contributing to its maintenance. While many pNP conditions are initiated by damage to the peripheral nervous system (PNS), their persistence appears to rely on maladaptive processes within the central nervous system (CNS). The potential existence of an autonomous pain-generating mechanism in the CNS creates significant implications for the development of new neuropathic pain treatments; thus, work towards its resolution is crucial. Here, we seek to identify evidence for PNS and CNS independently generating neuropathic pain signals. Recent preclinical studies in pNP support and provide key details concerning the role of multiple mechanisms leading to fiber hyperexcitability and sustained electrical discharge to the CNS. In studies regarding central mechanisms, new preclinical evidence includes the mapping of novel inhibitory circuitry and identification of the molecular basis of microglia-neuron crosstalk. Recent clinical evidence demonstrates the essential role of peripheral mechanisms, mostly via studies that block the initially damaged peripheral circuitry. Clinical central mechanism studies use imaging to identify potentially self-sustaining infra-slow CNS oscillatory activity that may be unique to pNP patients. While new preclinical evidence supports and expands upon the key role of central mechanisms in neuropathic pain, clinical evidence for an autonomous central mechanism remains relatively limited. Recent findings from both preclinical and clinical studies recapitulate the critical contribution of peripheral input to maintenance of neuropathic pain. Further clinical investigations on the possibility of standalone central contributions to pNP may be assisted by a reconsideration of the agreed terms or criteria for diagnosing the presence of central sensitization in humans.

  1. Direct visualization of neo-vessel formation following peripheral injection of bone marrow derived CD34+ cells in experimental myocardial damage.

    PubMed

    Ciulla, M M; Ferrero, S; Gianelli, U; Paliotti, R; Magrini, F; Braidotti, P

    2007-01-01

    The definitive fate of peripherally injected PKH26 labelled bone marrow mononuclear cells expressing the CD34+ antigen following experimental myocardial cryodamage in rats (n=10) has been examined by direct visualization on photoconverted light and electron microscopy images. One week after the injection in each rat of about 150,000 CD34+ cells early stage PKH26+ vascular structures were localized in the infarcted areas, suggesting that a potential benefit of this therapeutic approach consists in the regeneration of the vasculature.

  2. Elevation of serum IgE level and peripheral eosinophil count during T lymphocyte-directed gene therapy for ADA deficiency: implication of Tc2-like cells after gene transduction procedure.

    PubMed

    Kawamura, N; Ariga, T; Ohtsu, M; Yamada, M; Tame, A; Furuta, H; Kobayashi, I; Okano, M; Yanagihara, Y; Sakiyama, Y

    1998-11-01

    We have successfully carried out T-cell-directed gene therapy for a boy with severe combined immunodeficiency due to adenosine deaminase deficiency (ADA SCID) and unexpectedly found an elevation of serum IgE level and peripheral eosinophil count during the course. More than 90% of transduced cells cultured for 7-11 days before infusion into the patient were positive for CD8 and expressed Th2-type cytokine genes such as IL-4, IL-5 and IL-13. Furthermore, CD4(+) T-depleted PBMC (peripheral blood mononuclear cells) from the patient synthesized IgE in vitro by stimulation with IL-4. Collectively, these results suggested that Tc2-like cells in the transduced cells have distinct immunological functions to help IgE synthesis and activate eosinophils.

  3. From the Cover: Adipose tissue mass can be regulated through the vasculature

    NASA Astrophysics Data System (ADS)

    Rupnick, Maria A.; Panigrahy, Dipak; Zhang, Chen-Yu; Dallabrida, Susan M.; Lowell, Bradford B.; Langer, Robert; Judah Folkman, M.

    2002-08-01

    Tumor growth is angiogenesis dependent. We hypothesized that nonneoplastic tissue growth also depends on neovascularization. We chose adipose tissue as an experimental system because of its remodeling capacity. Mice from different obesity models received anti-angiogenic agents. Treatment resulted in dose-dependent, reversible weight reduction and adipose tissue loss. Marked vascular remodeling was evident in adipose tissue sections, which revealed decreased endothelial proliferation and increased apoptosis in treated mice compared with controls. Continuous treatment maintained mice near normal body weights for age without adverse effects. Metabolic adaptations in food intake, metabolic rate, and energy substrate utilization were associated with anti-angiogenic weight loss. We conclude that adipose tissue mass is sensitive to angiogenesis inhibitors and can be regulated by its vasculature.

  4. Speckle variance OCT imaging of the vasculature in live mammalian embryos

    NASA Astrophysics Data System (ADS)

    Sudheendran, N.; Syed, S. H.; Dickinson, M. E.; Larina, I. V.; Larin, K. V.

    2011-03-01

    Live imaging of normal and abnormal vascular development in mammalian embryos is important tool in embryonic research, which can potentially contribute to understanding, prevention and treatment of cardiovascular birth defects. Here, we used speckle variance analysis of swept source optical coherence tomography (OCT) data sets acquired from live mouse embryos to reconstruct the 3-D structure of the embryonic vasculature. Both Doppler OCT and speckle variance algorithms were used to reconstruct the vascular structure. The results demonstrates that speckle variance imaging provides more accurate representation of the vascular structure, as it is not sensitive to the blood flow direction, while the Doppler OCT imaging misses blood flow component perpendicular to the beam direction. These studies suggest that speckle variance imaging is a promising tool to study vascular development in cultured mouse embryos.

  5. Enzyme prodrug therapy designed to target L-methioninase to the tumor vasculature.

    PubMed

    Van Rite, Brent D; Lazrak, Yahya A; Pagnon, Magali L; Palwai, Naveen R; Neves, Luís F F; McFetridge, Peter S; Harrison, Roger G

    2011-02-28

    A new approach for enzyme prodrug therapy for cancer was tested using human endothelial cells and two breast cancer cell lines in vitro. The concept is to use the human annexin V protein to selectively target the enzyme L-methioninase to the tumor vasculature. The major finding was that enzyme prodrug treatment using the L-methioninase-annexin V fusion protein and selenomethionine as the prodrug over 3 days was shown to be lethal to the endothelial cells and the cancer cells, while having little or no effect with the prodrug but with no fusion protein present. Thus, this new approach appears promising. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  6. Anti-platelet agents augment cisplatin nanoparticle cytotoxicity by enhancing tumor vasculature permeability and drug delivery

    NASA Astrophysics Data System (ADS)

    Pandey, Ambarish; Sarangi, Sasmit; Chien, Kelly; Sengupta, Poulomi; Papa, Anne-Laure; Basu, Sudipta; Sengupta, Shiladitya

    2014-11-01

    Tumor vasculature is critically dependent on platelet mediated hemostasis and disruption of the same can augment delivery of nano-formulation based chemotherapeutic agents which depend on enhanced permeability and retention for tumor penetration. Here, we evaluated the role of Clopidogrel, a well-known inhibitor of platelet aggregation, in potentiating the tumor cytotoxicity of cisplatin nano-formulation in a murine breast cancer model. In vivo studies in murine syngeneic 4T1 breast cancer model showed a significant greater penetration of macromolecular fluorescent nanoparticles after clopidogrel pretreatment. Compared to self-assembling cisplatin nanoparticles (SACNs), combination therapy with clopidogrel and SACN was associated with a 4 fold greater delivery of cisplatin to tumor tissue and a greater reduction in tumor growth as well as higher survival rate. Clopidogrel enhances therapeutic efficiency of novel cisplatin based nano-formulations agents by increasing tumor drug delivery and can be used as a potential targeting agent for novel nano-formulation based chemotherapeutics.

  7. Automated Protein Localization of Blood Brain Barrier Vasculature in Brightfield IHC Images

    PubMed Central

    Keenan, Brendan T.; Pack, Allan I.; Shackleford, James A.

    2016-01-01

    In this paper, we present an objective method for localization of proteins in blood brain barrier (BBB) vasculature using standard immunohistochemistry (IHC) techniques and bright-field microscopy. Images from the hippocampal region at the BBB are acquired using bright-field microscopy and subjected to our segmentation pipeline which is designed to automatically identify and segment microvessels containing the protein glucose transporter 1 (GLUT1). Gabor filtering and k-means clustering are employed to isolate potential vascular structures within cryosectioned slabs of the hippocampus, which are subsequently subjected to feature extraction followed by classification via decision forest. The false positive rate (FPR) of microvessel classification is characterized using synthetic and non-synthetic IHC image data for image entropies ranging between 3 and 8 bits. The average FPR for synthetic and non-synthetic IHC image data was found to be 5.48% and 5.04%, respectively. PMID:26828723

  8. Cerebral aneurysms: relations between geometry, hemodynamics and aneurysm location in the cerebral vasculature

    NASA Astrophysics Data System (ADS)

    Passerini, Tiziano; Veneziani, Alessandro; Sangalli, Laura; Secchi, Piercesare; Vantini, Simone

    2010-11-01

    In cerebral blood circulation, the interplay of arterial geometrical features and flow dynamics is thought to play a significant role in the development of aneurysms. In the framework of the Aneurisk project, patient-specific morphology reconstructions were conducted with the open-source software VMTK (www.vmtk.org) on a set of computational angiography images provided by Ospedale Niguarda (Milano, Italy). Computational fluid dynamics (CFD) simulations were performed with a software based on the library LifeV (www.lifev.org). The joint statistical analysis of geometries and simulations highlights the possible association of certain spatial patterns of radius, curvature and shear load along the Internal Carotid Artery (ICA) with the presence, position and previous event of rupture of an aneurysm in the entire cerebral vasculature. Moreover, some possible landmarks are identified to be monitored for the assessment of a Potential Rupture Risk Index.

  9. Ultrastructural Localization of Adiponectin protein in Vasculature of Normal and Atherosclerotic mice

    PubMed Central

    Mori, Takuya; Koyama, Yoshihisa; Maeda, Norikazu; Nakamura, Yukiko; Fujishima, Yuya; Matsuda, Keisuke; Funahashi, Tohru; Shimada, Shoichi; Shimomura, Iichiro

    2014-01-01

    Adiponectin, adipose-specific secretory protein, abundantly circulates in bloodstream and its concentration is around 1000-fold higher than that of other cytokines and hormones. Hypoadiponectinemia is a risk factor for atherosclerosis. There is little or no information on ultrastructural localization of adiponectin in the vasculature. Herein we investigated the localization of vascular adiponectin in the aorta using the immunoelectron microscopic technique. In wild-type (WT) mice, adiponectin was mainly detected on the luminal surface membrane of endothelial cells (ECs) and also found intracellularly in the endocytic vesicles of ECs. In the atherosclerotic lesions of apolipoprotein E-knockout (ApoE-KO) mice, adiponectin was detected in ECs, on the cell surface membrane of synthetic smooth muscle cells, and on the surface of monocytes adherent to ECs. Changes in adiponectin localization within the wall of the aorta may provide novel insight into the pathogenesis of atherosclerosis. PMID:24809933

  10. Macroscopic two-pump two-vasculature cardiovascular model to support treatment of acute heart failure.

    PubMed

    Sugimachi, Masaru; Sunagawa, Kenji; Uemura, Kazunori; Kamiya, Atsunori; Shimizu, Shuji; Inagaki, Masashi; Shishido, Toshiaki

    2009-01-01

    Comprehensive understanding of hemodynamics remains a challenge even for expert cardiologists, partially due to a lack of an appropriate macroscopic model. We attempted to amend three major problems of Guyton's conceptual model (unknown left atrial pressure, unilateral heart damage, blood redistribution) and developed a comprehensive macroscopic model of hemodynamics that provides quantitative information. We incorporated a third axis of left atrial pressure, resulting in a 3D coordinate system. Pump functions of left and right heart are expressed by an integrated cardiac output curve, and the capacitive function of total vasculature by a venous return surface. The equations for both the cardiac output curve and venous return surface would facilitate precise diagnosis (especially evaluation of blood volume) and choice of appropriate treatments, including application to autopilot systems.

  11. Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature

    PubMed Central

    Kolaczkowska, Elzbieta; Jenne, Craig N.; Surewaard, Bas G. J.; Thanabalasuriar, Ajitha; Lee, Woo-Yong; Sanz, Maria-Jesus; Mowen, Kerri; Opdenakker, Ghislain; Kubes, Paul

    2015-01-01

    Neutrophil extracellular traps (NETs) composed of DNA decorated with histones and proteases trap and kill bacteria but also injure host tissue. Here we show that during a bloodstream infection with methicillin-resistant Staphylococcus aureus, the majority of bacteria are sequestered immediately by hepatic Kupffer cells, resulting in transient increases in liver enzymes, focal ischaemic areas and a robust neutrophil infiltration into the liver. The neutrophils release NETs into the liver vasculature, which remain anchored to the vascular wall via von Willebrand factor and reveal significant neutrophil elastase (NE) proteolytic activity. Importantly, DNase although very effective at DNA removal, and somewhat effective at inhibiting NE proteolytic activity, fails to remove the majority of histones from the vessel wall and only partly reduces injury. By contrast, inhibition of NET production as modelled by PAD4-deficiency, or prevention of NET formation and proteolytic activity as modelled in NE−/− mice prevent collateral host tissue damage. PMID:25809117

  12. A developmental defect in astrocytes inhibits programmed regression of the hyaloid vasculature in the mammalian eye

    PubMed Central

    Zhang, Cheng; Asnaghi, Laura; Gongora, Celine; Patek, Bonnie; Hose, Stacey; Ma, Bo; Fard, Masoud Aghsaei; Brako, Lawrence; Singh, Kamaljeet; Goldberg, Morton F.; Handa, James T.; Lo, Woo-Kuen; Eberhart, Charles G.; Zigler, J. Samuel; Sinha, Debasish

    2012-01-01

    Previously we reported the novel observation that astrocytes ensheath the persistent hyaloid artery, both in the Nuc1 spontaneous mutant rat, and in human PFV (persistent fetal vasculature) disease (Developmental Dynamics 234:36–47, 2005). We now show that astrocytes isolated from both optic nerve and retina of Nuc1 rats migrate faster than wild type astrocytes. Aquaporin 4 (AQP4), the major water channel in astrocytes, has been shown to be important in astrocyte migration. We demonstrate that AQP4 expression is elevated in the astrocytes in PFV conditions, and we hypothesize that this causes the cells to migrate abnormally into the vitreous where they ensheath the hyaloid artery. This abnormal association of astrocytes with the hyaloid artery may impede the normal macrophage-mediated remodeling and regression of the hyaloid system. PMID:21354650

  13. A developmental defect in astrocytes inhibits programmed regression of the hyaloid vasculature in the mammalian eye.

    PubMed

    Zhang, Cheng; Asnaghi, Laura; Gongora, Celine; Patek, Bonnie; Hose, Stacey; Ma, Bo; Fard, Masoud Aghsaei; Brako, Lawrence; Singh, Kamaljeet; Goldberg, Morton F; Handa, James T; Lo, Woo-Kuen; Eberhart, Charles G; Zigler, J Samuel; Sinha, Debasish

    2011-05-01

    Previously we reported the novel observation that astrocytes ensheath the persistent hyaloid artery, both in the Nuc1 spontaneous mutant rat, and in human PFV (persistent fetal vasculature) disease (Developmental Dynamics 234:36-47, 2005). We now show that astrocytes isolated from both the optic nerve and retina of Nuc1 rats migrate faster than wild type astrocytes. Aquaporin 4 (AQP4), the major water channel in astrocytes, has been shown to be important in astrocyte migration. We demonstrate that AQP4 expression is elevated in the astrocytes in PFV conditions, and we hypothesize that this causes the cells to migrate abnormally into the vitreous where they ensheath the hyaloid artery. This abnormal association of astrocytes with the hyaloid artery may impede the normal macrophage-mediated remodeling and regression of the hyaloid system. Copyright © 2011 Elsevier GmbH. All rights reserved.

  14. Detecting abnormal vasculature from photoacoustic signals using wavelet-packet features

    NASA Astrophysics Data System (ADS)

    Zalev, Jason; Kolios, Michael C.

    2011-03-01

    Photoacoustic systems can produce high-resolution, high-contrast images of vascular structures. To reconstruct images at very high-resolution, signals must be collected from many transducer locations, which can be time consuming due to limitations in transducer array technology. A method is presented to quickly discriminate between normal and abnormal tissue based on the structural morphology of vasculature. To demonstrate that the approach may be useful for cancer detection, a special simulator that produces photoacoustic signals from 3D models of vascular tissue is developed. Results show that it is possible to differentiate tissue classes even when it is not possible to resolve individual blood vessels. Performance of the algorithm remains strong as the number of transducer locations decreases and in the presence of noise.

  15. High affinity capture and concentration of quinacrine in polymorphonuclear neutrophils via vacuolar ATPase-mediated ion trapping: Comparison with other peripheral blood leukocytes and implications for the distribution of cationic drugs

    SciTech Connect

    Roy, Caroline; Gagné, Valérie; Fernandes, Maria J.G.; Marceau, François

    2013-07-15

    Many cationic drugs are concentrated in acidic cell compartments due to low retro-diffusion of the protonated molecule (ion trapping), with an ensuing vacuolar and autophagic cytopathology. In solid tissues, there is evidence that phagocytic cells, e.g., histiocytes, preferentially concentrate cationic drugs. We hypothesized that peripheral blood leukocytes could differentially take up a fluorescent model cation, quinacrine, depending on their phagocytic competence. Quinacrine transport parameters were determined in purified or total leukocyte suspensions at 37 °C. Purified polymorphonuclear leukocytes (PMNLs, essentially neutrophils) exhibited a quinacrine uptake velocity inferior to that of lymphocytes, but a consistently higher affinity (apparent K{sub M} 1.1 vs. 6.3 μM, respectively). However, the vacuolar (V)-ATPase inhibitor bafilomycin A1 prevented quinacrine transport or initiated its release in either cell type. PMNLs capture most of the quinacrine added at low concentrations to fresh peripheral blood leukocytes compared with lymphocytes and monocytes (cytofluorometry). Accumulation of the autophagy marker LC3-II occurred rapidly and at low drug concentrations in quinacrine-treated PMNLs (significant at ≥ 2.5 μM, ≥ 2 h). Lymphocytes contained more LAMP1 than PMNLs, suggesting that the mass of lysosomes and late endosomes is a determinant of quinacrine uptake V{sub max}. PMNLs, however, exhibited the highest capacity for pinocytosis (uptake of fluorescent dextran into endosomes). The selectivity of quinacrine distribution in peripheral blood leukocytes may be determined by the collaboration of a non-concentrating plasma membrane transport mechanism, tentatively identified as pinocytosis in PMNLs, with V-ATPase-mediated concentration. Intracellular reservoirs of cationic drugs are a potential source of toxicity (e.g., loss of lysosomal function in phagocytes). - Highlights: • Quinacrine is concentrated in acidic organelles via V-ATPase-mediated ion

  16. Abnormal calcium homeostasis in peripheral neuropathies

    PubMed Central

    Fernyhough, Paul; Calcutt, Nigel A.

    2010-01-01

    Abnormal neuronal calcium (Ca2+) homeostasis has been implicated in numerous diseases of the nervous system. The pathogenesis of two increasingly common disorders of the peripheral nervous system, namely neuropathic pain and diabetic polyneuropathy, has been associated with aberrant Ca2+ channel expression and function. Here we review the current state of knowledge regarding the role of Ca2+ dyshomeostasis and associated mitochondrial dysfunction in painful and diabetic neuropathies. The central impact of both alterations of Ca2+ signalling at the plasma membrane and also intracellular Ca2+ handling on sensory neuron function is discussed and related to abnormal endoplasmic reticulum performance. We also present new data highlighting sub-optimal axonal Ca 2+ signalling in diabetic neuropathy and discuss the putative role for this abnormality in the induction of axonal degeneration in peripheral neuropathies. The accumulating evidence implicating Ca2+ dysregulation with both painful and degenerative neuropathies, along with recent advances in understanding of regional variations in Ca2+ channel and pump structures, makes modulation of neuronal Ca2+ handling an increasingly viable approach for therapeutic interventions against the painful and degenerative aspects of many peripheral neuropathies. PMID:20034667

  17. Barriers of the peripheral nerve

    PubMed Central

    Peltonen, Sirkku; Alanne, Maria; Peltonen, Juha

    2013-01-01

    This review introduces the traditionally defined anatomic compartments of the peripheral nerves based on light and electron microscopic topography and then explores the cellular and the most recent molecular basis of the different barrier functions operative in peripheral nerves. We also elucidate where, and how, the homeostasis of the normal human peripheral nerve is controlled in situ and how claudin-containing tight junctions contribute to the barriers of peripheral nerve. Also, the human timeline of the development of the barriers of the peripheral nerve is depicted. Finally, potential future therapeutic modalities interfering with the barriers of the peripheral nerve are discussed. PMID:24665400

  18. [Peripheral facial nerve palsy].

    PubMed

    Nauta, J M; Timmenga, N M; Cats, H

    1993-04-01

    There are different etiological factors concerning the acute peripheral facial nerve palsy. In the majority of the cases, however, no etiological factor can be found. These cases are called idiopathic facial palsy or Bells palsy. Perhaps local anaesthetics could play a role as an etiological factor. By means of a case-report this form of facial nerve palsy will be discussed.

  19. Peripheral neuropathies 1988

    SciTech Connect

    Assal, J.P.; Liniger, C.

    1990-01-01

    The authors present results and experience in sixteen specific disciplines related to the study of nerve physiopathology, diagnosis and treatment. Twenty-two different peripheral neuropathies are presented, and different models related to health care strategies are discussed. The authors report on Inflammatory and autoimmune neuropathies and Genetic neuropathies.

  20. Treatment of peripheral neuropathies.

    PubMed Central

    Hallett, M; Tandon, D; Berardelli, A

    1985-01-01

    There are three general approaches to treatment of peripheral neuropathy. First, an attempt should be made to reverse the pathophysiological process if its nature can be elucidated. Second, nerve metabolism can be stimulated and regeneration encouraged. Third, even if the neuropathy itself cannot be improved, symptomatic therapy can be employed. This review outlines the options available for each approach. PMID:3003254

  1. Atherosclerosis and Alzheimer--diseases with a common cause? Inflammation, oxysterols, vasculature.

    PubMed

    Lathe, Richard; Sapronova, Alexandra; Kotelevtsev, Yuri

    2014-03-21

    Aging is accompanied by increasing vulnerability to pathologies such as atherosclerosis (ATH) and Alzheimer disease (AD). Are these different pathologies, or different presentations with a similar underlying pathoetiology? Both ATH and AD involve inflammation, macrophage infiltration, and occlusion of the vasculature. Allelic variants in common genes including APOE predispose to both diseases. In both there is strong evidence of disease association with viral and bacterial pathogens including herpes simplex and Chlamydophila. Furthermore, ablation of components of the immune system (or of bone marrow-derived macrophages alone) in animal models restricts disease development in both cases, arguing that both are accentuated by inflammatory/immune pathways. We discuss that amyloid β, a distinguishing feature of AD, also plays a key role in ATH. Several drugs, at least in mouse models, are effective in preventing the development of both ATH and AD. Given similar age-dependence, genetic underpinnings, involvement of the vasculature, association with infection, Aβ involvement, the central role of macrophages, and drug overlap, we conclude that the two conditions reflect different manifestations of a common pathoetiology. Infection and inflammation selectively induce the expression of cholesterol 25-hydroxylase (CH25H). Acutely, the production of 'immunosterol' 25-hydroxycholesterol (25OHC) defends against enveloped viruses. We present evidence that chronic macrophage CH25H upregulation leads to catalyzed esterification of sterols via 25OHC-driven allosteric activation of ACAT (acyl-CoA cholesterol acyltransferase/SOAT), intracellular accumulation of cholesteryl esters and lipid droplets, vascular occlusion, and overt disease. We postulate that AD and ATH are both caused by chronic immunologic challenge that induces CH25H expression and protection against particular infectious agents, but at the expense of longer-term pathology.

  2. 3D reconstruction of digitized histological sections for vasculature quantification in the mouse hind limb

    NASA Astrophysics Data System (ADS)

    Xu, Yiwen; Pickering, J. Geoffrey; Nong, Zengxuan; Gibson, Eli; Ward, Aaron D.

    2014-03-01

    In contrast to imaging modalities such as magnetic resonance imaging and micro computed tomography, digital histology reveals multiple stained tissue features at high resolution (0.25μm/pixel). However, the two-dimensional (2D) nature of histology challenges three-dimensional (3D) quantification and visualization of the different tissue components, cellular structures, and subcellular elements. This limitation is particularly relevant to the vasculature, which has a complex and variable structure within tissues. The objective of this study was to perform a fully automated 3D reconstruction of histology tissue in the mouse hind limb preserving the accurate systemic orientation of the tissues, stained with hematoxylin and immunostained for smooth muscle α actin. We performed a 3D reconstruction using pairwise rigid registrations of 5μm thick, paraffin-embedded serial sections, digitized at 0.25μm/pixel. Each registration was performed using the iterative closest points algorithm on blood vessel landmarks. Landmarks were vessel centroids, determined according to a signed distance map of each pixel to a decision boundary in hue-saturation-value color space; this decision boundary was determined based on manual annotation of a separate training set. Cell nuclei were then automatically extracted and corresponded to refine the vessel landmark registration. Homologous nucleus landmark pairs appearing on not more than two adjacent slides were chosen to avoid registrations which force curved or non-sectionorthogonal structures to be straight and section-orthogonal. The median accumulated target registration errors ± interquartile ranges for the vessel landmark registration, and the nucleus landmark refinement were 43.4+/-42.8μm and 2.9+/-1.7μm, respectively (p<0.0001). Fully automatic and accurate 3D rigid reconstruction of mouse hind limb histology imaging is feasible based on extracted vasculature and nuclei.

  3. Computational study of the contribution of the vasculature on the dynamic response of the brain.

    PubMed

    Zhang, Liying; Bae, Jinho; Hardy, Warren N; Monson, Kenneth L; Manley, Geoffrey T; Goldsmith, Werner; Yang, King H; King, Albert I

    2002-11-01

    Brain tissue architecture consists of a complex network of neurons and vasculature interspersed within a matrix of supporting cells. The role of the relatively stiffer blood vessels on the more compliant brain tissues during rapid loading has not been properly investigated. Two 2-D finite element models of the human head were developed. The basic model (Model I) consisted of the skull, dura matter, cerebral spinal fluid (CSF), tentorium, brain tissue and the parasagittal bridging veins. The pia mater was also included but in a simplified form which does not correspond to the convolutions of the brain. In Model II, major branches of the cerebral arteries were added to Model I. Material properties for the brain tissues and vasculature were taken from those reported in the literature. The model was first validated against intracranial pressure and brain/skull relative motion data from cadaveric tests. Two loading conditions, an anterior-posterior linear acceleration and a flexion-extension angular velocity pulse, were applied to both models. Resulting maximum principal strain, shear strain and intracranial pressure throughout the intracranial tissue were calculated and compared. Overall, the maximum principal strain/stress in the brain was lower in the model that included simulated blood vessels. The inclusion of the cerebral vessels added regional strength to the brain substance, and thereby contributed to the load bearing capacity of this composite brain model during head impact, analogous to reinforcing bars in a reinforced concrete structure. In addition to the neurovasculature, the pia membrane, which conforms to the numerous gyri and sulci not modeled in this study, may add to the structural strength of the brain. Results from this investigation suggest that the fine anatomical substructures of the brain should not be ignored in traumatic brain injury modeling. However, incorporation of blood vessels in a 3-D FE head model is not practical at this stage due to

  4. Differentiation between normal and tumor vasculature of animal and human glioma by FTIR imaging.

    PubMed

    Wehbe, Katia; Pineau, Raphael; Eimer, Sandrine; Vital, Anne; Loiseau, Hugues; Déléris, Gérard

    2010-12-01

    Malignant gliomas are very aggressive tumors, highly angiogenic and invading heterogeneously the surrounding brain parenchyma, making their resection very difficult. To overcome the limits of current diagnostic imaging techniques used for gliomas, we proposed using FTIR imaging, with a spatial resolution from 6 to 10 μm, to provide molecular information for their histological examination, based on discrimination between normal and tumor vasculature. Differentiation between normal and tumor blood vessel spectra by hierarchical cluster analysis was performed on tissue sections obtained from xenografted brain tumors of Rag-gamma mice 28 days after intracranial implantation of glioma cells, as well as for human brain tumors obtained in clinics. Classical pathological examination and immunohistochemistry were performed in parallel to the FTIR spectral imaging of brain tissues. First on the animal model, classification of FTIR spectra of blood vessels could be performed using spectral intervals based on fatty acyl (3050-2800 cm(-1)) and carbohydrate (1180-950 cm(-1)) absorptions, with the formation of two clusters corresponding to healthy and tumor parts of the tissue sections. Further data treatments on these two spectral intervals provided interpretable information about the molecular contents involved in the differentiation between normal and tumor blood vessels, the latter presenting a higher level of fatty acyl chain unsaturation and an unexpected loss of absorption from osidic residues. This classification method was further successfully tested on human glioma tissue sections. These findings demonstrate that FTIR imaging could highlight discriminant molecular markers to distinguish between normal and tumor vasculature, and help to delimitate areas of corresponding tissue.

  5. Atherosclerosis and Alzheimer - diseases with a common cause? Inflammation, oxysterols, vasculature

    PubMed Central

    2014-01-01

    Background Aging is accompanied by increasing vulnerability to pathologies such as atherosclerosis (ATH) and Alzheimer disease (AD). Are these different pathologies, or different presentations with a similar underlying pathoetiology? Discussion Both ATH and AD involve inflammation, macrophage infiltration, and occlusion of the vasculature. Allelic variants in common genes including APOE predispose to both diseases. In both there is strong evidence of disease association with viral and bacterial pathogens including herpes simplex and Chlamydophila. Furthermore, ablation of components of the immune system (or of bone marrow-derived macrophages alone) in animal models restricts disease development in both cases, arguing that both are accentuated by inflammatory/immune pathways. We discuss that amyloid β, a distinguishing feature of AD, also plays a key role in ATH. Several drugs, at least in mouse models, are effective in preventing the development of both ATH and AD. Given similar age-dependence, genetic underpinnings, involvement of the vasculature, association with infection, Aβ involvement, the central role of macrophages, and drug overlap, we conclude that the two conditions reflect different manifestations of a common pathoetiology. Mechanism Infection and inflammation selectively induce the expression of cholesterol 25-hydroxylase (CH25H). Acutely, the production of ‘immunosterol’ 25-hydroxycholesterol (25OHC) defends against enveloped viruses. We present evidence that chronic macrophage CH25H upregulation leads to catalyzed esterification of sterols via 25OHC-driven allosteric activation of ACAT (acyl-CoA cholesterol acyltransferase/SOAT), intracellular accumulation of cholesteryl esters and lipid droplets, vascular occlusion, and overt disease. Summary We postulate that AD and ATH are both caused by chronic immunologic challenge that induces CH25H expression and protection against particular infectious agents, but at the expense of longer-term pathology

  6. Alterations of Retinal Vasculature in Cystathionine-Beta-Synthase Mutant Mice, a Model of Hyperhomocysteinemia

    PubMed Central

    Tawfik, Amany; Al-Shabrawey, Mohamed; Roon, Penny; Sonne, Srinivas; Covar, Jason A.; Matragoon, Surapoon; Ganapathy, Preethi S.; Atherton, Sally S.; El-Remessy, Azza; Ganapathy, Vadivel; Smith, Sylvia B.

    2013-01-01

    Purpose. Mice with moderate/severe hyperhomocysteinemia due to deficiency or absence of the cbs gene encoding cystathionine-beta-synthase (CBS) have marked retinal disruption, ganglion cell loss, optic nerve mitochondrial dysfunction, and ERG defects; those with mild hyperhomocysteinemia have delayed retinal morphological/functional phenotype. Excess homocysteine is a risk factor for cardiovascular diseases; however, it is not known whether excess homocysteine alters retinal vasculature. Methods. Cbs+/+, cbs+/−, and cbs−/− mice (age ∼3 weeks) were subjected to angiography; retinas were harvested for cryosections, flat-mount preparations, or trypsin digestion and subjected to immunofluorescence microscopy to visualize vessels using isolectin-B4, to detect angiogenesis using anti-VEGF and anti-endoglin (anti-CD105) and activated glial cells (anti-glial fibrillary acidic protein [anti-GFAP]) and to investigate the blood–retinal barrier using the tight junction markers zonula occludens-1 (ZO-1) and occludin. Expression of vegf was determined by quantitative RT-PCR (qRT-PCR) and immunoblotting. Human retinal endothelial cells (HRECs) were treated with excess homocysteine to analyze permeability. Results. Angiography revealed vascular leakage in cbs−/− mice; immunohistochemical analysis demonstrated vascular patterns consistent with ischemia; isolectin-B4 labeling revealed a capillary-free zone centrally and new vessels with capillary tufts midperipherally. This was associated with increased vegf mRNA and protein, CD105, and GFAP in cbs−/− retinas concomitant with a marked decrease in ZO-1 and occludin. Homocysteine-treated HRECs showed increased permeability. Conclusions. Severe elevation of homocysteine in cbs−/− mutant mice is accompanied by alterations in retinal vasculature (ischemia, neovascularization, and incompetent blood–retinal barrier). The marked disruption of retinal structure and decreased visual function reported in cbs−/− mice

  7. Selective Alpha-Particle Mediated Depletion of Tumor Vasculature with Vascular Normalization

    PubMed Central

    Seshan, Surya V.; Kappel, Barry J.; Chattopadhyay, Debjit; May, Chad; McDevitt, Michael R.; Nolan, Daniel; Mittal, Vivek; Benezra, Robert; Scheinberg, David A.

    2007-01-01

    Background Abnormal regulation of angiogenesis in tumors results in the formation of vessels that are necessary for tumor growth, but compromised in structure and function. Abnormal tumor vasculature impairs oxygen and drug delivery and results in radiotherapy and chemotherapy resistance, respectively. Alpha particles are extraordinarily potent, short-ranged radiations with geometry uniquely suitable for selectively killing neovasculature. Methodology and Principal Findings Actinium-225 (225Ac)-E4G10, an alpha-emitting antibody construct reactive with the unengaged form of vascular endothelial cadherin, is capable of potent, selective killing of tumor neovascular endothelium and late endothelial progenitors in bone-marrow and blood. No specific normal-tissue uptake of E4G10 was seen by imaging or post-mortem biodistribution studies in mice. In a mouse-model of prostatic carcinoma, 225Ac-E4G10 treatment resulted in inhibition of tumor growth, lower serum prostate specific antigen level and markedly prolonged survival, which was further enhanced by subsequent administration of paclitaxel. Immunohistochemistry revealed lower vessel density and enhanced tumor cell apoptosis in 225Ac-E4G10 treated tumors. Additionally, the residual tumor vasculature appeared normalized as evident by enhanced pericyte coverage following 225Ac-E4G10 therapy. However, no toxicity was observed in vascularized normal organs following 225Ac-E4G10 therapy. Conclusions The data suggest that alpha-particle immunotherapy to neovasculature, alone or in combination with sequential chemotherapy, is an effective approach to cancer therapy. PMID:17342201

  8. Mechanisms of the biphasic effects of peroxides on the retinal vasculature of newborn and adult pigs.

    PubMed

    Abran, D; Hardy, P; Varma, D R; Chemtob, S

    1995-09-01

    We tested whether the ontogenic differences in the constrictor effects of peroxides on the retinal vasculature were modulated by dilator cyclo-oxygenase products. Retinal arteriole (100-200 microns) vasomotor response to H2O2, t-butyl hydroperoxide, and cumene hydroperoxide were studied in isolated eyecup preparations using video camera monitoring of vessel diameter. A time- and dose-dependent biphasic retinal vasomotor response to all peroxides was observed on tissues of newborn and adult pigs. A rapid vasoconstriction (first 2 min) was followed by a relaxation which was greater in the adult than in the newborn tissues. The constrictor as well as the dilator response to peroxides and the observed increase in prostanoids were blocked by the cyclo-oxygenase inhibitor indomethacin. The peroxide-induced relaxation was inhibited or markedly attenuated by the prostaglandin I2 synthase blockers, trans-2-phenyl cyclopropylamine and minoxidil on tissues of newborn and adult animals. These agents also prevented the increase of the prostaglandin I2 receptor-coupled second messenger, cyclic 3',5'-adenosine monophosphate. Our data indicate that prostaglandin I2 plays a major role in counteracting the initial constrictor effects of peroxides in the retinal vasculature, and that the reversal of this constriction is greater in the adult than the newborn. These findings suggest that reduced reversal of vasoconstriction by the dilator prostaglandin I2 during an oxidative stress in the newborn may facilitate vasoconstriction by the dilator prostaglandin I2 during an oxidative stress in the newborn may facilitate neovascularization in retinopathy of prematurity.

  9. Nogo-B receptor deficiency causes cerebral vasculature defects during embryonic development in mice

    PubMed Central

    Rana, Ujala; Liu, Zhong; Kumar, Suresh N.; Zhao, Baofeng; Hu, Wenquan; Bordas, Michelle; Cossette, Stephanie; Szabo, Sara; Foeckler, Jamie; Weiler, Hartmut; Chrzanowska-Wodnicka, Magdalena; Holtz, Mary L.; Misra, Ravindra P.; Salato, Valerie; North, Paula; Ramchandran, Ramani; Miao, Qing Robert

    2016-01-01

    Nogo-B receptor (NgBR) was identified as a receptor specific for Nogo-B. Our previous work has shown that Nogo-B and its receptor (NgBR) are essential for chemotaxis and morphogenesis of endothelial cells in vitro and intersomitic vessel formation via Akt pathway in zebrafish. Here, we further demonstrated the roles of NgBR in regulating vasculature development in mouse embryo and primitive blood vessel formation in embryoid body culture systems, respectively. Our results showed that NgBR homozygous knockout mice are embryonically lethal at E7.5 or earlier, and Tie2Cre-mediated endothelial cell-specific NgBR knockout (NgBR ecKO) mice die at E11.5 and have severe blood vessel assembly defects in embryo. In addition, mutant embryos exhibit dilation of cerebral blood vessel, resulting in thin-walled endothelial caverns. The similar vascular defects also were detected in Cdh5(PAC)-CreERT2 NgBR inducible ecKO mice. Murine NgBR gene-targeting embryonic stem cells (ESC) were generated by homologous recombination approaches. Homozygous knockout of NgBR in ESC results in cell apoptosis. Heterozygous knockout of NgBR does not affect ESC cell survival, but reduces the formation and branching of primitive blood vessels in embryoid body culture systems. Mechanistically, NgBR knockdown not only decreases both Nogo-B and VEGF-stimulated endothelial cell migration by abolishing Akt phosphorylation, but also decreases the expression of CCM1 and CCM2 proteins. Furthermore, we performed immunofluorescence (IF) staining of NgBR in human cerebral cavernous malformation patient tissue sections. The quantitative analysis results showed that NgBR expression levels in CD31 positive endothelial cells is significantly decreased in patient tissue sections. These results suggest that NgBR may be one of important genes coordinating the cerebral vasculature development. PMID:26746789

  10. Genetic factors regulating lung vasculature and immune cell functions associate with resistance to pneumococcal infection.

    PubMed

    Jonczyk, Magda S; Simon, Michelle; Kumar, Saumya; Fernandes, Vitor E; Sylvius, Nicolas; Mallon, Ann-Marie; Denny, Paul; Andrew, Peter W

    2014-01-01

    Streptococcus pneumoniae is an important human pathogen responsible for high mortality and morbidity worldwide. The susceptibility to pneumococcal infections is controlled by as yet unknown genetic factors. To elucidate these factors could help to develop new medical treatments and tools to identify those most at risk. In recent years genome wide association studies (GWAS) in mice and humans have proved successful in identification of causal genes involved in many complex diseases for example diabetes, systemic lupus or cholesterol metabolism. In this study a GWAS approach was used to map genetic loci associated with susceptibility to pneumococcal infection in 26 inbred mouse strains. As a result four candidate QTLs were identified on chromosomes 7, 13, 18 and 19. Interestingly, the QTL on chromosome 7 was located within S. pneumoniae resistance QTL (Spir1) identified previously in a linkage study of BALB/cOlaHsd and CBA/CaOlaHsd F2 intercrosses. We showed that only a limited number of genes encoded within the QTLs carried phenotype-associated polymorphisms (22 genes out of several hundred located within the QTLs). These candidate genes are known to regulate TGFβ signalling, smooth muscle and immune cells functions. Interestingly, our pulmonary histopathology and gene expression data demonstrated, lung vasculature plays an important role in resistance to pneumococcal infection. Therefore we concluded that the cumulative effect of these candidate genes on vasculature and immune cells functions as contributory factors in the observed differences in susceptibility to pneumococcal infection. We also propose that TGFβ-mediated regulation of fibroblast differentiation plays an important role in development of invasive pneumococcal disease. Gene expression data submitted to the NCBI Gene Expression Omnibus Accession No: GSE49533 SNP data submitted to NCBI dbSNP Short Genetic Variation http://www.ncbi.nlm.nih.gov/projects/SNP/snp_viewTable.cgi?handle=MUSPNEUMONIA.

  11. iNKT Cell Emigration out of the Lung Vasculature Requires Neutrophils and Monocyte-Derived Dendritic Cells in Inflammation

    PubMed Central

    Thanabalasuriar, A; Neupane, A.S; Wang, J; Krummel, M.F; Kubes, P

    2017-01-01

    iNKT cells are a subset of innate T cells that recognize glycolipids presented on CD1d molecules and protect against a variety of bacterial infections including S. pneumoniae. Using lung intravital imaging, we examined the behavior and mechanism of pulmonary iNKT cell activation in response to the potent iNKT cell ligand α-galactosylceramide or during S. pneumoniae infection. In untreated mice the major fraction of iNKT cells resided in the vasculature, but a small critical population resided in the extravascular space in proximity to monocyte-derived DCs. Administration of either α-GalCer or S. pneumoniae, induced CD1d dependent rapid recruitment of neutrophils out of the vasculature. This neutrophil exodus paved the way for extravasation of iNKT cells from the lung vasculature via CCL17. Depletion of monocyte-derived DCs abrogated both the neutrophil and subsequent iNKT cell extravasation. Moreover, impairing iNKT cell migration out of the lung vasculature by blocking CCL17 greatly increased susceptibility to S. pneumoniae infection, suggesting a critical role for the secondary wave of iNKT cells in host defense. PMID:27653688

  12. Lama1 mutations lead to vitreoretinal blood vessel formation, persistence of fetal vasculature, and epiretinal membrane formation in mice

    PubMed Central

    2011-01-01

    Background Valuable insights into the complex process of retinal vascular development can be gained using models with abnormal retinal vasculature. Two such models are the recently described mouse lines with mutations in Lama1, an important component of the retinal internal limiting membrane (ILM). These mutants have a persistence of the fetal vasculature of vitreous (FVV) but lack a primary retinal vascular plexus. The present study provides a detailed analysis of astrocyte and vascular development in these Lama1 mutants. Results Although astrocytes and blood vessels initially migrate into Lama1 mutant retinas, both traverse the peripapillary ILM into the vitreous by P3. Once in the vitreous, blood vessels anastomose with vessels of the vasa hyaloidea propria, part of the FVV, and eventually re-enter the retina where they dive to form the inner and outer retinal capillary networks. Astrocytes continue proliferating within the vitreous to form a dense mesh that resembles epiretinal membranes associated with persistent fetal vasculature and proliferative vitreoretinopathy. Conclusions Lama1 and a fully intact ILM are required for normal retinal vascular development. Mutations in Lama1 allow developing retinal vessels to enter the vitreous where they anastomose with vessels of the hyaloid system which persist and expand. Together, these vessels branch into the retina to form fairly normal inner retinal vascular capillary plexi. The Lama1 mutants described in this report are potential models for studying the human conditions persistent fetal vasculature and proliferative vitreoretinopathy. PMID:21999428

  13. A CD276 Antibody Guided Missile with One Warhead and Two Targets: The Tumor and Its Vasculature.

    PubMed

    Khan, Kabir A; Kerbel, Robert S

    2017-04-10

    In this issue of Cancer Cell, Seaman et al. demonstrate that antibody drug conjugates (ADCs) against CD276 expressed by tumor cells and tumor vasculature have promising anti-tumor activity while showing little toxicity. Importantly, these agents have the potential to target both angiogenic vessels and non-angiogenic vessels co-opted by tumor cells.

  14. What Is Peripheral Artery Disease?

    MedlinePlus

    ... from the NHLBI on Twitter. What Is Peripheral Artery Disease? Peripheral artery disease (P.A.D.) is ... that affects blood flow to the legs. Normal Artery and Artery With Plaque Buildup The illustration shows ...

  15. Peripheral Artery Disease and Diabetes

    MedlinePlus

    ... Artery Disease Venous Thromboembolism Aortic Aneurysm More Peripheral Artery Disease & Diabetes Updated:Jan 26,2016 People with ... developing atherosclerosis, the most common cause of peripheral artery disease (PAD) . And individuals with PAD have a ...

  16. Angioplasty and stent placement - peripheral arteries

    MedlinePlus

    Percutaneous transluminal angioplasty - peripheral artery; PTA - peripheral artery; Angioplasty - peripheral arteries; Iliac artery -angioplasty; Femoral artery - angioplasty; Popliteal artery - angioplasty; Tibial artery - angioplasty; Peroneal artery - ...

  17. High affinity capture and concentration of quinacrine in polymorphonuclear neutrophils via vacuolar ATPase-mediated ion trapping: comparison with other peripheral blood leukocytes and implications for the distribution of cationic drugs.

    PubMed

    Roy, Caroline; Gagné, Valérie; Fernandes, Maria J G; Marceau, François

    2013-07-15

    Many cationic drugs are concentrated in acidic cell compartments due to low retro-diffusion of the protonated molecule (ion trapping), with an ensuing vacuolar and autophagic cytopathology. In solid tissues, there is evidence that phagocytic cells, e.g., histiocytes, preferentially concentrate cationic drugs. We hypothesized that peripheral blood leukocytes could differentially take up a fluorescent model cation, quinacrine, depending on their phagocytic competence. Quinacrine transport parameters were determined in purified or total leukocyte suspensions at 37 °C. Purified polymorphonuclear leukocytes (PMNLs, essentially neutrophils) exhibited a quinacrine uptake velocity inferior to that of lymphocytes, but a consistently higher affinity (apparent KM 1.1 vs. 6.3 μM, respectively). However, the vacuolar (V)-ATPase inhibitor bafilomycin A1 prevented quinacrine transport or initiated its release in either cell type. PMNLs capture most of the quinacrine added at low concentrations to fresh peripheral blood leukocytes compared with lymphocytes and monocytes (cytofluorometry). Accumulation of the autophagy marker LC3-II occurred rapidly and at low drug concentrations in quinacrine-treated PMNLs (significant at ≥2.5 μM, ≥2 h). Lymphocytes contained more LAMP1 than PMNLs, suggesting that the mass of lysosomes and late endosomes is a determinant of quinacrine uptake Vmax. PMNLs, however, exhibited the highest capacity for pinocytosis (uptake of fluorescent dextran into endosomes). The selectivity of quinacrine distribution in peripheral blood leukocytes may be determined by the collaboration of a non-concentrating plasma membrane transport mechanism, tentatively identified as pinocytosis in PMNLs, with V-ATPase-mediated concentration. Intracellular reservoirs of cationic drugs are a potential source of toxicity (e.g., loss of lysosomal function in phagocytes).

  18. Acid-Sensing Ion Channels as Potential Pharmacological Targets in Peripheral and Central Nervous System Diseases.

    PubMed

    Radu, Beatrice Mihaela; Banciu, Adela; Banciu, Daniel Dumitru; Radu, Mihai

    2016-01-01

    Acid-sensing ion channels (ASICs) are widely expressed in the body and represent good sensors for detecting protons. The pH drop in the nervous system is equivalent to ischemia and acidosis, and ASICs are very good detectors in discriminating slight changes in acidity. ASICs are important pharmacological targets being involved in a variety of pathophysiological processes affecting both the peripheral nervous system (e.g., peripheral pain, diabetic neuropathy) and the central nervous system (e.g., stroke, epilepsy, migraine, anxiety, fear, depression, neurodegenerative diseases, etc.). This review discusses the role played by ASICs in different pathologies and the pharmacological agents acting on ASICs that might represent promising drugs. As the majority of above-mentioned pathologies involve not only neuronal dysfunctions but also microvascular alterations, in the next future, ASICs may be also considered as potential pharmacological targets at the vasculature level. Perspectives and limitations in the use of ASICs antagonists and modulators as pharmaceutical agents are also discussed.

  19. Ultrasound of Peripheral Nerves

    PubMed Central

    Suk, Jung Im; Walker, Francis O.; Cartwright, Michael S.

    2013-01-01

    Over the last decade, neuromuscular ultrasound has emerged as a useful tool for the diagnosis of peripheral nerve disorders. This article reviews sonographic findings of normal nerves including key quantitative ultrasound measurements that are helpful in the evaluation of focal and possibly generalized peripheral neuropathies. It also discusses several recent papers outlining the evidence base for the use of this technology, as well as new findings in compressive, traumatic, and generalized neuropathies. Ultrasound is well suited for use in electrodiagnostic laboratories where physicians, experienced in both the clinical evaluation of patients and the application of hands-on technology, can integrate findings from the patient’s history, physical examination, electrophysiological studies, and imaging for diagnosis and management. PMID:23314937

  20. Inherited peripheral neuropathies.

    PubMed

    Shy, Michael E

    2011-04-01

    Mutations in genes expressed in Schwann cells and the axons they ensheathe cause the hereditary motor and sensory neuropathies, also known as Charcot-Marie-Tooth disease (CMT). More than 40 different genes have been shown to cause inherited neuropathies; chromosomal localizations of many other distinct inherited neuropathies have been mapped, and new genetic causes for inherited neuropathies continue to be discovered. How to keep track of all of these disorders, when to pursue genetic testing, and what tests to order for specific patients are difficult challenges for any neurologist. This review addresses these issues and provides illustrative cases to help in dealing with them. CMT serves as a living system to identify molecules necessary for normal peripheral nervous system (PNS) function. Understanding how these various molecules interact will provide a better understanding of the pathogenesis of peripheral neuropathies in general as well as other neurodegenerative disorders involving the PNS.

  1. [Peripheral neuropathies: Diagnostic strategy].

    PubMed

    Magy, L

    2017-02-28

    Diagnosing a peripheral neuropathy is sometimes challenging, as the causes are diverse and the clinical pictures heterogeneous. Overall, diagnosing a patient with peripheral neuropathy will require some knowledge in almost every field of medicine. Therefore, it appears crucial to adopt a diagnostic strategy that is based on solid clinical and neurophysiological grounds. The present paper describes a three-step diagnostic strategy: (1) to delineate a clinico-pathologic entity from clinical and electrodiagnostic findings; (2) to propose a list of plausible causes based on step one, history and clinical context; (3) to use appropriate workup in order to determine the cause or mechanism of the neuropathy. The three steps of this diagnostic strategy necessitate a high level of expertise and interaction between physicians is highly desirable. Finally, an aggressive course and a severe impairment should lead to relentlessly look for a curable cause.

  2. Immunotherapy in Peripheral Neuropathies.

    PubMed

    Léger, Jean-Marc; Guimarães-Costa, Raquel; Muntean, Cristina

    2016-01-01

    Immunotherapy has been investigated in a small subset of peripheral neuropathies, including an acute one, Guillain-Barré syndrome, and 3 chronic forms: chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, and neuropathy associated with IgM anti-myelin-associated glycoprotein. Several experimental studies and clinical data are strongly suggestive of an immune-mediated pathogenesis. Either cell-mediated mechanisms or antibody responses to Schwann cell, compact myelin, or nodal antigens are considered to act together in an aberrant immune response to cause damage to peripheral nerves. Immunomodulatory treatments used in these neuropathies aim to act at various steps of this pathogenic process. However, there are many phenotypic variants and, consequently, there is a significant difference in the response to immunotherapy between these neuropathies, as well as a need to improve our knowledge and long-term management of chronic forms.

  3. Peripheral arterial disease

    PubMed Central

    2011-01-01

    Introduction Up to 20% of adults aged over 55 years have detectable peripheral arterial disease of the legs, but this may cause symptoms of intermittent claudication in only a small proportion of affected people. The main risk factors are smoking and diabetes mellitus, but other risk factors for cardiovascular disease are also associated with peripheral arterial disease. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for people with chronic peripheral arterial disease? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2010. Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review. We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 70 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review, we present information relating to the effectiveness and safety of the following interventions: antiplatelet agents, bypass surgery, cilostazol, exercise, pentoxifylline, percutaneous transluminal angioplasty (PTA), prostaglandins, smoking cessation, and statins. PMID:21477401

  4. Peripheral arterial disease

    PubMed Central

    2009-01-01

    Introduction Up to 20% of adults aged over 55 years have detectable peripheral arterial disease of the legs, but this may cause symptoms of intermittent claudication in only a small proportion of affected people. The main risk factors are smoking and diabetes mellitus, but other risk factors for cardiovascular disease are also associated with peripheral arterial disease. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for people with chronic peripheral arterial disease? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2009. (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 59 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: antiplatelet agents; bypass surgery; cilostazol; exercise; pentoxifylline; percutaneous transluminal angioplasty (PTA); prostaglandins; smoking cessation; and statins. PMID:19454099

  5. Wntless is required for peripheral lung differentiation and pulmonary vascular development.

    PubMed

    Cornett, Bridget; Snowball, John; Varisco, Brian M; Lang, Richard; Whitsett, Jeffrey; Sinner, Debora

    2013-07-01

    Wntless (Wls), a gene highly conserved across the animal kingdom, encodes for a transmembrane protein that mediates Wnt ligand secretion. Wls is expressed in developing lung, wherein Wnt signaling is necessary for pulmonary morphogenesis. We hypothesize that Wls plays a critical role in modulating Wnt signaling during lung development and therefore affects processes critical for pulmonary morphogenesis. We generated conditional Wls mutant mice utilizing Shh-Cre and Dermo1-Cre mice to delete Wls in the embryonic respiratory epithelium and mesenchyme, respectively. Epithelial deletion of Wls disrupted lung branching morphogenesis, peripheral lung development and pulmonary endothelial differentiation. Epithelial Wls mutant mice died at birth due to respiratory failure caused by lung hypoplasia and pulmonary hemorrhage. In the lungs of these mice, VEGF and Tie2-angiopoietin signaling pathways, which mediate vascular development, were downregulated from early stages of development. In contrast, deletion of Wls in mesenchymal cells of the developing lung did not alter branching morphogenesis or early mesenchymal differentiation. In vitro assays support the concept that Wls acts in part via Wnt5a to regulate pulmonary vascular development. We conclude that epithelial Wls modulates Wnt ligand activities critical for pulmonary vascular differentiation and peripheral lung morphogenesis. These studies provide a new framework for understanding the molecular mechanisms underlying normal pulmonary vasculature formation and the dysmorphic pulmonary vasculature development associated with congenital lung disease.

  6. Sodium Channels, Mitochondria, and Axonal Degeneration in Peripheral Neuropathy.

    PubMed

    Persson, Anna-Karin; Hoeijmakers, Janneke G J; Estacion, Mark; Black, Joel A; Waxman, Stephen G

    2016-05-01

    Peripheral neuropathy results from damage to peripheral nerves and is often accompanied by pain in affected limbs. Treatment represents an unmet medical need and a thorough understanding of the mechanisms underlying axonal injury is needed. Longer nerve fibers tend to degenerate first (length-dependence), and patients carrying pathogenic mutations throughout life usually become symptomatic in mid- or late-life (time-dependence). The activity of voltage-gated sodium channels can contribute to axonal injury and sodium channel gain-of-function mutations have been linked to peripheral neuropathy. Recent studies have implicated sodium channel activity, mitochondrial compromise, and reverse-mode Na(+)/Ca(2+) exchange in time- and length-dependent axonal injury. Elucidation of molecular mechanisms underlying axonal injury in peripheral neuropathy may provide new therapeutic strategies for this painful and debilitating condition.

  7. Sex-based differential regulation of oxidative stress in the vasculature by nitric oxide

    PubMed Central

    Morales, Rommel C.; Bahnson, Edward S.M.; Havelka, George E.; Cantu-Medellin, Nadiezhda; Kelley, Eric E.; Kibbe, Melina R.

    2015-01-01

    Background Nitric oxide (•NO) is more effective at inhibiting neointimal hyperplasia following arterial injury in male versus female rodents, though the etiology is unclear. Given that superoxide (O2•−) regulates cellular proliferation, and •NO regulates superoxide dismutase-1 (SOD-1) in the vasculature, we hypothesized that •NO differentially regulates SOD-1 based on sex. Materials and methods Male and female vascular smooth muscle cells (VSMC) were harvested from the aortae of Sprague-Dawley rats. O2•− levels were quantified by electron paramagnetic resonance (EPR) and HPLC. sod-1 gene expression was assayed by qPCR. SOD-1, SOD-2, and catalase protein levels were detected by Western blot. SOD-1 activity was measured via colorimetric assay. The rat carotid artery injury model was performed on Sprague-Dawley rats ±•NO treatment and SOD-1 protein levels were examined by Western blot. Results In vitro, male VSMC have higher O2•− levels and lower SOD − 1 activity at baseline compared to female VSMC (P < 0.05). •NO decreased O2•− levels and increased SOD − 1 activity in male (P<0.05) but not female VSMC. •NO also increased sod− 1 gene expression and SOD − 1 protein levels in male (P<0.05) but not female VSMC. In vivo, SOD-1 levels were 3.7-fold higher in female versus male carotid arteries at baseline. After injury, SOD-1 levels decreased in both sexes, but •NO increased SOD-1 levels 3-fold above controls in males, but returned to baseline in females. Conclusions Our results provide evidence that regulation of the redox environment at baseline and following exposure to •NO is sex-dependent in the vasculature. These data suggest that sex-based differential redox regulation may be one mechanism by which •NO is more effective at inhibiting neointimal hyperplasia in male versus female rodents. PMID:25617803

  8. In vivo 3D morphology of astrocyte–vasculature interactions in the somatosensory cortex: implications for neurovascular coupling

    PubMed Central

    McCaslin, Addason F H; Chen, Brenda R; Radosevich, Andrew J; Cauli, Bruno; Hillman, Elizabeth M C

    2011-01-01

    Astrocytes are increasingly believed to play an important role in neurovascular coupling. Recent in vivo studies have shown that intracellular calcium levels in astrocytes correlate with reactivity in adjacent diving arterioles. However, the hemodynamic response to stimulation involves a complex orchestration of vessel dilations and constrictions that spread rapidly over wide distances. In this work, we study the three-dimensional cytoarchitecture of astrocytes and their interrelations with blood vessels down through layer IV of the mouse somatosensory cortex using in vivo two-photon microscopy. Vessels and astrocytes were visualized through intravenous dextran-conjugated fluorescein and cortically applied sulforhodamine 101 (SR101), respectively. In addition to exploring astrocyte density, vascular proximity, and microvascular density, we found that sheathing of subpial vessels by astrocyte processes was continuous along all capillaries, arterioles, and veins, comprising a highly interconnected pathway through which signals could feasibly be relayed over long distances via gap junctions. An inner SR101-positive sheath noted along pial and diving arterioles was determined to be nonastrocytic, and appears to represent selective SR101 staining of arterial endothelial cells. Our findings underscore the intimate relationship between astrocytes and all cortical blood vessels, and suggest that astrocytes could influence neurovascular regulation at a range of sites, including the capillary bed and pial arterioles. PMID:21139630

  9. Clinical peripherality: development of a peripherality index for rural health services

    PubMed Central

    Swan, Gillian M; Selvaraj, Sivasubramaniam; Godden, David J

    2008-01-01

    Background The configuration of rural health services is influenced by geography. Rural health practitioners provide a broader range of services to smaller populations scattered over wider areas or more difficult terrain than their urban counterparts. This has implications for training and quality assurance of outcomes. This exploratory study describes the development of a "clinical peripherality" indicator that has potential application to remote and rural general practice communities for planning and research purposes. Methods Profiles of general practice communities in Scotland were created from a variety of public data sources. Four candidate variables were chosen that described demographic and geographic characteristics of each practice: population density, number of patients on the practice list, travel time to nearest specialist led hospital and travel time to Health Board administrative headquarters. A clinical peripherality index, based on these variables, was derived using factor analysis. Relationships between the clinical peripherality index and services offered by the practices and the staff profile of the practices were explored in a series of univariate analyses. Results Factor analysis on the four candidate variables yielded a robust one-factor solution explaining 75% variance with factor loadings ranging from 0.83 to 0.89. Rural and remote areas had higher median values and a greater scatter of clinical peripherality indices among their practices than an urban comparison area. The range of services offered and the profile of staffing of practices was associated with the peripherality index. Conclusion Clinical peripherality is determined by the nature of the practice and its location relative to secondary care and administrative and educational facilities. It has features of both gravity model-based and travel time/accessibility indicators and has the potential to be applied to training of staff for rural and remote locations and to other aspects

  10. Vasculature segmentation for radio frequency ablation of non-resectable hepatic tumors

    NASA Astrophysics Data System (ADS)

    Hemler, Paul F.; McCreedy, Evan S.; Cheng, Ruida; Wood, Brad; McAuliffe, Matthew J.

    2006-03-01

    In Radio Frequency Ablation (RFA) procedures, hepatic tumor tissue is heated to a temperature where necrosis is insured. Unfortunately, recent results suggest that heating tumor tissue to necrosis is complicated because nearby major blood vessels provide a cooling effect. Therefore, it is fundamentally important for physicians to perform a careful analysis of the spatial relationship of diseased tissue to larger liver blood vessels. The liver contains many of these large vessels, which affect the RFA ablation shape and size. There are many sophisticated vasculature detection and segmentation techniques reported in the literature that identify continuous vessels as the diameter changes size and it transgresses through many bifurcation levels. However, the larger blood vessels near the treatment area are the only vessels required for proper RFA treatment plan formulation and analysis. With physician guidance and interaction, our system can segment those vessels which are most likely to affect the RFA ablations. We have found that our system provides the physician with therapeutic, geometric and spatial information necessary to accurately plan treatment of tumors near large blood vessels. The segmented liver vessels near the treatment region are also necessary for computing isolevel heating profiles used to evaluate different proposed treatment configurations.

  11. Congenital cataract associated with persistent fetal vasculature: findings from IoLunder2.

    PubMed

    Solebo, A L; Russell-Eggitt, I; Cumberland, P; Rahi, J S

    2016-09-01

    PurposeTo describe the frequency, characteristics, and treatment outcome of persistent fetal vasculature (PFV) in children undergoing surgery for congenital and infantile cataract in the first 2 years of life.Patients and methodsObservational population-based cohort study with case identification through active surveillance and standardised data collection via a national clinical network, the British Isles Congenital Cataract Interest Group (BCCIG).ResultsThe IoLunder2 cohort comprises 246 children undergoing surgery for bilateral and unilateral congenital and infantile cataract in the first 2 years of life. A total of 58/246 (24%) children had PFV (%): overall, 46/95 (46%) with unilateral cataract, and 12/141 (8%) with bilateral disease. Anterior segment vascular remnants were more common in bilateral than unilateral disease (75 vs 11%, P=0.01). At 1 year after surgery, 20% of children with bilateral PFV and 24% with unilateral had achieved normal vision for age within the operated eye. The prevalence of post-operative glaucoma was 9% (of children with bilateral disease) and 4% (unilateral).ConclusionPFV is significantly more common than previously reported, and outcomes are comparable to that for congenital and infantile cataract overall.

  12. Comparing the Organs and Vasculature of the Head and Neck in Five Murine Species.

    PubMed

    Kim, Min Jae; Kim, Yoo Yeon; Chao, Janet Ren; Park, Hae Sang; Chang, Jiwon; Oh, Dawoon; Lee, Jae Jun; Kang, Tae Chun; Suh, Jun-Gyo; Lee, Jun Ho

    2017-01-01

    The purpose of the present study was to delineate the cervical and facial vascular and associated anatomy in five murine species, and compare them for optimal use in research studies focused on understanding the pathology and treatment of diseases in humans. The specific adult male animals examined were mice (C57BL/6J), rats (F344), mongolian gerbils (Merionesunguiculatus), hamsters (Syrian), and guinea pigs (Hartley). To stain the vasculature and organs, of the face and neck, each animal was systemically perfused using the vital stain, Trypan Blue. Following this step, the detailed anatomy of the head and neck could be easily visualized in all species. Unique morphological characteristics were demonstrated by comparing the five species, including symmetry of the common carotid origin bilaterally in the Mongolian Gerbil, a large submandibular gland in the hamster and an enlarged buccal branch in the Guinea Pig. In reviewing the anatomical details, this staining technique proves superior for direct surgical visualization and identification. The anatomical details provided through these five species atlas will help experimental researchers in the future to select the most appropriate animal model for specific laboratory studies aimed to improve our understanding and treatment of diseases in patients. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  13. Three-dimensional cartography of hematopoietic clusters in the vasculature of whole mouse embryos.

    PubMed

    Yokomizo, Tomomasa; Dzierzak, Elaine

    2010-11-01

    Hematopoietic cell clusters in the aorta of vertebrate embryos play a pivotal role in the formation of the adult blood system. Despite their importance, hematopoietic clusters have not been systematically quantitated or mapped because of technical limitations posed by the opaqueness of whole mouse embryos. Here, we combine an approach to make whole mouse embryos transparent, with multicolor marking, to allow observation of hematopoietic clusters using high-resolution 3-dimensional confocal microscopy. Our method provides the first complete map and temporal quantitation of all hematopoietic clusters in the mouse embryonic vasculature. We show that clusters peak in number at embryonic day 10.5, localize to specific vascular subregions and are heterogeneous, indicating a basal endothelial to non-basal (outer cluster) hematopoietic cell transition. Clusters enriched with the c-Kit(+)CD31(+)SSEA1(-) cell population contain functional hematopoietic progenitors and stem cells. Thus, three-dimensional cartography of transparent mouse embryos provides novel insight into the vascular subregions instrumental in hematopoietic progenitor/stem cell development, and represents an important technological advancement for comprehensive in situ hematopoietic cluster analysis.

  14. Three-dimensional cartography of hematopoietic clusters in the vasculature of whole mouse embryos

    PubMed Central

    Yokomizo, Tomomasa; Dzierzak, Elaine

    2010-01-01

    Hematopoietic cell clusters in the aorta of vertebrate embryos play a pivotal role in the formation of the adult blood system. Despite their importance, hematopoietic clusters have not been systematically quantitated or mapped because of technical limitations posed by the opaqueness of whole mouse embryos. Here, we combine an approach to make whole mouse embryos transparent, with multicolor marking, to allow observation of hematopoietic clusters using high-resolution 3-dimensional confocal microscopy. Our method provides the first complete map and temporal quantitation of all hematopoietic clusters in the mouse embryonic vasculature. We show that clusters peak in number at embryonic day 10.5, localize to specific vascular subregions and are heterogeneous, indicating a basal endothelial to non-basal (outer cluster) hematopoietic cell transition. Clusters enriched with the c-Kit+CD31+SSEA1– cell population contain functional hematopoietic progenitors and stem cells. Thus, three-dimensional cartography of transparent mouse embryos provides novel insight into the vascular subregions instrumental in hematopoietic progenitor/stem cell development, and represents an important technological advancement for comprehensive in situ hematopoietic cluster analysis. PMID:20876651

  15. Correction: The importance of microglia in the development of the vasculature in the central nervous system.

    PubMed

    Arnold, Tom; Betsholtz, Christer

    2013-06-25

    After the publication of this work 1 it was brought to our attention that citations in the article were not correspondingly numbered in the reference list. To avoid confusion, the article is republished here in its entirety, with the citations referenced correctly.The Publisher and authors apologize to the readers for the inconvenience caused. The body's vascular system is thought to have developed in order to supply oxygen and nutrients to cells beyond the reach of simple diffusion. Hence, relative hypoxia in the growing central nervous system (CNS) is a major driving force for the ingression and refinement of the complex vascular bed that serves it. However, even before the establishment of this CNS vascular system, CNS-specific macrophages (microglia) migrate into the brain. Recent studies in mice point to the fundamental importance of microglia in shaping CNS vasculature during development, and re-shaping these vessels during pathological insults. In this review, we discuss the origin of CNS microglia and their localization within the brain based on data obtained in mice. We then review evidence supporting a functional role of these microglia in developmental angiogenesis. Although pathologic processes such as CNS ischemia may subvert the developmental functions of microglia/macrophages with significant effects on brain neo-angiogenesis, we have left this topic to other recent reviews 23.

  16. The importance of microglia in the development of the vasculature in the central nervous system.

    PubMed

    Arnold, Tom; Betsholtz, Christer

    2013-02-19

    The body's vascular system is thought to have developed in order to supply oxygen and nutrients to cells beyond the reach of simple diffusion. Hence, relative hypoxia in the growing central nervous system (CNS) is a major driving force for the ingression and refinement of the complex vascular bed that serves it. However, even before the establishment of this CNS vascular system, CNS-specific macrophages (microglia) migrate into the brain. Recent studies in mice point to the fundamental importance of microglia in shaping CNS vasculature during development, and re-shaping these vessels during pathological insults. In this review, we discuss the origin of CNS microglia and their localization within the brain based on data obtained in mice. We then review evidence supporting a functional role of these microglia in developmental angiogenesis. Although pathologic processes such as CNS ischemia may subvert the developmental functions of microglia/macrophages with significant effects on brain neo-angiogenesis, we have left this topic to other recent reviews (Nat Rev Immunol 9:259-270, 2009 and Trends Mol Med 17:743-752, 2011).

  17. Using Non-Invasive Multi-Spectral Imaging to Quantitatively Assess Tissue Vasculature

    SciTech Connect

    Vogel, A; Chernomordik, V; Riley, J; Hassan, M; Amyot, F; Dasgeb, B; Demos, S G; Pursley, R; Little, R; Yarchoan, R; Tao, Y; Gandjbakhche, A H

    2007-10-04

    This research describes a non-invasive, non-contact method used to quantitatively analyze the functional characteristics of tissue. Multi-spectral images collected at several near-infrared wavelengths are input into a mathematical optical skin model that considers the contributions from different analytes in the epidermis and dermis skin layers. Through a reconstruction algorithm, we can quantify the percent of blood in a given area of tissue and the fraction of that blood that is oxygenated. Imaging normal tissue confirms previously reported values for the percent of blood in tissue and the percent of blood that is oxygenated in tissue and surrounding vasculature, for the normal state and when ischemia is induced. This methodology has been applied to assess vascular Kaposi's sarcoma lesions and the surrounding tissue before and during experimental therapies. The multi-spectral imaging technique has been combined with laser Doppler imaging to gain additional information. Results indicate that these techniques are able to provide quantitative and functional information about tissue changes during experimental drug therapy and investigate progression of disease before changes are visibly apparent, suggesting a potential for them to be used as complementary imaging techniques to clinical assessment.

  18. Selenoprotein expression in endothelial cells from different human vasculature and species.

    PubMed

    Miller, S; Walker, S W; Arthur, J R; Lewin, M H; Pickard, K; Nicol, F; Howie, A F; Beckett, G J

    2002-10-09

    Selenium (Se) can protect endothelial cells (EC) from oxidative damage by altering the expression of selenoproteins with antioxidant function such as cytoplasmic glutathione peroxidase (cyGPX), phospholipid hydroperoxide glutathione peroxidase (PHGPX) and thioredoxin reductase (TR). If the role of Se on EC function is to be studied, it is essential that a model system be chosen which reflects selenoprotein expression in human EC derived from vessels prone to developing atheroma. We have used [75Se]-selenite labelling and selenoenzyme measurements to compare the selenoproteins expressed by cultures of EC isolated from different human vasculature with EC bovine and porcine aorta. Only small differences were observed in selenoprotein expression and activity in EC originating from human coronary artery, human umbilical vein (HUVEC), human umbilical artery and the human EC line EAhy926. The selenoprotein profile in HUVEC was consistent over eight passages and HUVEC isolated from four cords also showed little variability. In contrast, EC isolated from pig and bovine aorta showed marked differences in selenoprotein expression when compared to human cells. This study firmly establishes the suitability and consistency of using HUVEC (and possibly the human cell line EAhy926) as a model to study the effects of Se on EC function in relation to atheroma development in the coronary artery. Bovine or porcine EC appear to be an inappropriate model.

  19. Surgical anatomy of the liver, hepatic vasculature and bile ducts in the rat.

    PubMed

    Martins, Paulo Ney Aguiar; Neuhaus, Peter

    2007-04-01

    The rat is the most used experimental model in surgical research. Virtually all procedures in clinical liver surgery can be performed in the rat. However, the use of the rat model in liver surgery is limited by its small size and limited knowledge of the liver anatomy. As in humans, the rat liver vasculature and biliary system have many anatomical variations. The development of surgical techniques, and the study of liver function and diseases require detailed knowledge of the regional anatomy. The objective of this study was to describe and illustrate systematically the surgical anatomy of the rat liver to facilitate the planning and performance of studies in this animal. Knowledge of the diameter and length of liver vessels is also important for the selection of catheters and perivascular devices. Twelve Wistar rat livers were dissected using a surgical microscope. Hepatic and extrahepatic anatomical structures were measured under magnification with a millimeter scale. In this study, we describe the rat liver topographical anatomy, compare it with the human liver and review the literature. Increased knowledge of the rat liver anatomy and microsurgical skills permit individualized dissection, parenchymal section, embolization and ligature of vascular and biliary branches.

  20. Binaural blood flow control by astrocytes: listening to synapses and the vasculature.

    PubMed

    Mishra, Anusha

    2017-03-15

    Astrocytes are the most common glial cells in the brain with fine processes and endfeet that intimately contact both neuronal synapses and the cerebral vasculature. They play an important role in mediating neurovascular coupling (NVC) via several astrocytic Ca(2+) -dependent signalling pathways such as K(+) release through BK channels, and the production and release of arachidonic acid metabolites. They are also involved in maintaining the resting tone of the cerebral vessels by releasing ATP and COX-1 derivatives. Evidence also supports a role for astrocytes in maintaining blood pressure-dependent change in cerebrovascular tone, and perhaps also in blood vessel-to-neuron signalling as posited by the 'hemo-neural hypothesis'. Thus, astrocytes are emerging as new stars in preserving the intricate balance between the high energy demand of active neurons and the supply of oxygen and nutrients from the blood by maintaining both resting blood flow and activity-evoked changes therein. Following neuropathology, astrocytes become reactive and many of their key signalling mechanisms are altered, including those involved in NVC. Furthermore, as they can respond to changes in vascular pressure, cardiovascular diseases might exert previously unknown effects on the central nervous system by altering astrocyte function. This review discusses the role of astrocytes in neurovascular signalling in both physiology and pathology, and the impact of these findings on understanding BOLD-fMRI signals.

  1. Functionalized near-infrared quantum dots for in vivo tumor vasculature imaging

    NASA Astrophysics Data System (ADS)

    Hu, Rui; Yong, Ken-Tye; Roy, Indrajit; Ding, Hong; Law, Wing-Cheung; Cai, Hongxing; Zhang, Xihe; Vathy, Lisa A.; Bergey, Earl J.; Prasad, Paras N.

    2010-04-01

    In this paper, we report the use of near-infrared (NIR)-emitting alloyed quantum dots (QDs) as efficient optical probes for high contrast in vivo imaging of tumors. Alloyed CdTe1 - xSex/CdS QDs were prepared in the non-aqueous phase using the hot colloidal synthesis approach. Water dispersion of the QDs were accomplished by their encapsulation within polyethyleneglycol (PEG)-grafted phospholipid micelles. For tumor-specific delivery in vivo, the micelle-encapsulated QDs were conjugated with the cyclic arginine-glycine-aspartic acid (cRGD) peptide, which targets the αvβ3 integrins overexpressed in the angiogenic tumor vasculatures. Using in vivo NIR optical imaging of mice bearing pancreatic cancer xenografts, implanted both subcutaneously and orthotopically, we have demonstrated that systemically delivered cRGD-conjugated QDs, but not the unconjugated ones, can efficiently target and label the tumors with high signal-to-noise ratio. Histopathological analysis of major organs of the treated mice showed no evidence of systemic toxicity associated with these QDs. These experiments suggest that cRGD-conjugated NIR QDs can serve as safe and efficient probes for optical bioimaging of tumors in vivo. Furthermore, by co-encapsulating these QDs and anticancer drugs within these micelles, we have demonstrated a promising theranostic, nanosized platform for both cancer imaging and therapy.

  2. Surgical Anatomy of the Gastrointestinal Tract and Its Vasculature in the Laboratory Rat.

    PubMed

    Vdoviaková, Katarína; Petrovová, Eva; Maloveská, Marcela; Krešáková, Lenka; Teleky, Jana; Elias, Mario Zefanias Joao; Petrášová, Darina

    2016-01-01

    The aim of this study was to describe and illustrate the morphology of the stomach, liver, intestine, and their vasculature to support the planning of surgical therapeutic methods in abdominal cavity. On adult Wistar rats corrosion casts were prepared from the arterial system and Duracryl Dental and PUR SP were used as a casting medium and was performed macroscopic anatomical dissection of the stomach, liver, and intestine was performed. The rat stomach was a large, semilunar shaped sac with composite lining. On the stomach was very marked fundus, which formed a blind sac (saccus cecus). The rat liver was divided into six lobes, but without gall bladder. Intestine of the rat was simple, but cecum had a shape as a stomach. The following variations were observed in the origin of the cranial mesenteric artery. On the corrosion cast specimens we noticed the presence of the anastomosis between middle colic artery (a. colica media) and left colic artery (a. colica sinistra). We investigated the second anastomosis between middle colic artery and left colic artery. The results of this study reveal that the functional anatomical relationship between the rat stomach, liver and intestine is important for the development of surgical research in human and veterinary medicine.

  3. The sinus venosus contributes to coronary vasculature through VEGFC-stimulated angiogenesis

    PubMed Central

    Chen, Heidi I.; Sharma, Bikram; Akerberg, Brynn N.; Numi, Harri J.; Kivelä, Riikka; Saharinen, Pipsa; Aghajanian, Haig; McKay, Andrew S.; Bogard, Patrick E.; Chang, Andrew H.; Jacobs, Andrew H.; Epstein, Jonathan A.; Stankunas, Kryn; Alitalo, Kari; Red-Horse, Kristy

    2014-01-01

    Identifying coronary artery progenitors and their developmental pathways could inspire novel regenerative treatments for heart disease. Multiple sources of coronary vessels have been proposed, including the sinus venosus (SV), endocardium and proepicardium, but their relative contributions to the coronary circulation and the molecular mechanisms regulating their development are poorly understood. We created an ApjCreER mouse line as a lineage-tracing tool to map SV-derived vessels onto the heart and compared the resulting lineage pattern with endocardial and proepicardial contributions to the coronary circulation. The data showed a striking compartmentalization to coronary development. ApjCreER-traced vessels contributed to a large number of arteries, capillaries and veins on the dorsal and lateral sides of the heart. By contrast, untraced vessels predominated in the midline of the ventral aspect and ventricular septum, which are vessel populations primarily derived from the endocardium. The proepicardium gave rise to a smaller fraction of vessels spaced relatively uniformly throughout the ventricular walls. Dorsal (SV-derived) and ventral (endocardial-derived) coronary vessels developed in response to different growth signals. The absence of VEGFC, which is expressed in the epicardium, dramatically inhibited dorsal and lateral coronary growth but left vessels on the ventral side unaffected. We propose that complementary SV-derived and endocardial-derived migratory routes unite to form the coronary vasculature and that the former requires VEGFC, revealing its role as a tissue-specific mediator of blood endothelial development. PMID:25377552

  4. Assessment of vinyl polysiloxane as an innovative injection material for the anatomical study of vasculature.

    PubMed

    Dargaud, Jacques; Chalvet, Laurane; Del Corso, Marco; Cerboni, Elsa; Feugier, Patrick; Mertens, Patrick; Simon, Emile

    2016-04-01

    There are numerous injection materials for the study of vasculature in anatomical specimens, each having its own advantages and disadvantages. Latex and resins are the most widely used injection materials but need several days to set. The development of new materials taking shorter time to polymerize might be very useful to improve anatomic specimen study conditions. The aim of the present study was to evaluate vinyl polysiloxane (VPS), a silicon material widely used for dental impressions with the advantage to set very rapidly, as an injection material. We assessed the preparation, use, diffusion and setting time of the product in different anatomical regions (central nervous system, external carotid/jugular, lower limb) to observe its behavior in variably sized vessels. Our results suggest that VPS might be of interest for the study of vessels in anatomical specimens. The main strengths of the product are represented by (1) simplicity of use, as it is a ready-to-use material, (2) very rapid polymerization, (3) availability in a range of viscosities making easier the exploration of small vessels, (4) its better elasticity compared to resins, (5) and finally its availability in a range of colors making it a material of choice for vascular system dissections including those with very small caliber vessels.

  5. Opposing actions of TRPV4 channel activation in the lung vasculature.

    PubMed

    Ke, Sun-Kui; Chen, Lan; Duan, Hong-Bing; Tu, Yuan-Rong

    2015-12-01

    Transient receptor potential vanilloid 4 (TRPV4) calcium channels are known to promote endothelium-dependent relaxation of mouse mesenteric arteries but TRPV4's role in the pulmonary vasculature is uncertain. Thus, we characterized TRPV4 channel vascular tone regulation in mouse main pulmonary artery rings and in the isolated perfused pulmonary circulation and studied possible mechanisms behind these characterizations. Using myography and a TRPV4 specific agonist GSK1016790A in a C57BL/6 WT mouse model of isolated constant-flow lung perfusion, we studied vascular tone regulation in arterial rings from the main left and right pulmonary arteries and vascular resistance of the intra-pulmonary circulation beyond the second branches of the pulmonary arteries. Removal of the endothelium confirmed endothelial dependence. GSK1016790A relaxed the main pulmonary artery (EC50 4 × 10(-8)mol/L), which was inhibited by removal of the endothelium from main pulmonary artery rings. GSK1016790A significantly increased vascular resistance of the pulmonary circulation in isolated perfused lungs, but these effects were inhibited by a TRPV4 antagonist AB159908. A nitric oxide inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and K(+) channel blockers apamin plus charybdotoxin (ChTx) significantly inhibited GSK1016790A in the main pulmonary artery and in an isolated perfused lung in vitro. Activated TRPV4 channels increase pulmonary vascular resistance and vasodilate the main pulmonary artery. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy

    PubMed Central

    Adapala, Ravi K.; Thoppil, Roslin J.; Ghosh, Kaustabh; Cappelli, Holly; Dudley, Andrew C.; Paruchuri, Sailaja; Keshamouni, Venkateshwar; Klagsbrun, Michael; Meszaros, J. Gary; Chilian, William M.; Ingber, Donald E.; Thodeti, Charles K.

    2016-01-01

    Tumor vessels are characterized by abnormal morphology and hyper-permeability that together cause inefficient delivery of chemotherapeutic agents. Although VEGF has been established as a critical regulator of tumor angiogenesis, the role of mechanical signaling in the regulation of tumor vasculature or tumor endothelial cell (TEC) function is not known. Here, we show that the mechanosensitive ion channel TRPV4 regulates tumor angiogenesis and tumor vessel maturation via modulation of TEC mechanosensitivity. We found that TEC exhibit reduced TRPV4 expression and function, which is correlated with aberrant mechanosensitivity towards ECM stiffness, increased migration and abnormal angiogenesis by TEC. Further, syngeneic tumor experiments revealed that the absence of TRPV4 induced increased vascular density, vessel diameter and reduced pericyte coverage resulting in enhanced tumor growth in TRPV4 KO mice. Importantly, overexpression or pharmacological activation of TRPV4 restored aberrant TEC mechanosensitivity, migration and normalized abnormal angiogenesis in vitro by modulating Rho activity. Finally, a small molecule activator of TRPV4, GSK1016790A, in combination with anti-cancer drug Cisplatin, significantly reduced tumor growth in WT mice by inducing vessel maturation. Our findings demonstrate TRPV4 channels to be critical regulators of tumor angiogenesis and represent a novel target for anti-angiogenic and vascular normalization therapies. PMID:25867067

  7. Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy.

    PubMed

    Adapala, R K; Thoppil, R J; Ghosh, K; Cappelli, H C; Dudley, A C; Paruchuri, S; Keshamouni, V; Klagsbrun, M; Meszaros, J G; Chilian, W M; Ingber, D E; Thodeti, C K

    2016-01-21

    Tumor vessels are characterized by abnormal morphology and hyperpermeability that together cause inefficient delivery of chemotherapeutic agents. Although vascular endothelial growth factor has been established as a critical regulator of tumor angiogenesis, the role of mechanical signaling in the regulation of tumor vasculature or tumor endothelial cell (TEC) function is not known. Here we show that the mechanosensitive ion channel transient receptor potential vanilloid 4 (TRPV4) regulates tumor angiogenesis and tumor vessel maturation via modulation of TEC mechanosensitivity. We found that TECs exhibit reduced TRPV4 expression and function, which is correlated with aberrant mechanosensitivity towards extracellular matrix stiffness, increased migration and abnormal angiogenesis by TEC. Further, syngeneic tumor experiments revealed that the absence of TRPV4 induced increased vascular density, vessel diameter and reduced pericyte coverage resulting in enhanced tumor growth in TRPV4 knockout mice. Importantly, overexpression or pharmacological activation of TRPV4 restored aberrant TEC mechanosensitivity, migration and normalized abnormal angiogenesis in vitro by modulating Rho activity. Finally, a small molecule activator of TRPV4, GSK1016790A, in combination with anticancer drug cisplatin, significantly reduced tumor growth in wild-type mice by inducing vessel maturation. Our findings demonstrate TRPV4 channels to be critical regulators of tumor angiogenesis and represent a novel target for anti-angiogenic and vascular normalization therapies.

  8. Mechanosignaling in the vasculature: emerging concepts in sensing, transduction and physiological responses

    PubMed Central

    Fujiwara, Keigi; Pérez, Néstor Gustavo; Ushio-Fukai, Masuko; Fisher, Aron B.

    2015-01-01

    Cells are constantly exposed to mechanical forces that play a role in modulating cellular structure and function. The cardiovascular system experiences physical forces in the form of shear stress and stretch associated with blood flow and contraction, respectively. These forces are sensed by endothelial cells and cardiomyocytes and lead to responses that control vascular and cardiac homeostasis. This was highlighted at the Pan American Physiological Society meeting at Iguassu Falls, Brazil, in a symposium titled “Mechanosignaling in the Vasculature.” This symposium presented recent research that showed the existence of a vital link between mechanosensing and downstream redox sensitive signaling cascades. This link helps to transduce and transmit the physical force into an observable physiological response. The speakers showcased how mechanosensors such as ion channels, membrane receptor kinases, adhesion molecules, and other cellular components transduce the force via redox signals (such as reactive oxygen species and nitric oxide) to receptors (transcription factors, growth factors, etc.). Receptor activated pathways then lead to cellular responses including cellular proliferation, contraction, and remodeling. These responses have major relevance to the physiology and pathophysiology of various cardiovascular diseases. Thus an understanding of the complex series of events, from the initial sensing through the final response, is essential for progress in this field. Overall, this symposium addressed some important emerging concepts in the field of mechanosignaling and the eventual pathophysiological responses. PMID:25862828

  9. Vasculature of the ophthalmic rete in night herons (Nycticorax nycticorax): scanning electron microscopy of corrosion casts.

    PubMed

    Ninomiya, Hiroyoshi

    2002-09-01

    Vasculature of the ophthalmic rete (rete ophthalmicum) in the night heron (Nycticorax nycticorax) was studied using scanning electron microscopy of vascular corrosion casts and light microscopy on tissue sections. Most blood to the eyeball and a lesser volume of blood to the brain passed through the ophthalmic rete via the external ophthalmic artery. The collateral retial arterioles originated from the external ophthalmic artery forming a flat and fusiform-shaped arterial network at the ventrotemporal region of the eyeball. The arterial network was intermixed with a similar complex of the veins from the eye. The ophthalmotemporal artery, which supplied the eyeball posteriorly, and supraorbital and infraorbital arteries, which supplied the eyeball anteriorly, originated from the rete. Blood from the eye, which is a site of potential heat loss, drained into the ophthalmic rete via the ophthalmotemporal vein. On the casts of retial arterioles, slit-like cleavages at branching sites representing flap valves, which might play a role as sluice valves, were seen. In addition, marks of circularly running grooves, which might represent tufts of smooth muscle cells and might contribute to a sphincter activity, were observed. These anatomical specializations of the avian ophthalmic rete, involving parallel arrangement of arteries and veins, may function to facilitate counter-current heat exchange and to regulate blood pressure and volume to the eye and the brain.

  10. Manufactured Aluminum Oxide Nanoparticles Decrease Expression of Tight Junction Proteins in Brain Vasculature

    PubMed Central

    Yokel, Robert A.; Hennig, Bernhard

    2009-01-01

    Manufactured nanoparticles of aluminum oxide (nano-alumina) have been widely used in the environment; however, their potential toxicity provides a growing concern for human health. The present study focuses on the hypothesis that nano-alumina can affect the blood-brain barrier and induce endothelial toxicity. In the first series of experiments, human brain microvascular endothelial cells (HBMEC) were exposed to alumina and control nanoparticles in dose- and time-responsive manners. Treatment with nano-alumina markedly reduced HBMEC viability, altered mitochondrial potential, increased cellular oxidation, and decreased tight junction protein expression as compared to control nanoparticles. Alterations of tight junction protein levels were prevented by cellular enrichment with glutathione. In the second series of experiments, rats were infused with nano-alumina at the dose of 29 mg/kg and the brains were stained for expression of tight junction proteins. Treatment with nano-alumina resulted in a marked fragmentation and disruption of integrity of claudin-5 and occludin. These results indicate that cerebral vasculature can be affected by nano-alumina. In addition, our data indicate that alterations of mitochondrial functions may be the underlying mechanism of nano-alumina toxicity. PMID:18830698

  11. Smartphone-Based Accurate Analysis of Retinal Vasculature towards Point-of-Care Diagnostics

    PubMed Central

    Xu, Xiayu; Ding, Wenxiang; Wang, Xuemin; Cao, Ruofan; Zhang, Maiye; Lv, Peilin; Xu, Feng

    2016-01-01

    Retinal vasculature analysis is important for the early diagnostics of various eye and systemic diseases, making it a potentially useful biomarker, especially for resource-limited regions and countries. Here we developed a smartphone-based retinal image analysis system for point-of-care diagnostics that is able to load a fundus image, segment retinal vessels, analyze individual vessel width, and store or uplink results. The proposed system was not only evaluated on widely used public databases and compared with the state-of-the-art methods, but also validated on clinical images directly acquired with a smartphone. An Android app is also developed to facilitate on-site application of the proposed methods. Both visual assessment and quantitative assessment showed that the proposed methods achieved comparable results to the state-of-the-art methods that require high-standard workstations. The proposed system holds great potential for the early diagnostics of various diseases, such as diabetic retinopathy, for resource-limited regions and countries. PMID:27698369

  12. Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature

    PubMed Central

    Wang, Hong; Upchurch, Charles T.; Liu, Zhenqi

    2011-01-01

    Insulin, at physiological concentrations, regulates the volume of microvasculature perfused within skeletal and cardiac muscle. It can also, by relaxing the larger resistance vessels, increase total muscle blood flow. Both of these effects require endothelial cell nitric oxide generation and smooth muscle cell relaxation, and each could increase delivery of insulin and nutrients to muscle. The capillary microvasculature possesses the greatest endothelial surface area of the body. Yet, whether insulin acts on the capillary endothelial cell is not known. Here, we review insulin's actions at each of three levels of the arterial vasculature as well as recent data suggesting that insulin can regulate a vesicular transport system within the endothelial cell. This latter action, if it occurs at the capillary level, could enhance insulin delivery to muscle interstitium and thereby complement insulin's actions on arteriolar endothelium to increase insulin delivery. We also review work that suggests that this action of insulin on vesicle transport depends on endothelial cell nitric oxide generation and that insulin's ability to regulate this vesicular transport system is impaired by inflammatory cytokines that provoke insulin resistance. PMID:21610226

  13. Circulatory therapeutics: use of antihypertensive agents and their effects on the vasculature

    PubMed Central

    Schiffrin, Ernesto L

    2010-01-01

    Abstract This review addresses the use of the different antihypertensive agents currently available and some in development, and their effects on the vasculature. The different classes of agents used in the treatment of hypertension, and the results of recent large clinical trials, dosing protocols and adverse effects are first briefly summarized. The consequences on blood vessels of the use of antihypertensive drugs and the differential effects on the biology of large and small arteries resulting in modulation of vascular remodelling and dysfunction in hypertensive patients are then described. Large elastic conduit arteries exhibit outward hypertrophic remodelling and increased stiffness, which contributes to raise systolic blood pressure and afterload on the heart. Small resistance arteries undergo eutrophic or hypertrophic inward remodelling, and impair tissue perfusion. By these mechanisms both large and small arteries may contribute to trigger cardiovascular events. Some antihypertensive agents correct these changes, which could contribute to improved outcome. The mechanisms that at the level of the vascular wall lead to remodelling and can be beneficially affected by antihypertensive agents will also be addressed. These include vasoconstriction, growth and inflammation. The molecular pathways contributing to growth and inflammation will be summarily described. Further identification of these signalling pathways should allow identification of novel targets leading to development of new and improved medications for the treatment of hypertension and cardiovascular disease. PMID:20345850

  14. Circulatory therapeutics: use of antihypertensive agents and their effects on the vasculature.

    PubMed

    Schiffrin, Ernesto L

    2010-05-01

    This review addresses the use of the different antihypertensive agents currently available and some in development, and their effects on the vasculature. The different classes of agents used in the treatment of hypertension, and the results of recent large clinical trials, dosing protocols and adverse effects are first briefly summarized. The consequences on blood vessels of the use of antihypertensive drugs and the differential effects on the biology of large and small arteries resulting in modulation of vascular remodelling and dysfunction in hypertensive patients are then described. Large elastic conduit arteries exhibit outward hypertrophic remodelling and increased stiffness, which contributes to raise systolic blood pressure and afterload on the heart. Small resistance arteries undergo eutrophic or hypertrophic inward remodelling, and impair tissue perfusion. By these mechanisms both large and small arteries may contribute to trigger cardiovascular events. Some antihypertensive agents correct these changes, which could contribute to improved outcome. The mechanisms that at the level of the vascular wall lead to remodelling and can be beneficially affected by antihypertensive agents will also be addressed. These include vasoconstriction, growth and inflammation. The molecular pathways contributing to growth and inflammation will be summarily described. Further identification of these signalling pathways should allow identification of novel targets leading to development of new and improved medications for the treatment of hypertension and cardiovascular disease.

  15. Impact of a Combined High Cholesterol Diet and High Glucose Environment on Vasculature

    PubMed Central

    Cui, Taixing; Tang, Dongqi; Wang, Xing Li

    2013-01-01

    Aims Vascular complications are the leading cause of mortality and morbidity in patients with diabetes. However, proper animal models of diabetic vasculopathy that recapitulate the accelerated progression of vascular lesions in human are unavailable. In the present study, we developed a zebrafish model of diabetic vascular complications and the methodology for quantifying vascular lesion formation real-time in the living diabetic zebrafish. Methods and Results Wild type zebrafish (AB) and transgenic zebrafish lines of fli1:EGFP, lyz:EGFP, gata1:dsRed, double transgenic zebrafish of gata1:dsRed/fli1:EGFP were exposed to high cholesterol diet and 3% glucose (HCD-HG) for 10 days. The zebrafish model with HCD-HG treatment was characterized by significantly increased tissue levels of insulin, glucagon, glucose, total triglyceride and cholesterol. Confocal microscopic analysis further revealed that the diabetic larvae developed clearly thickened endothelial layers, distinct perivascular lipid depositions, substantial accumulations of inflammatory cells in the injured vasculature, and a decreased velocity of blood flow. Moreover, the vascular abnormalities were improved by the treatment of pioglitazone and metformin. Conclusion A combination of high cholesterol diet and high glucose exposure induces a rapid onset of vascular complications in zebrafish similar to the early atherosclerotic vascular injuries in mammalian diabetic models, suggesting that zebrafish may be used as a novel animal model for diabetic vasculopathy. PMID:24349075

  16. Surgical Anatomy of the Gastrointestinal Tract and Its Vasculature in the Laboratory Rat

    PubMed Central

    Vdoviaková, Katarína; Petrovová, Eva; Maloveská, Marcela; Krešáková, Lenka; Teleky, Jana; Elias, Mario Zefanias Joao; Petrášová, Darina

    2016-01-01

    The aim of this study was to describe and illustrate the morphology of the stomach, liver, intestine, and their vasculature to support the planning of surgical therapeutic methods in abdominal cavity. On adult Wistar rats corrosion casts were prepared from the arterial system and Duracryl Dental and PUR SP were used as a casting medium and was performed macroscopic anatomical dissection of the stomach, liver, and intestine was performed. The rat stomach was a large, semilunar shaped sac with composite lining. On the stomach was very marked fundus, which formed a blind sac (saccus cecus). The rat liver was divided into six lobes, but without gall bladder. Intestine of the rat was simple, but cecum had a shape as a stomach. The following variations were observed in the origin of the cranial mesenteric artery. On the corrosion cast specimens we noticed the presence of the anastomosis between middle colic artery (a. colica media) and left colic artery (a. colica sinistra). We investigated the second anastomosis between middle colic artery and left colic artery. The results of this study reveal that the functional anatomical relationship between the rat stomach, liver and intestine is important for the development of surgical research in human and veterinary medicine. PMID:26819602

  17. Ambient temperature affects glabrous skin vasculature and sweating responses to mental task in humans.

    PubMed

    Hayashi, Naoyuki; Someya, Nami; Hirooka, Yoshitaka; Koga, Shunsaku

    2008-09-01

    We compared responses in heart rate (HR), mean blood pressure (MAP), sweating rate (SR), sweating expulsion (SwE), and skin vascular conductance (VC) to mental task among different ambient temperature (Ta) conditions, i.e., 12, 16, 20, and 24 degrees C. Seven subjects (27+/-5 yrs, 64+/-14 kg) underwent a 2-min color word conflict test (CWT) after 2 mins of baseline data acquisition following a 20-min resting period. All subjects wore long sleeve shirts and long pants. The skin blood flow was measured with a laser Doppler probe on the left index finger pulp to calculate skin VC, and the SR and sweating expulsion (SwE) were measured with a ventilated capsule on the left thenar. CWT significantly increased the HR and MAP, while there was no significant effect of Ta on the magnitudes of these responses. CWT significantly decreased the skin VC when the Ta was 24 degrees C, whereas it significantly increased the skin VC when the Ta was 12 or 16 degrees C. CWT significantly increased SR and SwE in all Ta conditions, and the SwE was greater in warmer conditions. These findings suggest that different ambient temperatures induce different responses in finger skin vasculature to mental task, implying the independent response of cutaneous vasomotor tone and sweat glands in glabrous skin to mental task.

  18. Comparison of Indocyanine Green Angiography and Laser Speckle Contrast Imaging for the Assessment of Vasculature Perfusion

    PubMed Central

    Towle, Erica L.; Richards, Lisa M.; Kazmi, S. M. Shams; Fox, Douglas J.; Dunn, Andrew K.

    2013-01-01

    BACKGROUND Assessment of the vasculature is critical for overall success in cranial vascular neurological surgery procedures. Although several methods of monitoring cortical perfusion intraoperatively are available, not all are appropriate or convenient in a surgical environment. Recently, 2 optical methods of care have emerged that are able to obtain high spatial resolution images with easily implemented instrumentation: indocyanine green (ICG) angiography and laser speckle contrast imaging (LSCI). OBJECTIVE To evaluate the usefulness of ICG and LSCI in measuring vessel perfusion. METHODS An experimental setup was developed that simultaneously collects measurements of ICG fluorescence and LSCI in a rodent model. A 785-nm laser diode was used for both excitation of the ICG dye and the LSCI illumination. A photothrombotic clot model was used to occlude specific vessels within the field of view to enable comparison of the 2 methods for monitoring vessel perfusion. RESULTS The induced blood flow change demonstrated that ICG is an excellent method for visualizing the volume and type of vessel at a single point in time; however, it is not always an accurate representation of blood flow. In contrast, LSCI provides a continuous and accurate measurement of blood flow changes without the need of an external contrast agent. CONCLUSION These 2 methods should be used together to obtain a complete understanding of tissue perfusion. PMID:22843129

  19. In-vivo imaging of nanoshell extravasation from solid tumor vasculature by photoacoustic microscopy

    NASA Astrophysics Data System (ADS)

    Li, Meng-Lin; Schwartz, Jon A.; Wang, James; Stoica, George; Wang, Lihong V.

    2007-02-01

    In this study, high resolution reflection-mode (backward-mode) photoacoustic microscopy (PAM) is used to noninvasively image progressive extravasation and accumulation of nanoshells within a solid tumor in vivo. This study takes advantage of the strong near-infrared absorption of nanoshells, a novel type of optically tunable gold nanoparticles that tend to extravasate from leaky tumor vasculatures (i.e., passive targeting) via the "enhanced permeability and retention" effect due to their nanoscale size. Tumors were grown in immunocompetent BALB/c mice by subcutaneous inoculation of CT26.wt murine colon carcinoma cells. PEGylated nanoshells with a peak optical absorption at ~800 nm were intravenously administered. Pre-scans prior to nanoshell injection were taken using a 584-nm laser source to highlight blood content and an 800-nm laser source to mark the background limit for nanoshell accumulation. After injection, the three-dimensional nanoshell distribution inside the tumor was monitored by PAM for 7 hours. Experimental results show that nanoshell accumulation is heterogeneous in tumors: more concentrated within the tumor cortex and largely absent from the tumor core. This correlates with others' observation that drug delivery within tumor cores is ineffective because of both high interstitial pressure and tendency to necrosis of tumor cores. Since nanoshells have been recently applied to thermal therapy for subcutaneous tumors, we anticipate that PAM will be important to this therapeutic technique.

  20. Manufactured aluminum oxide nanoparticles decrease expression of tight junction proteins in brain vasculature.

    PubMed

    Chen, Lei; Yokel, Robert A; Hennig, Bernhard; Toborek, Michal

    2008-12-01

    Manufactured nanoparticles of aluminum oxide (nano-alumina) have been widely used in the environment; however, their potential toxicity provides a growing concern for human health. The present study focuses on the hypothesis that nano-alumina can affect the blood-brain barrier and induce endothelial toxicity. In the first series of experiments, human brain microvascular endothelial cells (HBMEC) were exposed to alumina and control nanoparticles in dose- and time-responsive manners. Treatment with nano-alumina markedly reduced HBMEC viability, altered mitochondrial potential, increased cellular oxidation, and decreased tight junction protein expression as compared to control nanoparticles. Alterations of tight junction protein levels were prevented by cellular enrichment with glutathione. In the second series of experiments, rats were infused with nano-alumina at the dose of 29 mg/kg and the brains were stained for expression of tight junction proteins. Treatment with nano-alumina resulted in a marked fragmentation and disruption of integrity of claudin-5 and occludin. These results indicate that cerebral vasculature can be affected by nano-alumina. In addition, our data indicate that alterations of mitochondrial functions may be the underlying mechanism of nano-alumina toxicity.

  1. Photoacoustic imaging of living mouse brain vasculature using hollow gold nanospheres

    PubMed Central

    Lu, Wei; Huang, Qian; Ku, Geng; Wen, Xiaoxia; Zhou, Min; Guzatov, Dmitry; Brecht, Peter; Su, Richard; Oraevsky, Alexander; Wang, Lihong V.; Li, Chun

    2010-01-01

    Photoacoustic tomography (PAT) also referred to as optoacoustic tomography (OAT) is a hybrid imaging modality that employs nonionizing optical radiation and ultrasonic detection. Here, we describe the application of a new class of optical contrast agents based on mesoscopic hollow gold nanospheres (HAuNS) to PAT. HAuNS are ~40 nm in diameter with a hollow interior and consist of a thin gold wall. They display strong resonance absorption tuned to the near infrared (NIR) range, with an absorption peak at 800 nm, whose photoacoustic efficiency is significantly greater than that of blood. Following surface conjugation with thiolated poly(ethylene glycol), the pegylated HAuNS (PEG-HAuNS) had distribution and elimination half-lives of 1.38±0.38 and 71.82±30.46 h, respectively. Compared with PAT images based on the intrinsic optical contrast in nude mice, the PAT images acquired within 2 h after intravenous administration of PEG-HAuNS showed the brain vasculature with greater clarity and detail. The image depicted brain blood vessels as small as ~100 µm in diameter using PEG-HAuNS as contrast agents. Preliminary results showed no acute toxicity to the liver, spleen, or kidneys in mice following a single imaging dose of PEG-HAuNS. Our results indicate that PEG-HAuNS are promising contrast agents for PAT, with high spatial resolution and enhanced sensitivity. PMID:20036000

  2. Expression and function of potassium channels in the human placental vasculature.

    PubMed

    Wareing, Mark; Bai, Xilian; Seghier, Fella; Turner, Claire M; Greenwood, Susan L; Baker, Philip N; Taggart, Michael J; Fyfe, Gregor K

    2006-08-01

    In the placental vasculature, where oxygenation may be an important regulator of vascular reactivity, there is a paucity of data on the expression of potassium (K) channels, which are important mediators of vascular smooth muscle tone. We therefore addressed the expression and function of several K channel subtypes in human placentas. The expression of voltage-gated (Kv)2.1, KV9.3, large-conductance Ca2+-activated K channel (BKCa), inward-rectified K+ channel (KIR)6.1, and two-pore domain inwardly rectifying potassium channel-related acid-sensitive K channels (TASK)1 in chorionic plate arteries, veins, and placental homogenate was assessed by RT-PCR and Western blot analysis. Functional activity of K channels was assessed pharmacologically in small chorionic plate arteries and veins by wire myography using 4-aminopyridine, iberiotoxin, pinacidil, and anandamide. Experiments were performed at 20, 7, and 2% oxygen to assess the effect of oxygenation on the efficacy of K channel modulators. KV2.1, KV9.3, BKCa, KIR6.1, and TASK1 channels were all demonstrated to be expressed at the message level. KV2.1, BKCa, KIR6.1, and TASK1 were all demonstrated at the protein level. Pharmacological manipulation of voltage-gated and ATP-sensitive channels produced the most marked modifications in vascular tone, in both arteries and veins. We conclude that K channels play an important role in controlling placental vascular function.

  3. Smartphone-Based Accurate Analysis of Retinal Vasculature towards Point-of-Care Diagnostics.

    PubMed

    Xu, Xiayu; Ding, Wenxiang; Wang, Xuemin; Cao, Ruofan; Zhang, Maiye; Lv, Peilin; Xu, Feng

    2016-10-04

    Retinal vasculature analysis is important for the early diagnostics of various eye and systemic diseases, making it a potentially useful biomarker, especially for resource-limited regions and countries. Here we developed a smartphone-based retinal image analysis system for point-of-care diagnostics that is able to load a fundus image, segment retinal vessels, analyze individual vessel width, and store or uplink results. The proposed system was not only evaluated on widely used public databases and compared with the state-of-the-art methods, but also validated on clinical images directly acquired with a smartphone. An Android app is also developed to facilitate on-site application of the proposed methods. Both visual assessment and quantitative assessment showed that the proposed methods achieved comparable results to the state-of-the-art methods that require high-standard workstations. The proposed system holds great potential for the early diagnostics of various diseases, such as diabetic retinopathy, for resource-limited regions and countries.

  4. Physiological and genomic basis of mechanical-functional trade-off in plant vasculature

    PubMed Central

    Sengupta, Sonali; Majumder, Arun Lahiri

    2014-01-01

    Some areas in plant abiotic stress research are not frequently addressed by genomic and molecular tools. One such area is the cross reaction of gravitational force with upward capillary pull of water and the mechanical-functional trade-off in plant vasculature. Although frost, drought and flooding stress greatly impact these physiological processes and consequently plant performance, the genomic and molecular basis of such trade-off is only sporadically addressed and so is its adaptive value. Embolism resistance is an important multiple stress- opposition trait and do offer scopes for critical insight to unravel and modify the input of living cells in the process and their biotechnological intervention may be of great importance. Vascular plants employ different physiological strategies to cope with embolism and variation is observed across the kingdom. The genomic resources in this area have started to emerge and open up possibilities of synthesis, validation and utilization of the new knowledge-base. This review article assesses the research till date on this issue and discusses new possibilities for bridging physiology and genomics of a plant, and foresees its implementation in crop science. PMID:24904619

  5. Bim expression in endothelial cells and pericytes is essential for regression of the fetal ocular vasculature.

    PubMed

    Wang, Shoujian; Zaitoun, Ismail S; Johnson, Ryan P; Jamali, Nasim; Gurel, Zafer; Wintheiser, Catherine M; Strasser, Andreas; Lindner, Volkhard; Sheibani, Nader; Sorenson, Christine M

    2017-01-01

    Apoptosis plays a central role in developmental and pathological angiogenesis and vessel regression. Bim is a pro-apoptotic Bcl-2 family member that plays a prominent role in both developmental and pathological ocular vessel regression, and neovascularization. Endothelial cells (EC) and pericytes (PC) each play unique roles during vascular development, maintenance and regression. We recently showed that germline deletion of Bim results in persistent hyaloid vasculature, increased retinal vascular density and prevents retinal vessel regression in response to hyperoxia. To determine whether retinal vascular regression is attributable to Bim expression in EC or PC we generated mice carrying a conditional Bim allele (BimFlox/Flox) and VE-cadherin-cre (BimEC mice) or Pdgfrb-cre (BimPC mice). BimEC and BimPC mice demonstrated attenuated hyaloid vessel regression and postnatal retinal vascular remodeling. We also observed decreased retinal vascular apoptosis and proliferation. Unlike global Bim -/- mice, mice conditionally lacking Bim in EC or PC underwent hyperoxia-mediated vessel obliteration and subsequent retinal neovascularization during oxygen-induced ischemic retinopathy similar to control littermates. Thus, understanding the cell autonomous role Bim plays in the retinal vascular homeostasis will give us new insight into how to modulate pathological retinal neovascularization and vessel regression to preserve vision.

  6. The PPAR-RXR transcriptional complex in the vasculature: energy in the balance.

    PubMed

    Plutzky, Jorge

    2011-04-15

    The peroxisome proliferator-activated receptors (PPARs) and the retinoid X receptors (RXRs) are ligand-activated transcription factors that coordinately regulate gene expression. This PPAR-RXR transcriptional complex plays a critical role in energy balance, including triglyceride metabolism, fatty acid handling and storage, and glucose homeostasis: processes whose dysregulation characterize obesity, diabetes, and atherosclerosis. PPARs and RXRs are also involved directly in inflammatory and vascular responses in endothelial and vascular smooth muscle cells. New insights into fundamental aspects of PPAR and RXR biology, and their actions in the vasculature, continue to appear. Although RXRs are obligate heterodimeric partners for PPAR action, the part that RXRs, and their endogenous retinoid mediators, exert in the vessel wall is less well understood. Biological insights into PPAR-RXRs may help inform interpretation of clinical trials with synthetic PPAR agonists and prospects for future PPAR therapeutics. Importantly, the extensive data establishing a key role for PPARs and RXRs in energy balance, inflammation, and vascular biology stands separately from the clinical experience with any given synthetic PPAR agonist. Both the basic science data and the clinical experience with PPAR agonists identify the need to better understand these important transcriptional regulators.

  7. Response of the forelimb vasculature to vasoactive agents: effects of ouabain.

    PubMed

    Dobbins, D E; Swindall, B T; Haddy, F J; Dabney, J M

    1985-01-01

    The effect of the local intra-arterial infusion of ouabain (11.8 micrograms/min.) on the response of the forelimb to vasoactive agents was examined. In seven dogs, bolus injections of CaCl2, MgSO4, KCl, norepinephrine, adenosine, acetylcholine, PGE1 and saline were made into the forelimb perfused at constant flow before and three times during ouabain infusion. Ouabain blocked potassium vasodilation and changed the response to CaCl2 from vasoconstriction to vasodilation. The response of the forelimb to the other vasoactive agents was initially unaffected by ouabain but with time the forelimb vasculature became less sensitive to all agents studied. These changes were not seen in a series of 5 saline infused control animals. In a third series of animals steady-state dose responses to CaCl2, Ca-gluconate and KCl were explored by infusing solutions intrabrachially at three dosages. Before ouabain, forelimb resistance increased as a function of Ca++ and decreased as a function of K+. Ouabain completely blocked potassium vasodilation and on the average blocked Ca++ vasoconstriction although a number of animals evidenced vasodilation to Ca++ during ouabain infusion. These data indicate that K+ vasodilation is Na+, K+-ATPase dependent and that Na+, K+-ATPase inhibition unmasks a vasodilatory action of locally applied Ca++.

  8. Segmentation methods for breast vasculature in dual-energy contrast-enhanced digital breast tomosynthesis

    NASA Astrophysics Data System (ADS)

    Lau, Kristen C.; Lee, Hyo Min; Singh, Tanushriya; Maidment, Andrew D. A.

    2015-03-01

    Dual-energy contrast-enhanced digital breast tomosynthesis (DE CE-DBT) uses an iodinated contrast agent to image the three-dimensional breast vasculature. The University of Pennsylvania has an ongoing DE CE-DBT clinical study in patients with known breast cancers. The breast is compressed continuously and imaged at four time points (1 pre-contrast; 3 post-contrast). DE images are obtained by a weighted logarithmic subtraction of the high-energy (HE) and low-energy (LE) image pairs. Temporal subtraction of the post-contrast DE images from the pre-contrast DE image is performed to analyze iodine uptake. Our previous work investigated image registration methods to correct for patient motion, enhancing the evaluation of vascular kinetics. In this project we investigate a segmentation algorithm which identifies blood vessels in the breast from our temporal DE subtraction images. Anisotropic diffusion filtering, Gabor filtering, and morphological filtering are used for the enhancement of vessel features. Vessel labeling methods are then used to distinguish vessel and background features successfully. Statistical and clinical evaluations of segmentation accuracy in DE-CBT images are ongoing.

  9. Cerebral vasculature is the major target of oxidative protein alterations in bacterial meningitis.

    PubMed

    Schaper, Manuela; Gergely, Suzanne; Lykkesfeldt, Jens; Zbären, Jakob; Leib, Stephen L; Täuber, Martin G; Christen, Stephan

    2002-07-01

    We have previously shown that antioxidants such as a-phenyl-tert-butyl nitrone or N-acetylcysteine attenuate cortical neuronal injury in infant rats with bacterial meningitis, suggesting that oxidative alterations play an important role in this disease. However, the precise mechanism(s) by which antioxidants inhibit this injury remain(s) unclear. We therefore studied the extent and location of protein oxidation in the brain using various biochemical and immunochemical methods. In cortical parenchyma, a trend for increased protein carbonyls was not evident until 21 hours after infection and the activity of glutamine synthetase (another index of protein oxidation) remained unchanged. Consistent with these results, there was no evidence for oxidative alterations in the cortex by various immunohistochemical methods even in cortical lesions. In contrast, there was a marked increase in carbonyls, 4-hydroxynonenal protein adducts and manganese superoxide dismutase in the cerebral vasculature. Elevated lipid peroxidation was also observed in cerebrospinal fluid and occasionally in the hippocampus. All of these oxidative alterations were inhibited by treatment of infected animals with N-acetylcysteine or alpha-phenyl-tert-butyl nitrone. Because N-acetylcysteine does not readily cross the blood-brain barrier and has no effect on the loss of endogenous brain antioxidants, its neuroprotective effect is likely based on extraparenchymal action such as inhibition of vascular oxidative alterations.

  10. Pulmonary vasculature directed adenovirus increases epithelial lining fluid alpha-1 antitrypsin levels.

    PubMed

    Buggio, Maurizio; Towe, Christopher; Annan, Anand; Kaliberov, Sergey; Lu, Zhi Hong; Stephens, Calvin; Arbeit, Jeffrey M; Curiel, David T

    2016-01-01

    Gene therapy for inherited serum deficiency disorders has previously been limited by the balance between obtaining adequate expression and causing hepatic toxicity. Our group has previously described modifications of a replication deficient human adenovirus serotype 5 that increase pulmonary vasculature transgene expression. In the present study, we use a modified pulmonary targeted adenovirus to express human alpha-1 antitrypsin (A1AT) in C57BL/6 J mice. Using the targeted adenovirus, we were able to achieve similar increases in serum A1AT levels with less liver viral uptake. We also increased pulmonary epithelial lining fluid A1AT levels by more than an order of magnitude compared to that of untargeted adenovirus expressing A1AT in a mouse model. These gains are achieved along with evidence of decreased systemic inflammation and no evidence for increased inflammation within the vector-targeted end organ. In addition to comprising a step towards clinically viable gene therapy for A1AT, maximization of protein production at the site of action represents a significant technical advancement in the field of systemically delivered pulmonary targeted gene therapy. It also provides an alternative to the previous limitations of hepatic viral transduction and associated toxicities. Copyright © 2016 John Wiley & Sons, Ltd.

  11. Vasculature of the orbital rete in the Japanese deer (Cervus nippon).

    PubMed

    Ninomiya, H.; Masui, M.

    1999-01-01

    The vasculature of the orbital rete (rete mirabile ophthalmicum) in Japanese deer (Cervus nippon) was studied using corrosion casting, scanning electron microscopy, and histology. The orbital rete is a flat, triangular- or leaf-shaped arterial network, which consists of a complex of small arterioles, that intermixes with a similar complex of the supraorbital vein at the base of the orbital cavity. Blood to the retina passes through the orbital rete. The orbital retial arterioles leave the parent external ophthalmic artery at right angles forming T-shaped bifurcations, and follow a tortuous, undulating course. Each retial arteriole is connected by side branches and forms a rope-ladder-like network. Some of the side branches are surrounded by a groove representing the intra-arterial cushion that regulates blood flow at branching sites. The central retinal artery supplying the retina originates from the orbital rete. The ciliary arteries supplying the choroid arise from the external ophthalmic artery proximal to the orbital rete. The anatomical specializations of the orbital rete may involve buffering the blood pressure and flow to the retina and regulating ocular tissue temperature as in the carotid rete. In addition, the orbital rete may help dampen the tension that the vessel exerts on the retina, by stretching in response to eyeball movement.

  12. Inflammatory lipid mediator generation elicited by viable hemolysin- forming Escherichia coli in lung vasculature

    PubMed Central

    1990-01-01

    Escherichia coli hemolysin, a transmembrane pore-forming exotoxin, is considered an important virulence factor for E. coli-related extraintestinal infections and sepsis. The possible significance of hemolysin liberation for induction of inflammatory lipid mediators was investigated in isolated rabbit lungs infused with viable bacteria (concentration range, 10(4)-10(7)/ml). Hemolysin-secreting E. coli (E. coli-Hly+), but not an E. coli strain that releases an inactive form of the exotoxin, induced marked lung leukotriene (LT) generation with predominance of cysteinyl LTs. Eicosanoid synthesis was not inhibited in the presence of plasma with toxin-neutralizing capacity. Pre- application of 2 x 10(8) human granulocytes, which sequestered in the lung microvasculature, caused a severalfold increase in leukotriene generation in response to E. coli-Hly+ challenge both in the absence and presence of plasma. Data are presented indicating neutrophil- endothelial cell cooperation in arachidonic acid lipoxygenase metabolism as an underlying mechanism. We conclude that liberation of hemolysin from viable E. coli induces marked lipid mediator generation in lung vasculature, which is potentiated in the presence of neutrophil sequestration and may contribute to microcirculatory disturbances during the course of severe infections. PMID:2120384

  13. Prostaglandin F2 alpha as the luteolysin in swine: VI. Hormonal regulation of the movement of exogenous PGF2 alpha from the uterine lumen into the vasculature.

    PubMed

    Marengo, S R; Bazer, F W; Thatcher, W W; Wilcox, C J; Wetteman, R P

    1986-03-01

    To test the endocrine-exocrine theory of maternal recognition of pregnancy in the pig 16 gilts were assigned randomly to a 2 X 2 factorial involving pretreatment with sesame oil (SO) or estradiol valerate (5 mg; EV) injected on Days 11 through 14 of the estrous cycle and an intrauterine injection of saline (5 ml; SA) or prostaglandin F2 alpha (50 micrograms; PGF) on Day 14. Peripheral blood samples were collected for 120 min postinjection and analyzed for 15-keto-13,14-dihydro-PGF2 alpha (PGFM). PGFM concentrations were lower in EV than SO gilts (438 vs. 844 pg/ml; p less than 0.05). There was heterogeneity of regression between EV and SO gilts (p less than 0.01), with EV gilts having a slower release of PGF from the uterine lumen into the vasculature. Prostaglandin F2 alpha did not increase mean PGFM concentrations (p greater than 0.10), but resulted in an altered temporal pattern of PGFM (p less than 0.05) compared to SA gilts. There was an interaction between the two treatments over time, with EV-PGF gilts demonstrating a slower, more gradual release of PGFM than SO-PGF gilts. To test whether prostaglandins of the E series were involved in this mechanism, gilts were assigned to two 4 X 4 latin squares balanced for residual effects and treated with saline or flunixen meglumine (Banamine). Each gilt was treated with four PGE:PGF infusion sequences (SEQ) in each uterine horn: phosphate-buffered saline (PBS; PBS-SEQ), PGE1 (50 micrograms), PGE2 (50 micrograms), and PGE1 (25 micrograms) + PGE2 (25 micrograms) (PGE-SEQ), with each infusion followed 15 min later by PGF (25 micrograms).(ABSTRACT TRUNCATED AT 250 WORDS)

  14. Peripherally induced oromandibular dystonia

    PubMed Central

    Sankhla, C.; Lai, E.; Jankovic, J.

    1998-01-01

    OBJECTIVES—Oromandibular dystonia (OMD) is a focal dystonia manifested by involuntary muscle contractions producing repetitive, patterned mouth, jaw, and tongue movements. Dystonia is usually idiopathic (primary), but in some cases it follows peripheral injury. Peripherally induced cervical and limb dystonia is well recognised, and the aim of this study was to characterise peripherally induced OMD.
METHODS—The following inclusion criteria were used for peripherally induced OMD: (1) the onset of the dystonia was within a few days or months (up to 1 year) after the injury; (2) the trauma was well documented by the patient's history or a review of their medical and dental records; and (3) the onset of dystonia was anatomically related to the site of injury (facial and oral).
RESULTS—Twenty seven patients were identified in the database with OMD, temporally and anatomically related to prior injury or surgery. No additional precipitant other than trauma could be detected. None of the patients had any litigation pending. The mean age at onset was 50.11 (SD 14.15) (range 23-74) years and there was a 2:1 female preponderance. Mean latency between the initial trauma and the onset of OMD was 65 days (range 1 day-1 year). Ten (37%) patients had some evidence of predisposing factors such as family history of movement disorders, prior exposure to neuroleptic drugs, and associated dystonia affecting other regions or essential tremor. When compared with 21 patients with primary OMD, there was no difference for age at onset, female preponderance, and phenomenology. The frequency of dystonic writer's cramp, spasmodic dysphonia, bruxism, essential tremor, and family history of movement disorder, however, was lower in the post-traumatic group (p<0.05). In both groups the response to botulinum toxin treatment was superior to medical therapy (p<0.005). Surgical intervention for temporomandibular disorders was more frequent in the post-traumatic group and was associated with

  15. Central and peripheral control of food intake.

    PubMed

    Abdalla, M M I

    2017-01-01

    The maintenance of the body weight at a stable level is a major determinant in keeping the higher animals and mammals survive. Th e body weight depends on the balance between the energy intake and energy expenditure. Increased food intake over the energy expenditure of prolonged time period results in an obesity. Th e obesity has become an important worldwide health problem, even at low levels. The obesity has an evil effect on the health and is associated with a shorter life expectancy. A complex of central and peripheral physiological signals is involved in the control of the food intake. Centrally, the food intake is controlled by the hypothalamus, the brainstem, and endocannabinoids and peripherally by the satiety and adiposity signals. Comprehension of the signals that control food intake and energy balance may open a new therapeutic approaches directed against the obesity and its associated complications, as is the insulin resistance and others. In conclusion, the present review summarizes the current knowledge about the complex system of the peripheral and central regulatory mechanisms of food intake and their potential therapeutic implications in the treatment of obesity.

  16. A method for longitudinal, transcranial imaging of blood flow and remodeling of the cerebral vasculature in postnatal mice

    PubMed Central

    Letourneur, Annelise; Chen, Victoria; Waterman, Gar; Drew, Patrick J.

    2014-01-01

    Abstract In the weeks following birth, both the brain and the vascular network that supplies it undergo dramatic alteration. While studies of the postnatal evolution of the pial vasculature and blood flow through its vessels have been previously done histologically or acutely, here we describe a neonatal reinforced thin‐skull preparation for longitudinally imaging the development of the pial vasculature in mice using two‐photon laser scanning microscopy. Starting with mice as young as postnatal day 2 (P2), we are able to chronically image cortical areas >1 mm2, repeatedly for several consecutive days, allowing us to observe the remodeling of the pial arterial and venous networks. We used this method to measure blood velocity in individual vessels over multiple days, and show that blood flow through individual pial venules was correlated with subsequent diameter changes. This preparation allows the longitudinal imaging of the developing mammalian cerebral vascular network and its physiology. PMID:25524276

  17. hESC Differentiation toward an Autonomic Neuronal Cell Fate Depends on Distinct Cues from the Co-Patterning Vasculature

    PubMed Central

    Acevedo, Lisette M.; Lindquist, Jeffrey N.; Walsh, Breda M.; Sia, Peik; Cimadamore, Flavio; Chen, Connie; Denzel, Martin; Pernia, Cameron D.; Ranscht, Barbara; Terskikh, Alexey; Snyder, Evan Y.; Cheresh, David A.

    2015-01-01

    Summary To gain insight into the cellular and molecular cues that promote neurovascular co-patterning at the earliest stages of human embryogenesis, we developed a human embryonic stem cell model to mimic the developing epiblast. Contact of ectoderm-derived neural cells with mesoderm-derived vasculature is initiated via the neural crest (NC), not the neural tube (NT). Neurovascular co-patterning then ensues with specification of NC toward an autonomic fate requiring vascular endothelial cell (EC)-secreted nitric oxide (NO) and direct contact with vascular smooth muscle cells (VSMCs) via T-cadherin-mediated homotypic interactions. Once a neurovascular template has been established, NT-derived central neurons then align themselves with the vasculature. Our findings reveal that, in early human development, the autonomic nervous system forms in response to distinct molecular cues from VSMCs and ECs, providing a model for how other developing lineages might coordinate their co-patterning. PMID:26004631

  18. Morphogenesis of the lymphatic vasculature: A focus on new progenitors and cellular mechanisms important for constructing lymphatic vessels.

    PubMed

    Kazenwadel, Jan; Harvey, Natasha L

    2016-03-01

    Lymphatic vessels serve crucial roles in the regulation of tissue fluid homeostasis, dietary lipid absorption and immune cell trafficking. Defects in lymphatic vessel morphogenesis and function have been associated with lymphedema, obesity, hypertension and tumour metastasis. Morphogenetic events important for construction of the lymphatic vasculature during development include the specification and emergence of lymphatic endothelial progenitor cells, their differentiation and assembly into interconnected vessels and vascular remodeling, ultimately giving rise to a functional vascular network. Despite the embryonic origins of lymphatic endothelial progenitor cells being long debated, work performed over the last decade had overwhelmingly supported at least a great majority of progenitor cells arising from the venous vasculature. Here, we review the most recent advances in the field of lymphatic vessel morphogenesis, with a focus on studies that have identified novel sources of embryonic lymphatic endothelial progenitor cells, together with the cellular mechanisms by which lymphatic vessels are initially assembled. © 2015 Wiley Periodicals, Inc.

  19. Does the sequence of pulmonary vasculature ligation have any oncological impact during an anatomical lung resection for non-small-cell lung cancer?

    PubMed

    Toufektzian, Levon; Attia, Rizwan; Polydorou, Nicolaos; Veres, Lukacs

    2015-02-01

    A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was 'in patients with primary lung carcinoma, does the sequence of pulmonary vasculature ligation during anatomical lung resection influence the oncological outcomes?' A total of 48 papers were found using the reported search, of which 7 represented the best evidence to answer the question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Among six prospective studies included, five of them randomized patients to either pulmonary vein or artery occlusion first during anatomical lung resection, while one study was retrospective. Two reports did not find any difference between pulmonary vein and artery occlusion first during long-term follow-up in terms of either disease recurrence (51 vs 53%, P = 0.7), or 5-year overall survival (54 vs 50%, P = 0.82). One report did not find any difference with regard to circulating tumour cells either after thoracotomy (5.0 vs 3.9, P = 0.4), or after the completion of lobectomy (38.0 vs 70.0, P = 0.23). One report found a higher expression of CD44v6 (P = 0.008) and CK19 (P = 0.05) in patients undergoing pulmonary arterial occlusion first. One report found that pulmonary vein occlusion before that of the pulmonary arterial branches has a favourable outcome on circulating carcino-embryonic antigen (CEA) mRNA in the peripheral blood, while another one did not find a significant difference in circulating levels of CEA mRNA (P = 0.075) and CK19 mRNA (P = 0.086) with either method. Another study reported no correlation between circulating pin1 mRNA levels in peripheral blood after the completion of the resection and the sequence of ligation of pulmonary vessels (9.95 ± 0.91 vs 14.71 ± 1.64, P > 0.05). Based on the two studies assessing the long-term outcome of patients with primary lung cancer undergoing anatomical curative

  20. Correlative Imaging of the Murine Hind Limb Vasculature and Muscle Tissue by MicroCT and Light Microscopy

    PubMed Central

    Schaad, Laura; Hlushchuk, Ruslan; Barré, Sébastien; Gianni-Barrera, Roberto; Haberthür, David; Banfi, Andrea; Djonov, Valentin

    2017-01-01

    A detailed vascular visualization and adequate quantification is essential for the proper assessment of novel angiomodulating strategies. Here, we introduce an ex vivo micro-computed tomography (microCT)-based imaging approach for the 3D visualization of the entire vasculature down to the capillary level and rapid estimation of the vascular volume and vessel size distribution. After perfusion with μAngiofil®, a novel polymerizing contrast agent, low- and high-resolution scans (voxel side length: 2.58–0.66 μm) of the entire vasculature were acquired. Based on the microCT data, sites of interest were defined and samples further processed for correlative morphology. The solidified, autofluorescent μAngiofil® remained in the vasculature and allowed co-registering of the histological sections with the corresponding microCT-stack. The perfusion efficiency of μAngiofil® was validated based on lectin-stained histological sections: 98 ± 0.5% of the blood vessels were μAngiofil®-positive, whereas 93 ± 2.6% were lectin-positive. By applying this approach we analyzed the angiogenesis induced by the cell-based delivery of a controlled VEGF dose. Vascular density increased by 426% mainly through the augmentation of medium-sized vessels (20–40 μm). The introduced correlative and quantitative imaging approach is highly reproducible and allows a detailed 3D characterization of the vasculature and muscle tissue. Combined with histology, a broad range of complementary structural information can be obtained. PMID:28169309

  1. The three-dimensional organisation of the post-trabecular aqueous outflow pathway and limbal vasculature in the mouse.

    PubMed

    van der Merwe, Elizabeth L; Kidson, Susan H

    2014-08-01

    The mouse eye has been used as a model for studies on the microanatomy of the outflow pathways but most of what is known comes from histological sections. These studies have focused mainly on the morphological features of the trabecular meshwork, Schlemm's canal and aqueous channels that link to the superficial episcleral vasculature. However, the anatomical architecture of the aqueous outflow vessels and their relationship to each other and to the general vascular circulation is not well understood. The aim of this study was to provide a detailed description of the microarchitecture of the aqueous outflow vessels and their relationship to the superficial limbal/episcleral vasculature throughout the entire limbus. The aqueous outflow vessels and blood and lymphatic vessels were imaged in PECAM-1 and LYVE-1 immunostained whole anterior segments of adult mice and three-dimensional (3-D) reconstructions of the optical sections were generated to reveal the aqueous, blood and lymphatic architecture. The arterial supply, venous drainage, organisation of perilimbal vasculature, collector channels/aqueous veins and the morphology of Schlemm's canal were revealed in their entirety and the relationships between these structures is described. Schlemm's canal was PECAM-1 positive but there was no affinity for the lymphatic marker LYVE-1. We show that Schlemm's canal is a continuous circular structure and more often seen as a single, broad, varicose vessel with short regions appearing as a plexus. Aqueous veins link Schlemm's canal to the superficial vasculature and there were no direct links seen between the canal and the lymphatic vessels. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Brain-derived neurotrophic factor promotes vasculature-associated migration of neuronal precursors toward the ischemic striatum.

    PubMed

    Grade, Sofia; Weng, Yuan C; Snapyan, Marina; Kriz, Jasna; Malva, João O; Saghatelyan, Armen

    2013-01-01

    Stroke induces the recruitment of neuronal precursors from the subventricular zone (SVZ) into the ischemic striatum. In injured areas, de-routed neuroblasts use blood vessels as a physical scaffold to their migration, in a process that resembles the constitutive migration seen in the rostral migratory stream (RMS). The molecular mechanism underlying injury-induced vasculature-mediated migration of neuroblasts in the post-stroke striatum remains, however, elusive. Using adult mice we now demonstrate that endothelial cells in the ischemic striatum produce brain-derived neurotrophic factor (BDNF), a neurotrophin that promotes the vasculature-mediated migration of neuronal precursors in the RMS, and that recruited neuroblasts maintain expression of p75NTR, a low-affinity receptor for BDNF. Reactive astrocytes, which are widespread throughout the damaged area, ensheath blood vessels and express TrkB, a high-affinity receptor for BDNF. Despite the absence of BDNF mRNA, we observed strong BDNF immunolabeling in astrocytes, suggesting that these glial cells trap extracellular BDNF. Importantly, this pattern of expression is reminiscent of the adult RMS, where TrkB-expressing astrocytes bind and sequester vasculature-derived BDNF, leading to the entry of migrating cells into the stationary phase. Real-time imaging of cell migration in acute brain slices revealed a direct role for BDNF in promoting the migration of neuroblasts to ischemic areas. We also demonstrated that cells migrating in the ischemic striatum display higher exploratory behavior and longer stationary periods than cells migrating in the RMS. Our findings suggest that the mechanisms involved in the injury-induced vasculature-mediated migration of neuroblasts recapitulate, at least partially, those observed during constitutive migration in the RMS.

  3. Vasculatures in Tumors Growing From Preirradiated Tissues: Formed by Vasculogenesis and Resistant to Radiation and Antiangiogenic Therapy

    SciTech Connect

    Chen, Fang-Hsin; Chiang, Chi-Shiun; Wang, Chun-Chieh; Fu, Sheng-Yung; Tsai, Chien-Sheng; Jung, Shih-Ming; Wen, Chih-Jen; Lee, Chung-Chi; Hong, Ji-Hong

    2011-08-01

    Purpose: To investigate vasculatures and microenvironment in tumors growing from preirradiated tissues (pre-IR tumors) and study the vascular responses of pre-IR tumors to radiation and antiangiogenic therapy. Methods and Materials: Transgenic adenocarcinoma of the mouse prostate C1 tumors were implanted into unirradiated or preirradiated tissues and examined for vascularity, hypoxia, and tumor-associated macrophage (TAM) infiltrates by immunohistochemistry. The origin of tumor endothelial cells was studied by green fluorescent protein-tagged bone marrow (GFP-BM) transplantation. The response of tumor endothelial cells to radiation and antiangiogenic agent was evaluated by apoptotic assay. Results: The pre-IR tumors had obvious tumor bed effects (TBE), with slower growth rate, lower microvascular density (MVD), and more necrotic and hypoxic fraction compared with control tumors. The vessels were dilated, tightly adhered with pericytes, and incorporated with transplanted GFP-BM cells. In addition, hypoxic regions became aggregated with TAM. As pre-IR tumors developed, the TBE was overcome at the tumor edge where the MVD increased, TAM did not aggregate, and the GFP-BM cells did not incorporate into the vessels. The vessels at tumor edge were more sensitive to the following ionizing radiation and antiangiogenic agent than those in the central low MVD regions. Conclusions: This study demonstrates that vasculatures in regions with TBE are mainly formed by vasculogenesis and resistant to radiation and antiangiogenic therapy. Tumor bed effects could be overcome at the edge of larger tumors, but where vasculatures are formed by angiogenesis and sensitive to both treatments. Vasculatures formed by vasculogenesis should be the crucial target for the treatment of recurrent tumors after radiotherapy.

  4. Vasculatures in tumors growing from preirradiated tissues: formed by vasculogenesis and resistant to radiation and antiangiogenic therapy.

    PubMed

    Chen, Fang-Hsin; Chiang, Chi-Shiun; Wang, Chun-Chieh; Fu, Sheng-Yung; Tsai, Chien-Sheng; Jung, Shih-Ming; Wen, Chih-Jen; Lee, Chung-Chi; Hong, Ji-Hong

    2011-08-01

    To investigate vasculatures and microenvironment in tumors growing from preirradiated tissues (pre-IR tumors) and study the vascular responses of pre-IR tumors to radiation and antiangiogenic therapy. Transgenic adenocarcinoma of the mouse prostate C1 tumors were implanted into unirradiated or preirradiated tissues and examined for vascularity, hypoxia, and tumor-associated macrophage (TAM) infiltrates by immunohistochemistry. The origin of tumor endothelial cells was studied by green fluorescent protein-tagged bone marrow (GFP-BM) transplantation. The response of tumor endothelial cells to radiation and antiangiogenic agent was evaluated by apoptotic assay. The pre-IR tumors had obvious tumor bed effects (TBE), with slower growth rate, lower microvascular density (MVD), and more necrotic and hypoxic fraction compared with control tumors. The vessels were dilated, tightly adhered with pericytes, and incorporated with transplanted GFP-BM cells. In addition, hypoxic regions became aggregated with TAM. As pre-IR tumors developed, the TBE was overcome at the tumor edge where the MVD increased, TAM did not aggregate, and the GFP-BM cells did not incorporate into the vessels. The vessels at tumor edge were more sensitive to the following ionizing radiation and antiangiogenic agent than those in the central low MVD regions. This study demonstrates that vasculatures in regions with TBE are mainly formed by vasculogenesis and resistant to radiation and antiangiogenic therapy. Tumor bed effects could be overcome at the edge of larger tumors, but where vasculatures are formed by angiogenesis and sensitive to both treatments. Vasculatures formed by vasculogenesis should be the crucial target for the treatment of recurrent tumors after radiotherapy. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. Peripheral vision displays: The future

    NASA Technical Reports Server (NTRS)

    Assenhein, H. M.

    1984-01-01

    Several areas of research relating to peripheral vision displays used by aircraft pilots are outlined: fiber optics, display color, and holography. Various capacities and specifications of gas and solid state lasers are enumerated. These lasers are potential sources of green light for the peripheral vision displays. The relative radiance required for rod and cone vision at different wavelengths is presented graphically. Calculated and measured retinal sensitivities (foveal and peripheral) are given for wavelength produced by various lasers.

  6. Pigment epithelium-derived factor enhances tumor response to radiation through vasculature normalization in allografted lung cancer in mice.

    PubMed

    Xu, Z; Dong, Y; Peng, F; Yu, Z; Zuo, Y; Dai, Z; Chen, Y; Wang, J; Hu, X; Zhou, Q; Ma, H; Bao, Y; Gao, G; Chen, M

    2015-03-01

    This study aimed to explore the potential therapeutic effects of the combination of pigment epithelium-derived factor (PEDF) and radiation on lung cancer. The Lewis lung cancer (LLC) allografts in nude mice were treated with radiation, PEDF and PEDF combined with radiation. The morphologic changes of tumor vasculature and the hypoxic fraction of tumor tissues were evaluated. Significant inhibition of tumor growth was observed when radiation was applied between the 3rd and 7th day (the vasculature normalization window) after the initiation of PEDF treatment. During the vasculature normalization window, the tumor blood vessels in PEDF-treated mice were less tortuous and more uniform than those in the LLC allograft tumor treated with phosphate-buffered saline. Meanwhile, the thickness of the basement membrane was remarkably reduced and pericyte coverage was significantly increased with the PEDF treatment. We also found that tumor hypoxic fraction decreased during the 3rd to the 7th day after PEDF treatment, suggesting improved intratumoral oxygenation. Taken together, our results show that PEDF improved the effects of radiation therapy on LLC allografts by inducing a vascular normalization window from the 3rd to the 7th day after PEDF treatment. Our findings provide a basis for treating lung cancer with the combination of PEDF and radiation.

  7. Functional Response of Tumor Vasculature to PaCO2: Determination of Total and Microvascular Blood Volume by MRI

    PubMed Central

    Packard, Scott D; Mandeville, Joseph B; Ichikawa, Tomotsugu; Ikeda, Keiro; Terada, Kinya; Niloff, Stephanie; Chiocca, E Antonio; Rosen, Bruce R; Marota, John J A

    2003-01-01

    Abstract In order to identify differences in functional activity, we compared the reactivity of glioma vasculature and the native cerebral vasculature to both dilate and constrict in response to altered PaCO2. Gliomas were generated by unilateral implantation of U87MGdEGFR human glioma tumor cells into the striatum of adult female athymic rats. Relative changes in total and microvascular cerebral blood volume were determined by steady state contrast agent-enhanced magnetic resonance imaging for transitions from normocarbia to hypercarbia and hypocarbia. Although hypercarbia induced a significant increase in both total and microvascular blood volume in normal brain and glioma, reactivity of glioma vasculature was significantly blunted in comparison to normal striatum; glioma total CBV increased by 0.6±0.1% / mm Hg CO2 whereas normal striatum increased by 1.5±0.2%/ mm Hg CO2, (P < .0001, group t-test). Reactivity of microvascular blood volume was also significantly blunted. In contrast, hypocarbia decreased both total and microvascular blood volumes more in glioma than in normal striatum. These results indicate that cerebral blood vessels derived by tumor-directed angiogenesis do retain reactivity to CO2. Furthermore, reduced reactivity of tumor vessels to a single physiological perturbation, such as hypercarbia, should not be construed as a generalized reduction of functional activity of the tumor vascular bed. PMID:14511404

  8. “Do-it-yourself in vitro vasculature that recapitulates in vivo geometries for investigating endothelial-blood cell interactions”

    NASA Astrophysics Data System (ADS)

    Mannino, Robert G.; Myers, David R.; Ahn, Byungwook; Wang, Yichen; Margo Rollins; Gole, Hope; Lin, Angela S.; Guldberg, Robert E.; Giddens, Don P.; Timmins, Lucas H.; Lam, Wilbur A.

    2015-07-01

    Investigating biophysical cellular interactions in the circulation currently requires choosing between in vivo models, which are difficult to interpret due in part to the hemodynamic and geometric complexities of the vasculature; or in vitro systems, which suffer from non-physiologic assumptions and/or require specialized microfabrication facilities and expertise. To bridge that gap, we developed an in vitro “do-it-yourself” perfusable vasculature model that recapitulates in vivo geometries, such as aneurysms, stenoses, and bifurcations, and supports endothelial cell culture. These inexpensive, disposable devices can be created rapidly (<2 hours) with high precision and repeatability, using standard off-the-shelf laboratory supplies. Using these “endothelialized” systems, we demonstrate that spatial variation in vascular cell adhesion molecule (VCAM-1) expression correlates with the wall shear stress patterns of vascular geometries. We further observe that the presence of endothelial cells in stenoses reduces platelet adhesion but increases sickle cell disease (SCD) red blood cell (RBC) adhesion in bifurcations. Overall, our method enables researchers from all disciplines to study cellular interactions in physiologically relevant, yet simple-to-make, in vitro vasculature models.

  9. “Do-it-yourself in vitro vasculature that recapitulates in vivo geometries for investigating endothelial-blood cell interactions”

    PubMed Central

    Mannino, Robert G.; Myers, David R.; Ahn, Byungwook; Wang, Yichen; Margo Rollins; Gole, Hope; Lin, Angela S.; Guldberg, Robert E.; Giddens, Don P.; Timmins, Lucas H.; Lam, Wilbur A.

    2015-01-01

    Investigating biophysical cellular interactions in the circulation currently requires choosing between in vivo models, which are difficult to interpret due in part to the hemodynamic and geometric complexities of the vasculature; or in vitro systems, which suffer from non-physiologic assumptions and/or require specialized microfabrication facilities and expertise. To bridge that gap, we developed an in vitro “do-it-yourself” perfusable vasculature model that recapitulates in vivo geometries, such as aneurysms, stenoses, and bifurcations, and supports endothelial cell culture. These inexpensive, disposable devices can be created rapidly (<2 hours) with high precision and repeatability, using standard off-the-shelf laboratory supplies. Using these “endothelialized” systems, we demonstrate that spatial variation in vascular cell adhesion molecule (VCAM-1) expression correlates with the wall shear stress patterns of vascular geometries. We further observe that the presence of endothelial cells in stenoses reduces platelet adhesion but increases sickle cell disease (SCD) red blood cell (RBC) adhesion in bifurcations. Overall, our method enables researchers from all disciplines to study cellular interactions in physiologically relevant, yet simple-to-make, in vitro vasculature models. PMID:26202603

  10. Reduced bone mineral density and hyaloid vasculature remnants in a consanguineous recessive FEVR family with a mutation in LRP5.

    PubMed

    Downey, L M; Bottomley, H M; Sheridan, E; Ahmed, M; Gilmour, D F; Inglehearn, C F; Reddy, A; Agrawal, A; Bradbury, J; Toomes, C

    2006-09-01

    Familial exudative vitreoretinopathy (FEVR) is an inherited blinding condition characterised by abnormal development of the retinal vasculature. FEVR has multiple modes of inheritance, and homozygous mutations in LRP5 have recently been reported as underlying the recessive form of this disease. The aim of this study was to examine LRP5 in a consanguineous recessive FEVR family and to clarify the eye and bone phenotype associated with recessive FEVR. All family members were examined by slit lamp biomicroscopy and indirect ophthalmoscopy. Linkage to LRP5 was determined by genotyping microsatellite markers, constructing haplotypes and calculating lod scores. Mutation screening of LRP5 was performed by polymerase chain reaction amplification of genomic DNA followed by direct sequencing. Bone mineral density (BMD) was evaluated in all family members using dual energy x ray absorptiometry (DEXA). The clinical features observed in this family were consistent with a diagnosis of recessive FEVR. A homozygous LRP5 missense mutation, G550R, was identified in all affected individuals and all unaffected family members screened were heterozygous carriers of this mutation. Reduced BMD, hyaloid vasculature remnants, and nystagmus were features of the phenotype. Recessive mutations in LRP5 can cause FEVR with reduced BMD and hyaloid vasculature remnants. Assessment of a patient with a provisional diagnosis of FEVR should therefore include investigation of BMD, with reduced levels suggestive of an underlying LRP5 mutation.

  11. Reduced bone mineral density and hyaloid vasculature remnants in a consanguineous recessive FEVR family with a mutation in LRP5

    PubMed Central

    Downey, L M; Bottomley, H M; Sheridan, E; Ahmed, M; Gilmour, D F; Inglehearn, C F; Reddy, A; Agrawal, A; Bradbury, J; Toomes, C

    2006-01-01

    Background/aims Familial exudative vitreoretinopathy (FEVR) is an inherited blinding condition characterised by abnormal development of the retinal vasculature. FEVR has multiple modes of inheritance, and homozygous mutations in LRP5 have recently been reported as underlying the recessive form of this disease. The aim of this study was to examine LRP5 in a consanguineous recessive FEVR family and to clarify the eye and bone phenotype associated with recessive FEVR. Methods All family members were examined by slit lamp biomicroscopy and indirect ophthalmoscopy. Linkage to LRP5 was determined by genotyping microsatellite markers, constructing haplotypes and calculating lod scores. Mutation screening of LRP5 was performed by polymerase chain reaction amplification of genomic DNA followed by direct sequencing. Bone mineral density (BMD) was evaluated in all family members using dual energy x ray absorptiometry (DEXA). Results The clinical features observed in this family were consistent with a diagnosis of recessive FEVR. A homozygous LRP5 missense mutation, G550R, was identified in all affected individuals and all unaffected family members screened were heterozygous carriers of this mutation. Reduced BMD, hyaloid vasculature remnants, and nystagmus were features of the phenotype. Conclusion Recessive mutations in LRP5 can cause FEVR with reduced BMD and hyaloid vasculature remnants. Assessment of a patient with a provisional diagnosis of FEVR should therefore include investigation of BMD, with reduced levels suggestive of an underlying LRP5 mutation. PMID:16929062

  12. Evaluating changes in brain vasculature of murine embryos in utero due to maternal alcohol consumption using optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Raghunathan, Raksha; Wu, Chen; Singh, Manmohan; Liu, Chih-Hao; Miranda, Rajesh C.; Larin, Kirill V.

    2017-04-01

    Fetal Alcohol Syndrome (FAS) refers to the broad spectrum of developmental and behavioral effects caused due to prenatal alcohol exposure (PAE). Wide range of abnormalities vary depending on the amount of alcohol consumed and the period of consumption during gestation. PAE during early stages of pregnancy is very common. However a large number of women continue to consume alcohol even during the second trimester, a critical period for fetal neurogenesis and angiogenesis. Optical coherence tomography (OCT) has shown to be extremely useful in embryonic imaging. Our previous work showed that OCT is capable of quantitative assessment of ventriculomegaly caused by maternal alcohol consumption. Although structural changes and changes in blood flow in the fetal brain after maternal alcohol consumption have been studied, acute vasculature changes are not well documented. Speckle variance OCT (SVOCT), is a functional extension of OCT that has been used to study vasculature development in embryos. We use SVOCT, to detect vasculature changes in the embryonic brain in utero, minutes after maternal alcohol consumption.

  13. "Do-it-yourself in vitro vasculature that recapitulates in vivo geometries for investigating endothelial-blood cell interactions".

    PubMed

    Mannino, Robert G; Myers, David R; Ahn, Byungwook; Wang, Yichen; Margo Rollins; Gole, Hope; Lin, Angela S; Guldberg, Robert E; Giddens, Don P; Timmins, Lucas H; Lam, Wilbur A

    2015-07-23

    Investigating biophysical cellular interactions in the circulation currently requires choosing between in vivo models, which are difficult to interpret due in part to the hemodynamic and geometric complexities of the vasculature; or in vitro systems, which suffer from non-physiologic assumptions and/or require specialized microfabrication facilities and expertise. To bridge that gap, we developed an in vitro "do-it-yourself" perfusable vasculature model that recapitulates in vivo geometries, such as aneurysms, stenoses, and bifurcations, and supports endothelial cell culture. These inexpensive, disposable devices can be created rapidly (<2 hours) with high precision and repeatability, using standard off-the-shelf laboratory supplies. Using these "endothelialized" systems, we demonstrate that spatial variation in vascular cell adhesion molecule (VCAM-1) expression correlates with the wall shear stress patterns of vascular geometries. We further observe that the presence of endothelial cells in stenoses reduces platelet adhesion but increases sickle cell disease (SCD) red blood cell (RBC) adhesion in bifurcations. Overall, our method enables researchers from all disciplines to study cellular interactions in physiologically relevant, yet simple-to-make, in vitro vasculature models.

  14. Peripheral neuropathy: the importance of rare subtypes

    PubMed Central

    Callaghan, Brian C.; Price, Ray S.; Chen, Kevin S.; Feldman, Eva L.

    2016-01-01

    Importance Peripheral neuropathy is a prevalent condition that usually warrants a thorough history and examination, but limited diagnostic evaluation. Rare localizations of peripheral neuropathy, however, often require more extensive diagnostic testing and different treatments. Objective To describe rare localizations of peripheral neuropathy, including the appropriate diagnostic evaluation and available treatments. Evidence Review References were identified from PubMed searches with an emphasis on systematic reviews and randomized clinical trials. Articles were also identified through the use of the author's own files. Search terms included common rare neuropathy localizations and their causes, as well as epidemiology, pathophysiology, diagnosis, and treatment. Findings Diffuse, non-length dependent neuropathies, multiple mononeuropathies, polyradiculopathies, plexopathies, and radiculoplexus neuropathies are rare peripheral neuropathy localizations that often require extensive diagnostic testing. Atypical neuropathy features, such as acute/subacute onset, asymmetry, and/or motor predominant signs, are frequently present. The most common diffuse, non-length dependent neuropathies are Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), and amyotrophic lateral sclerosis (ALS). Effective disease modifying therapies exist for many diffuse, non-length dependent neuropathies including GBS, CIDP, MMN, and some paraprotein-associated demyelinating neuropathies. Vasculitic neuropathy (multiple mononeuropathy) also has efficacious treatment options, but definitive evidence of a treatment effect for IgM anti-MAG neuropathy and diabetic amyoptrophy (radiculoplexus neuropathy) is lacking. Conclusions and Relevance Recognition of rare localizations of periperhal neuropathy is essential given the implications for diagnostic testing and treatment. Electrodiagnostic studies are an important early step in the

  15. Histomorphometry of the placental vasculature and microcotyledons in Thoroughbred mares with chronic laminitis.

    PubMed

    Pazinato, Fernanda M; Curcio, Bruna da Rosa; Fernandes, Cristina G; Santos, Carlos A; Feijó, Lorena S; Varela, Antonio Sérgio; Nogueira, Carlos E W

    2017-03-15

    The objective of this study was to assess the placental vasculature and microcotyledons in pregnant mares with chronic laminitis. Twenty-six pregnant mares were enrolled in the study, 13 had chronic laminitis (Laminitis Group) and 13 were healthy mares (Healthy Group). Arterial systolic pressure and heart rate were measured in the last 30 days of gestation. After foaling, the fetal membranes were grossly evaluated and samples were harvested for histopathologic examination. All mares had digitalized images taken from chorioallantois for histomorphometry analyses (software-NIH ImageJ). Images were assessed for: (i) arterioles from the allantoic region: total and lumen vascular diameter and vascular wall thickness; (ii) microcotiledonary and capillary area/field. Mares in the Laminitis Group showed hypertension, shorter gestational length, lower placental weight and lower birthweight (p < 0.05) foal in comparison with mares in the Healthy Group. Laminitis mares had a reduction of vascular lumen diameters in the uterine body and pregnant horn (p < 0.05), vascular wall thickening in the pregnant horn (p < 0.05) and smaller capillary area/field in the microcotyledons of uterine body and pregnant horn (p < 0.05). In conclusion, pregnant mares with chronic laminitis presented signs of hypertension syndrome, and vascular abnormalitities in placental vessels such as reduction in the vascular lumen and capillary area in the microcotyledones, and thickening of the vascular wall. Foals born from mares with chronic laminitis showed lower birth weight and shorter gestation lengths.

  16. Effect of blood pressure on the retinal vasculature in a multi-ethnic Asian population.

    PubMed

    Jeganathan, V Swetha E; Sabanayagam, Charumathi; Tai, E Shyong; Lee, Jeannette; Sun, Cong; Kawasaki, Ryo; Nagarajan, Sangeetha; Huey-Shi, Maisie Ho; Sandar, Mya; Wong, Tien Yin

    2009-11-01

    Blood pressure has a significant effect on retinal arterioles. There are few data on whether this effect varies by race/ethnicity. We examined the relationship of blood pressure and retinal vascular caliber in a multi-ethnic Asian population. The study is population-based and cross sectional in design. A total of 3749 Chinese, Malay and Indian participants aged > or =24 years residing in Singapore were included in the study. Retinal vascular caliber was measured using a computer program from digital retinal photographs. The associations of retinal vascular caliber with blood pressure and hypertension in each racial/ethnic group were analyzed. The main outcome measures are retinal arteriolar caliber and venular caliber. The results show that retinal arterioles were narrower in persons with uncontrolled/untreated hypertension (140.0 microm) as compared with persons with controlled hypertension (142.1 microm, P=0.0001) and those with no hypertension (146.0 microm, P<0.0001). On controlling for age, gender, body mass index, lipids and smoking, each 10 mm Hg increase in mean arterial blood pressure was associated with a 3.1 microm decrease in arteriolar caliber (P<0.0001), with a similar magnitude seen in all three racial/ethnic groups: 3.1 microm in Chinese, 2.8 microm in Malays and 3.2 microm in Indians (P<0.0001 for all). Each 10 mm Hg increase in mean arterial blood pressure was associated with a 1.8 microm increase in venular caliber (P<0.0001); furthermore, the magnitude of this effect was similar across the three racial/ethnic groups. The effect of blood pressure on the retinal vasculature was similar across three major racial/ethnic groups in Asia.

  17. Infant Aphakia Treatment Study: Effects of persistent fetal vasculature on outcome at 1 year of age

    PubMed Central

    Morrison, David G.; Wilson, M. Edward; Trivedi, Rupal H.; Lambert, Scott R.; Lynn, Michael J.

    2011-01-01

    Background The Infant Aphakia Treatment Study (IATS) is a randomized trial comparing the treatment of unilateral congenital cataract with primary intraocular lens (IOL) implantation versus aphakic contact lens (CL). The purpose of this study was to compare the outcomes for infants with lens opacity associated with persistent fetal vasculature (PFV) to those without. Methods Retrospective subgroup analysis of grating visual acuity at 1 year of age and adverse events up to 1 year after surgery in eyes identified intraoperatively as having evidence of mild PFV from the IATS. Results Of 83 infants, 18 (22%: 11 CL, 7 IOL) had PFV. Median logMAR visual acuity was 0.88 for patients with PFV and 0.80 for patients without PFV (P = 0.46). One or more adverse events up to one year after surgery occurred in 12 infants (67%) with PFV and 30 infants (46%) without PFV (P = 0.18). The incidence of adverse events was significantly higher in patients with PFV compared to patients without PFV in the CL group (55% vs 20%, P = 0.049) but not in the IOL group (86% vs 71%, P = 0.65), possibly because all children receiving IOLs had higher rates of adverse events when compared to aphakic children (73% vs 29%, P < 0.001). Conclusions Aphakic infants with mild PFV treated with CL had a higher incidence of adverse events following lensectomy compared to children with other forms of unilateral congenital cataract; nevertheless, similar visual outcomes at one year after surgery were obtained. PMID:22108353

  18. Thick Acellular Heart Extracellular Matrix with Inherent Vasculature: A Potential Platform for Myocardial Tissue Regeneration

    PubMed Central

    Sarig, Udi; Au-Yeung, Gigi C.T.; Wang, Yao; Bronshtein, Tomer; Dahan, Nitsan; Boey, Freddy Y.C.; Venkatraman, Subbu S.

    2012-01-01

    The decellularization of porcine heart tissue offers many opportunities for the production of physiologically relevant myocardial mimetic scaffolds. Earlier, we reported the successful isolation of a thin porcine cardiac extracellular matrix (pcECM) exhibiting relevant bio-mechanical properties for myocardial tissue engineering. Nevertheless, since native cardiac tissue is much thicker, such thin scaffolds may offer limited regeneration capacity. However, generation of thicker myocardial mimetic tissue constructs is hindered by diffusion limitations (∼100 μm), and the lack of a proper vascular-like network within these constructs. In our present work, we focused on optimizing the decellularization procedure for thicker tissue slabs (10–15 mm), while retaining their inherent vasculature, and on characterizing the resulting pcECM. The trypsin/Triton-based perfusion procedure that resulted in a nonimmunogenic and cell-supportive pcECM was found to be more effective in cell removal and in the preservation of fiber morphology and structural characteristics than stirring, sonication, or sodium dodecyl sulfate/Triton-based procedures. Mass spectroscopy revealed that the pcECM is mainly composed of ECM proteins with no apparent cellular protein remains. Mechanical testing indicated that the obtained pcECM is viscoelastic in nature and possesses the typical stress-strain profile of biological materials. It is stiffer than native tissue yet exhibits matched mechanical properties in terms of energy dissipation, toughness, and ultimate stress behavior. Vascular network functionality was maintained to the first three–four branches from the main coronary vessels. Taken together, these results reaffirm the efficiency of the decellularization procedure reported herein for yielding thick nonimmunogenic cell-supportive pcECM scaffolds, preserving both native tissue ultra-structural properties and an inherent vascular network. When reseeded with the appropriate progenitor

  19. The microtubule depolymerizing agent CYT997 causes extensive ablation of tumor vasculature in vivo.

    PubMed

    Burns, Christopher J; Fantino, Emmanuelle; Powell, Andrew K; Shnyder, Steven D; Cooper, Patricia A; Nelson, Stuart; Christophi, Christopher; Malcontenti-Wilson, Cathy; Dubljevic, Valentina; Harte, Michael F; Joffe, Max; Phillips, Ian D; Segal, David; Wilks, Andrew F; Smith, Gregg D

    2011-12-01

    The orally active microtubule-disrupting agent (S)-1-ethyl-3-(2-methoxy-4-(5-methyl-4-((1-(pyridin-3-yl)butyl)amino)pyrimidin-2-yl)phenyl)urea (CYT997), reported previously by us (Bioorg Med Chem Lett 19:4639-4642, 2009; Mol Cancer Ther 8:3036-3045, 2009), is potently cytotoxic to a variety of cancer cell lines in vitro and shows antitumor activity in vivo. In addition to its cytotoxic activity, CYT997 possesses antivascular effects on tumor vasculature. To further characterize the vascular disrupting activity of CYT997 in terms of dose and temporal effects, we studied the activity of the compound on endothelial cells in vitro and on tumor blood flow in vivo by using a variety of techniques. In vitro, CYT997 is shown to potently inhibit the proliferation of vascular endothelial growth factor-stimulated human umbilical vein endothelial cells (IC(50) 3.7 ± 1.8 nM) and cause significant morphological changes at 100 nM, including membrane blebbing. Using the method of corrosion casting visualized with scanning electron microscopy, a single dose of CYT997 (7.5 mg/kg i.p.) in a metastatic cancer model was shown to cause destruction of tumor microvasculature in metastatic lesions. Furthermore, repeat dosing of CYT997 at 10 mg/kg and above (intraperitoneally, b.i.d.) was shown to effectively inhibit development of liver metastases. The time and dose dependence of the antivascular effects were studied in a DLD-1 colon adenocarcinoma xenograft model using the fluorescent dye Hoechst 33342. CYT997 demonstrated rapid and dose-dependent vascular shutdown, which persists for more than 24 h after a single oral dose. Together, the data demonstrate that CYT997 possesses potent antivascular activity and support continuing development of this promising compound.

  20. Choroidal vasculature characteristics based choroid segmentation for enhanced depth imaging optical coherence tomography images.

    PubMed

    Chen, Qiang; Niu, Sijie; Yuan, Songtao; Fan, Wen; Liu, Qinghuai

    2016-04-01

    In clinical research, it is important to measure choroidal thickness when eyes are affected by various diseases. The main purpose is to automatically segment choroid for enhanced depth imaging optical coherence tomography (EDI-OCT) images with five B-scans averaging. The authors present an automated choroid segmentation method based on choroidal vasculature characteristics for EDI-OCT images with five B-scans averaging. By considering the large vascular of the Haller's layer neighbor with the choroid-sclera junction (CSJ), the authors measured the intensity ascending distance and a maximum intensity image in the axial direction from a smoothed and normalized EDI-OCT image. Then, based on generated choroidal vessel image, the authors constructed the CSJ cost and constrain the CSJ search neighborhood. Finally, graph search with smooth constraints was utilized to obtain the CSJ boundary. Experimental results with 49 images from 10 eyes in 8 normal persons and 270 images from 57 eyes in 44 patients with several stages of diabetic retinopathy and age-related macular degeneration demonstrate that the proposed method can accurately segment the choroid of EDI-OCT images with five B-scans averaging. The mean choroid thickness difference and overlap ratio between the authors' proposed method and manual segmentation drawn by experts were -11.43 μm and 86.29%, respectively. Good performance was achieved for normal and pathologic eyes, which proves that the authors' method is effective for the automated choroid segmentation of the EDI-OCT images with five B-scans averaging.

  1. Endothelial α5 and αv integrins cooperate in remodeling of the vasculature during development

    PubMed Central

    van der Flier, Arjan; Badu-Nkansah, Kwabena; Whittaker, Charles A.; Crowley, Denise; Bronson, Roderick T.; Lacy-Hulbert, Adam; Hynes, Richard O.

    2010-01-01

    Integrin cell adhesion receptors and fibronectin, one of their extracellular matrix ligands, have been demonstrated to be important for angiogenesis using functional perturbation studies and complete knockout mouse models. Here, we report on the roles of the α5 and αv integrins, which are the major endothelial fibronectin receptors, in developmental angiogenesis. We generated an integrin α5-floxed mouse line and ablated α5 integrin in endothelial cells. Unexpectedly, endothelial-specific knockout of integrin α5 has no obvious effect on developmental angiogenesis. We provide evidence for genetic interaction between mutations in integrin α5 and αv and for overlapping functions and compensation between these integrins and perhaps others. Nonetheless, in embryos lacking both α5 and αv integrins in their endothelial cells, initial vasculogenesis and angiogenesis proceed normally, at least up to E11.5, including the formation of apparently normal embryonic vasculature and development of the branchial arches. However, in the absence of endothelial α5 and αv integrins, but not of either alone, there are extensive defects in remodeling of the great vessels and heart resulting in death at ~E14.5. We also found that fibronectin assembly is somewhat affected in integrin α5 knockout endothelial cells and markedly reduced in integrin α5/αv double-knockout endothelial cell lines. Therefore, neither α5 nor αv integrins are required in endothelial cells for initial vasculogenesis and angiogenesis, although they are required for remodeling of the heart and great vessels. These integrins on other cells, and/or other integrins on endothelial cells, might contribute to fibronectin assembly and vascular development. PMID:20570943

  2. DEVELOPMENTAL PROGRESSION OF THE CORONARY VASCULATURE IN HUMAN EMBRYOS AND FETUSES

    PubMed Central

    Tomanek, Robert J.

    2015-01-01

    Although considerable advances in our understanding of mammalian and avian embryonic coronary development have occurred during the last decade, our current knowledge of this topic in humans is limited. Accordingly, the aim of this study was to determine if the development of the human coronary vasculature in humans is like that of other mammals and avians. The data document a progression of events involving mesenchymal cell-containing villi from the proepicardium, establishment of blood islands and a capillary network. The major finding of the study is direct evidence that the capillary plexus associated with spindle cells and erythroblasts invades the base of the aorta to form coronary ostia. A role for the dorsal mesocardium is also indicated by the finding that cells from this region are continuous with the aorta and pulmonary artery. The development of the tunica media of the coronary arteries follows the same base-apex progression as in other species, with the development of branches occurring late in the embryonic period. The fetal period is characterized by 1) growth and a numerical increase in the smallest arterial branches, veins and venules, 2) innervation of arteries, 3) inclusion of elastic fibers in the tunica media of the coronary arteries and development of the tunica adventitia. In conclusion, the data demonstrate that the development of the coronary system in humans is similar to that of other mammalian and avian species, and for the first time documents that the formation of the ostia and coronary stems in humans occurs by ingrowth of a vascular plexus and associated cells from the epicardium. PMID:26475042

  3. Chlorine gas exposure disrupts nitric oxide homeostasis in the pulmonary vasculature

    PubMed Central

    Honavar, Jaideep; Bradley, Eddie; Bradley, Kelley; Oh, Joo Yeun; Vallejo, Matthew O.; Kelley, Eric E.; Cantu-Medellin, Nadiezhda; Doran, Stephen; Dell’italia, Louis J.; Matalon, Sadis; Patel, Rakesh P.

    2014-01-01

    Exposure to chlorine (Cl2) gas during industrial accidents or chemical warfare leads to significant airway and distal lung epithelial injury that continues post exposure. While lung epithelial injury is prevalent, relatively little is known about whether Cl2 gas also promotes injury to the pulmonary vasculature. To determine this, rats were subjected to a sub-lethal Cl2 gas exposure (400ppm, 30min) and then brought back to room air. Pulmonary arteries (PA) were isolated from rats at various times post-exposure and contractile (phenylephrine) and nitric oxide (NO)-dependent vasodilation (acetylcholine and mahmanonoate) responses measured ex-vivo. PA contractility did not change, however significant inhibition of NO-dependent vasodilation was observed that was maximal at 24–48 hours post exposure. Superoxide dismutase restored NO-dependent vasodilation suggesting a role for increased superoxide formation. This was supported by ~2-fold increase in superoxide formation (measured using 2-hydroethidine oxidation to 2-OH-E+) from PA isolated from Cl2 exposed rats. We next measured PA pressures in anesthetized rats. Surprisingly, PA pressures were significantly (~4mmHg) lower in rats that had been exposed to Cl2 gas 24 hours earlier suggesting that deficit in NO-signaling observed in isolated PA experiments did not manifest as increased PA pressures in vivo. Administration of the iNOS selective inhibitor 1400W, restored PA pressures to normal in Cl2 exposed, but not control rats suggesting that any deficit in NO-signaling due to increased superoxide formation in the PA, is offset by increased NO-formation from iNOS. These data indicate that disruption of endogenous NO-signaling mechanisms that maintain PA tone is an important aspect of post-Cl2 gas exposure toxicity. PMID:24769334

  4. Metalloproteinases facilitate connection of wound bed vessels to pre-existing skin graft vasculature.

    PubMed

    Knapik, Alicia; Hegland, Niels; Calcagni, Maurizio; Althaus, Martina; Vollmar, Brigitte; Giovanoli, Pietro; Lindenblatt, Nicole

    2012-07-01

    Despite advances in tissue engineering of human skin, the exact revascularization processes remain unclear. Therefore it was the aim of this study to investigate the vascular transformations during engraftment and to identify associated proteolytic factors. The modified dorsal skinfold chamber with autologous skin grafting was prepared in C57BL/6J mice, and intravital microscopy was performed. The expression of proteases and vascular factors was quantified by immunohistochemistry. Reperfusion of the skin graft after 72hours was followed by a temporary angiogenic response of the graft vessels. Wound bed bud formation appeared after 24 to 48hours representing starting points for capillary sprouting. In the reperfused skin graft larger buds developed over several days without transformation into angiogenic sprouts; instead pruning took place. MT1-MMP was detected at sprout tips of in-growing vessels. MMP-2 expression was located at the wound bed/graft connection sites. Pericytes were found to withdraw from the angiogenic vessel in order to facilitate sprouting. Skin graft vasculature responded with temporary angiogenesis to reperfusion, which was pruned after several days and exhibited a different morphology than regular sprouting angiogenesis present within the wound bed. Furthermore we identified MT1-MMP as sprout-tip located protease indicating its potential role as sprout growth facilitator as well as potentially in lysing the existing graft capillaries in order to connect to them. The differences between the wound bed and skin graft angiogenesis may represent a relevant insight into the processes of vascular pruning and may help in the engineering of skin substitutes. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. Choroidal vasculature characteristics based choroid segmentation for enhanced depth imaging optical coherence tomography images

    SciTech Connect

    Chen, Qiang; Niu, Sijie; Yuan, Songtao; Fan, Wen Liu, Qinghuai

    2016-04-15

    Purpose: In clinical research, it is important to measure choroidal thickness when eyes are affected by various diseases. The main purpose is to automatically segment choroid for enhanced depth imaging optical coherence tomography (EDI-OCT) images with five B-scans averaging. Methods: The authors present an automated choroid segmentation method based on choroidal vasculature characteristics for EDI-OCT images with five B-scans averaging. By considering the large vascular of the Haller’s layer neighbor with the choroid-sclera junction (CSJ), the authors measured the intensity ascending distance and a maximum intensity image in the axial direction from a smoothed and normalized EDI-OCT image. Then, based on generated choroidal vessel image, the authors constructed the CSJ cost and constrain the CSJ search neighborhood. Finally, graph search with smooth constraints was utilized to obtain the CSJ boundary. Results: Experimental results with 49 images from 10 eyes in 8 normal persons and 270 images from 57 eyes in 44 patients with several stages of diabetic retinopathy and age-related macular degeneration demonstrate that the proposed method can accurately segment the choroid of EDI-OCT images with five B-scans averaging. The mean choroid thickness difference and overlap ratio between the authors’ proposed method and manual segmentation drawn by experts were −11.43 μm and 86.29%, respectively. Conclusions: Good performance was achieved for normal and pathologic eyes, which proves that the authors’ method is effective for the automated choroid segmentation of the EDI-OCT images with five B-scans averaging.

  6. A mitochondrial redox oxygen sensor in the pulmonary vasculature and ductus arteriosus1

    PubMed Central

    Dunham-Snary, Kimberly J; Hong, Zhigang G; Xiong, Ping Y; Del Paggio, Joseph C; Herr, Julia E; Johri, Amer M; Archer, Stephen L

    2015-01-01

    The mammalian homeostatic oxygen sensing system (HOSS) initiates changes in vascular tone, respiration, and neurosecretion that optimize oxygen uptake and tissue oxygen delivery within seconds of detecting altered environmental or arterial PO2. The HOSS includes carotid body type 1 cells, adrenomedullary cells, neuroepithelial bodies, and smooth muscle cells (SMC) in pulmonary arteries (PA), ductus arteriosus (DA) and fetoplacental arteries. Hypoxic pulmonary vasoconstriction (HPV) optimises ventilation-perfusion matching. In utero, HPV diverts placentally-oxygenated blood from the non-ventilated lung through the DA. At birth, increased alveolar and arterial oxygen tension dilate the pulmonary vasculature and, constrict the DA, respectively, thereby transitioning the newborn to an air-breathing organism. Though modulated by endothelial-derived relaxing and constricting factors, O2-sensing is intrinsic to PA- and DASMCs. Within the SMC’s dynamic mitochondrial network, changes in PO2 alter the reduction-oxidation state of redox couples (NAD+/NADH, NADP+/NADPH) and the production of reactive oxygen species, ROS (e.g. H2O2) by Complexes I and III of the electron transport chain (ETC). ROS and redox couples regulate ion channels, transporters, and enzymes, changing intracellular calcium [Ca2+]i and calcium sensitivity and eliciting homeostatic responses to hypoxia. In PASMC, hypoxia inhibits ROS production and reduces redox couples, thereby inhibiting O2-sensitive voltage-gated potassium (Kv) channels, depolarizing the plasma membrane, activating voltage-gated calcium channels (CaL), increasing [Ca2+]i and causing vasoconstriction. In DASMC, elevated PO2 causes mitochondrial fission, increasing ETC Complex I activity and ROS production. The DASMC’s downstream response to elevated PO2 (Kv channel inhibition, CaL activation, increased [Ca2+]i and rho kinase activation) is similar to the PASMC’s hypoxic response. Impaired O2-sensing contributes to human diseases

  7. Aspects of gorgonopsian paleobiology and evolution: insights from the basicranium, occiput, osseous labyrinth, vasculature, and neuroanatomy.

    PubMed

    Araújo, Ricardo; Fernandez, Vincent; Polcyn, Michael J; Fröbisch, Jörg; Martins, Rui M S

    2017-01-01

    Synapsida, the clade including therapsids and thus also mammals, is one of the two major branches of amniotes. Organismal design, with modularity as a concept, offers insights into the evolution of therapsids, a group that experienced profound anatomical transformations throughout the past 270 Ma, eventually leading to the evolution of the mammalian bauplan. However, the anatomy of some therapsid groups remains obscure. Gorgonopsian braincase anatomy is poorly known and many anatomical aspects of the brain, cranial nerves, vasculature, and osseous labyrinth, remain unclear. We analyzed two gorgonopsian specimens, GPIT/RE/7124 and GPIT/RE/7119, using propagation phase contrast synchrotron micro-computed tomography. The lack of fusion between many basicranial and occipital bones in GPIT/RE/7124, which is an immature specimen, allowed us to reconstruct its anatomy and ontogenetic sequence, in comparison with the mature GPIT/RE/7119, in great detail. We explored the braincase and rendered various skull cavities. Notably, we found that there is a separate ossification between what was previously referred to as the "parasphenoid" and the basioccipital. We reinterpreted this element as a posterior ossification of the basisphenoid: the basipostsphenoid. Moreover, we show that the previously called "parasphenoid" is in fact the co-ossification of the dermal parasphenoid and the endochondral basipresphenoid. In line with previous descriptions, the anatomy of the osseous labyrinth is rendered in detail, revealing a unique discoid morphology of the horizontal semicircular canal, rather than toroidal, probably due to architectural constraints of the ossification of the opisthotic and supraoccipital. In addition, the orientation of the horizontal semicircular canal suggests that gorgonopsians had an anteriorly tilted alert head posture. The morphology of the brain endocast is in accordance with the more reptilian endocast shape of other non-mammaliaform neotherapsids.

  8. Focal adhesion kinase regulates smooth muscle cell recruitment to the developing vasculature

    PubMed Central

    Cheng, Zhaokang; Sundberg-Smith, Liisa J.; Mangiante, Lee E.; Sayers, Rebecca L.; Hakim, Zeenat S.; Musunuri, Srilaxmi; Maguire, Colin T.; Majesky, Mark W.; Zhou, Zhigang; Mack, Christopher P.; Taylor, Joan M.

    2011-01-01

    Objective The investment of newly formed endothelial cell tubes with differentiated smooth muscle cells (SMC) is critical for appropriate vessel formation, but the underlying mechanisms remain unknown. We previously showed that depletion of focal adhesion kinase (FAK) in the nkx2.5 expression domain led to aberrant outflow tract (OFT) morphogenesis and strove herein to determine the cell types and mechanisms involved. Methods and Results We crossed fakloxp targeted mice with available Cre drivers to deplete FAK in OFT SMC (FAKwnt and FAKnk) or coronary SMC (FAKcSMC). In each case, depletion of FAK led to defective vasculogenesis that was incompatible with post-natal life. Immunohistochemical analysis of the mutant vascular structures revealed that FAK was not required for progenitor cell proliferation, survival, or differentiation into SMC, but was necessary for subsequent SMC recruitment to developing vasculature. Using a novel FAK-null SMC culture model, we found that depletion of FAK did not influence SMC growth or survival, but blocked directional SMC motility and invasion toward the potent endothelial-derived chemokine, PDGFBB. FAK depletion resulted in un-stable lamellipodial protrusions due to defective spatial-temporal activation of the small GTPase, Rac-1 and lack of Rac1-dependent recruitment of cortactin (an actin stabilizing protein) to the leading edge. Moreover, FAK null SMC exhibited a significant reduction in PDGF-stimulated extracellular matrix degradation. Conclusions FAK drives PDGFBB-stimulated SMC chemotaxis/invasion and is essential for SMC to appropriately populate the aorticopulmonary septum and the coronary vascular plexus. PMID:21757658

  9. A mitochondrial redox oxygen sensor in the pulmonary vasculature and ductus arteriosus.

    PubMed

    Dunham-S