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Sample records for peripheral vasculature implications

  1. Amphetamine- and methamphetamine-induced hyperthermia: Implications of the effects produced in brain vasculature and peripheral organs to forebrain neurotoxicity

    PubMed Central

    Bowyer, John F; Hanig, Joseph P

    2014-01-01

    The adverse effects of amphetamine- (AMPH) and methamphetamine- (METH) induced hyperthermia on vasculature, peripheral organs and peripheral immune system are discussed. Hyperthermia alone does not produce amphetamine-like neurotoxicity but AMPH and METH exposures that do not produce hyperthermia (≥40°C) are minimally neurotoxic. Hyperthermia likely enhances AMPH and METH neurotoxicity directly through disruption of protein function, ion channels and enhanced ROS production. Forebrain neurotoxicity can also be indirectly influenced through the effects of AMPH- and METH- induced hyperthermia on vasculature. The hyperthermia and the hypertension produced by high doses amphetamines are a primary cause of transient breakdowns in the blood-brain barrier (BBB) resulting in concomitant regional neurodegeneration and neuroinflammation in laboratory animals. This BBB breakdown can occur in the amygdala, thalamus, striatum, sensory and motor cortex and hippocampus. Under these conditions, repetitive seizures greatly enhance neurodegeneration in hippocampus, thalamus and amygdala. Even when the BBB is less disrupted, AMPH- or METH- induced hyperthermia effects on brain vasculature may play a role in neurotoxicity. In this case, striatal and cortical vascular function are adversely affected, and even greater ROS, immune and damage responses are seen in the meninges and cortical surface vasculature. Finally, muscle and liver damage and elevated cytokines in blood can result when amphetamines produce hyperthermia. Proteins, from damaged muscle may activate the peripheral immune system and exacerbate liver damage. Liver damage can further increase cytokine levels, immune system activation and increase ammonia levels. These effects could potentially enhance vascular damage and neurotoxicity.

  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. Endoscopic Doppler optical coherence tomography and autofluorescence imaging of peripheral pulmonary nodules and vasculature

    PubMed Central

    Pahlevaninezhad, Hamid; Lee, Anthony M. D.; Ritchie, Alexander; Shaipanich, Tawimas; Zhang, Wei; Ionescu, Diana N.; Hohert, Geoffrey; MacAulay, Calum; Lam, Stephen; Lane, Pierre

    2015-01-01

    We present the first endoscopic Doppler optical coherence tomography and co-registered autofluorescence imaging (DOCT-AFI) of peripheral pulmonary nodules and vascular networks in vivo using a small 0.9 mm diameter catheter. Using exemplary images from volumetric data sets collected from 31 patients during flexible bronchoscopy, we demonstrate how DOCT and AFI offer complementary information that may increase the ability to locate and characterize pulmonary nodules. AFI offers a sensitive visual presentation for the rapid identification of suspicious airway sites, while co-registered OCT provides detailed structural information to assess the airway morphology. We demonstrate the ability of AFI to visualize vascular networks in vivo and validate this finding using Doppler and structural OCT. Given the advantages of higher resolution, smaller probe size, and ability to visualize vasculature, DOCT-AFI has the potential to increase diagnostic accuracy and minimize bleeding to guide biopsy of pulmonary nodules compared to radial endobronchial ultrasound, the current standard of care. PMID:26504665

  5. Peripheral arterial disease: implications beyond the peripheral circulation.

    PubMed

    Paraskevas, Kosmas I; Mukherjee, Debabrata; Whayne, Thomas F

    2013-11-01

    Peripheral arterial disease (PAD) affects a considerable percentage of the population. The manifestations of this disease are not always clinically overt. As a result, PAD remains underdiagnosed and undertreated. PAD is not just a disease of the peripheral arteries, but also an indication of generalized vascular atherosclerosis. PAD patients also have a high prevalence of other arterial diseases, such as coronary/carotid artery disease and abdominal aortic aneurysms. PAD is also a predictor of increased risk of lung and other cancers. The most often used examination for the establishment of the diagnosis of PAD, the ankle-brachial pressure index (ABPI), is also a predictor of generalized atherosclerosis, future cardiovascular events and cardiovascular mortality. Several markers that have been linked with PAD (e.g. C-reactive protein, serum bilirubin levels) may also have predictive value for other conditions besides PAD (e.g. kidney dysfunction). The management of PAD should therefore not be restricted to the peripheral circulation but should include measurements to manage and decrease the systemic atherosclerotic burden of the patient. PMID:23221278

  6. 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.

  7. 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

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

    PubMed

    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. MicroRNA in the Diseased Pulmonary Vasculature: Implications for the Basic Scientist and Clinician

    PubMed Central

    Jin, Richard C.; Min, Pil-Ki; Chan, Stephen Y.

    2015-01-01

    Since the first descriptions of their active functions more than ten years ago, small non-coding RNA species termed microRNA (miRNA) have emerged as essential regulators in a broad range of adaptive and maladaptive cellular processes. With an exceptionally rapid pace of discovery in this field, the dysregulation of many individual miRNAs has been implicated in the development and progression of various cardiovascular diseases. MiRNA are also expected to play crucial regulatory roles in the progression of pulmonary vascular diseases such as pulmonary hypertension (PH), yet direct insights in this field are only just emerging. This review will provide an overview of pulmonary hypertension and its molecular mechanisms, tailored for both basic scientists studying pulmonary vascular biology and physicians who manage PH in their clinical practice. We will describe the pathobiology of pulmonary hypertension and mechanisms of action of miRNA relevant to this disease. Moreover, we will summarize the potential roles of miRNA as biomarkers and therapeutic targets as well as future strategies for defining the cooperative actions of these powerful effectors in pulmonary vascular disease. PMID:26705533

  10. Contrast-enhanced 3D MRA with centric ordering in k space: a preliminary clinical experience in imaging the abdominal aorta and renal and peripheral arterial vasculature.

    PubMed

    Shetty, A N; Bis, K G; Vrachliotis, T G; Kirsch, M; Shirkhoda, A; Ellwood, R

    1998-01-01

    The objective of this study was to determine the clinical utility of a contrast-enhanced, centric reordered, three-dimensional (3D) MR angiography (MRA) pulse sequence in imaging the abdominal aorta and renal and peripheral lower extremity arteries. Twenty-eight MRA studies were performed on 23 patients and four volunteers at 1.5 T using a 3D contrast-enhanced, centric reordered pulse sequence. In 20 patients, the abdominal aorta and renal arteries were imaged, and in seven patients, the lower extremity arteries were imaged. In 19 patients, a total of 51 renal vessels were evaluated (33 renal arteries using .1 mmol/kg of gadopentetate dimeglumine and 18 renal arteries using .2 mmol/kg of gadoteridol). A total of 70 peripheral arterial segments were assessed using .2 mmol/kg of gadoteridol. Correlation with conventional angiography was made for the following 14 cases: renal artery stenosis (four cases), abdominal aortic stenosis (one case), arteriovenous fistula in a transplant kidney (one case), renal arteriovenous malformation (one case), common iliac artery aneurysms (one case), and peripheral lower extremity (six cases). Of the 70 peripheral arterial segments evaluated, in 35, there was correlation with x-ray angiography. The mean percent of aortic signal enhancement was significantly higher in the .2 mmol/kg dose group (370.8 +/- 190.3) than in the .1 mmol/kg dose group (184.5 +/- 128.9) (P = .02). However, there was no apparent difference between the two doses for visualization of the renal and accessory renal arteries. There was concordance between the contrast-enhanced 3D MRA studies and conventional angiography in all cases of renal artery and peripheral arterial stenoses and occlusions, including visualization of reconstituted peripheral arterial segments. There was no evidence of spin dephasing effects at sites of stenoses on the 3D contrast-enhanced MRA studies. Contrast-enhanced, centric reordered, 3D MRA can rapidly image the abdominal aorta and renal

  11. Ergot alkaloids induce vasoconstriction of bovine foregut vasculature

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  12. Peripheral arterial calcification: Prevalence, mechanism, detection, and clinical implications

    PubMed Central

    Rocha-Singh, Krishna J; Zeller, Thomas; Jaff, Michael R

    2014-01-01

    Vascular calcification (VC), particularly medial (Mönckeberg's medial sclerosis) arterial calcification, is common in patients with diabetes mellitus and chronic kidney disease and is associated with increased cardiovascular morbidity and mortality. Although, the underlying pathophysiological mechanisms and genetic pathways of VC are not fully known, hypocalcemia, hyperphosphatemia, and the suppression of parathyroid hormone activity are central to the development of vessel mineralization and, consequently, bone demineralization. In addition to preventive measures, such as the modification of atherosclerotic cardiovascular risk factors, current treatment strategies include the use of calcium-free phosphate binders, vitamin D analogs, and calcium mimetics that have shown promising results, albeit in small patient cohorts. The impact of intimal and medial VC on the safety and effectiveness of endovascular devices to treat symptomatic peripheral arterial disease (PAD) remains poorly defined. The absence of a generally accepted, validated vascular calcium grading scale hampers clinical progress in assessing the safety and utility of various endovascular devices (e.g., atherectomy) in treating calcified vessels. Accordingly, we propose the peripheral arterial calcium scoring system (PACSS) and a method for its clinical validation. A better understanding of the pathogenesis of vascular calcification and the development of optimal medical and endovascular treatment strategies are crucial as the population ages and presents with more chronic comorbidities. PMID:24402839

  13. Central and peripheral pulmonary vascular resistance: Implications for who should undergo pulmonary thromboendarterectomy.

    PubMed

    Poullis, Mike

    2015-08-01

    Pulmonary thromboendarterectomy remains a technically challenging procedure with variable outcomes with regard to improvement in pulmonary function. Reducing the resistance to flow between the pulmonary valve and the pulmonary capillary bed is the key aim of surgery. The resistance to flow is due to the combination of resistance due to the central clot and distal capillary resistance. We hypothesise that the use of fluid mechanics in combination with modern radiology and electronic circuit theory can potentially predict who should or should not undergo a thromboendarterectomy. Electronic circuit theory of two resistors in series was utilised to demonstrate the concept of a model of a central clot and the peripheral pulmonary capillary bed. A simplified 2D model of the lungs utilising finite element analysis and Poiseuille's law was constructed for proof of principle. Modelling predicts that cardiac output and anatomical obstruction interplay and can have profound effects on the outcomes after thromboendarterectomy. Identical pulmonary artery pressures, due to differing cardiac outputs and identical anatomical obstructions due to thrombus can have very different physiological outcomes with regard to changes in pulmonary artery pressure. Modelling the pulmonary vasculature to determine central and peripheral pulmonary vascular resistance may help in predicting who should undergo pulmonary thromboendarterectomy. Mathematical modelling can potentially predict which patients have haemodynamically significant clots in their pulmonary arteries that thromboendarterectomy may potentially help in the setting of pulmonary capillary disease. PMID:25997984

  14. Ghrelin: central and peripheral implications in anorexia nervosa.

    PubMed

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

    2013-01-01

    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

  15. 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

  16. Clinical implication of ocular torsion in peripheral vestibulopathy.

    PubMed

    Choi, Jin Woong; Kang, Seong Il; Rhee, Ji Hye; Choi, Byung Yoon; Choi, Byeong Yoon; Kim, Ji-Soo; Koo, Ja-Won

    2015-07-01

    Acute unilateral vestibular loss presents as ocular torsion (OT) and caloric unilateral weakness (UW). However, the amount of OT is frequently dissociated from UW depending on when the examination was performed and the extent and cause of the vestibular lesion. This study evaluated the relationship between OT and UW in peripheral vestibular diseases, including Ménière's disease (MD) and vestibular neuritis (VN), and determined whether it contributed to OT as a means of differentiating between the two diseases. A retrospective chart review was performed in 64 patients with VN and 67 patients with MD. We divided the patients into three groups according to the interval from symptom onset to when the tests were performed: within 7 (group A), from 8 to 30 (group B) and over 30 (group C) days. UW, OT and the chronological correlation/dissociation between the two parameters were analyzed. For the 64 patients with VN, the degree of OT and severity of UW were positively correlated in group A (r = 0.749, P < 0.001). OT and UW were significantly dissociated with time (P < 0.001). For the 67 patients with MD, no correlation between the degree of OT and severity of UW was seen in MD group A. No significant dissociation change was revealed among the groups (P = 0.114). The OT abnormality is remarkable during the acute phase of VN, whereas it might not be remarkable immediately after a vertigo attack in MD. This finding can be used to differentiate MD and VN, especially when no definite hearing loss is seen or VN recurs. PMID:24609644

  17. Clinical implications of peripheral myelin protein 22 for nerve compression and neural regeneration: a review.

    PubMed

    Hui-Chou, Helen G; Hashemi, Sharyhar S; Hoke, Ahmet; Dellon, A Lee

    2011-01-01

    Peripheral myelin protein 22 (PMP22) is a major component of the peripheral myelin sheath. The PMP22 gene is located on chromosome 17p11.2, and defects in PMP22 gene have been implicated in several common inherited peripheral neuropathies. Hereditary neuropathy with liability to pressure palsies (HNPP), Charcot-Marie Tooth disease type 1A (CMT1A), Dejerine-Sottas syndrome, and congenital hypomyelinating neuropathy are all associated with defects in PMP22 gene. The disease phenotypes mirror the range of expression of PMP22 due to the corresponding genetic defect. HNPP, characterized by a milder recurrent episodic focal demyelinating neuropathy, is attributed to a deletion leading to PMP22 underexpression. On the other end of the spectrum, CMT1A leads to a more uniform demyelination and axonal loss, resulting in severe progressive distal weakness and paresthesias; it is due to a duplication at 17p11.2 leading to PMP22 overexpression. Additional point mutations result in varying phenotypes due to dysfunction of the resultant PMP22 protein. All inherited neuropathies are diagnosed with a combination of physical findings on examination, electromyography, sural nerve biopsies, and genetic testing. Treatment and management of these disorders differ depending on the underlying genetic defect, nerves involved, and resulting functional impairments. A review of current literature elucidates clinical, microsurgical implications, and management of patients with PMP22-related neuropathy. PMID:20976668

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  19. An Interdependent Model of Central/Peripheral Chemoreception: Evidence and Implications for Ventilatory Control

    PubMed Central

    Smith, Curtis A.; Forster, Hubert V.; Blain, Grégory M.; Dempsey, Jerome A.

    2010-01-01

    In this review we discuss the implications for ventilatory control of newer evidence suggesting that central and peripheral chemoreceptors are not functionally separate but rather that they are dependent upon one another such that the sensitivity of the medullary chemoreceptors is critically determined by input from the carotid body chemoreceptors and vice versa i.e., they are interdependent. We examine potential interactions of the interdependent central and carotid body (CB) chemoreceptors with other ventilatory-related inputs such as central hypoxia, lung stretch, and exercise. The limitations of current approaches addressing this question are discussed and future studies are suggested. PMID:20206717

  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

    2015-04-01

    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. PMID:25637801

  1. Age-dependent changes in Ca2+ homeostasis in peripheral neurones: implications for changes in function.

    PubMed

    Buchholz, John N; Behringer, Erik J; Pottorf, William J; Pearce, William J; Vanterpool, Conwin K

    2007-06-01

    Calcium ions represent universal second messengers within neuronal cells integrating multiple cellular functions, such as release of neurotransmitters, gene expression, proliferation, excitability, and regulation of cell death or apoptotic pathways. The magnitude, duration and shape of stimulation-evoked intracellular calcium ([Ca2+]i) transients are determined by a complex interplay of mechanisms that modulate stimulation-evoked rises in [Ca2+]i that occur with normal neuronal function. Disruption of any of these mechanisms may have implications for the function and health of peripheral neurones during the aging process. This review focuses on the impact of advancing age on the overall function of peripheral adrenergic neurones and how these changes in function may be linked to age-related changes in modulation of [Ca2+]i regulation. The data in this review suggest that normal aging in peripheral autonomic neurones is a subtle process and does not always result in dramatic deterioration in their function. We present studies that support the idea that in order to maintain cell viability peripheral neurones are able to compensate for an age-related decline in the function of at least one of the neuronal calcium-buffering systems, smooth endoplasmic reticulum calcium ATPases, by increased function of other calcium-buffering systems, namely, the mitochondria and plasmalemma calcium extrusion. Increased mitochondrial calcium uptake may represent a 'weak point' in cellular compensation as this over time may contribute to cell death. In addition, we present more recent studies on [Ca2+]i regulation in the form of the modulation of release of calcium from smooth endoplasmic reticulum calcium stores. These studies suggest that the contribution of the release of calcium from smooth endoplasmic reticulum calcium stores is altered with age through a combination of altered ryanodine receptor levels and modulation of these receptors by neuronal nitric oxide containing neurones

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  3. 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

  4. [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. PMID:11002897

  5. Developmental angiogenesis: quail embryonic vasculature.

    PubMed

    Poole, T J; Coffin, J D

    1988-03-01

    We have examined the segregation and early morphogenesis of the embryonic vasculature by using a monoclonal antibody for immunofluorescence and by scanning electron microscopy. This antibody labels the presumptive endothelial cells (PECs) as they segregate from mesoderm. Similar embryos prepared for SEM revealed finer details of how these segregated cells interact to form the rudiments of the major blood vessels. Here we concentrate on the development of the dorsal aortae and the posterior cardinal veins. The dorsal aortae form from single PECs which segregate from the lateral mesoderm and aggregate into a loose cord ventral to the somites. These cells become more closely associated and a lumen forms. The posterior cardinal veins form from a loose plexus of cells segregated from the lateral mesoderm on its dorsal surface. These cells become intimately associated with the Wolffian ducts. PMID:3285464

  6. Tumour vasculature--a potential therapeutic target.

    PubMed Central

    Baillie, C. T.; Winslet, M. C.; Bradley, N. J.

    1995-01-01

    The tumour vasculature is vital for the establishment, growth and metastasis of solid tumours. Its physiological properties limit the effectiveness of conventional anti-cancer strategies. Therapeutic approaches directed at the tumour vasculature are reviewed, suggesting the potential of anti-angiogenesis and the targeting of vascular proliferation antigens as cancer treatments. PMID:7543770

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

    PubMed

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

    2014-11-01

    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 Ca(2+) 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

  8. 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

  9. 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.

  10. LOWER EXTREMITY MANIFESTATIONS OF PERIPHERAL ARTERY DISEASE: THE PATHOPHYSIOLOGIC AND FUNCTIONAL IMPLICATIONS OF LEG ISCHEMIA

    PubMed Central

    McDermott, Mary McGrae

    2015-01-01

    Lower extremity peripheral artery disease (PAD) is frequently under-diagnosed, in part because of the wide variety of leg symptoms manifested by patients with PAD and in part because of the high prevalence of asymptomatic PAD. In primary care medical practices, 30% to 60% of PAD patients report no exertional leg symptoms and approximately 45–50% report exertional leg symptoms that are not consistent with classic intermittent claudication. The prevalence and extent of functional impairment and functional decline in PAD may also be underappreciated. Functional impairment and functional decline is common in PAD, even among those who are asymptomatic. Lower extremity ischemia is also associated with pathophysiologic changes in calf skeletal muscle including smaller calf muscle area, increased calf muscle fat content, impaired leg strength, and impaired metabolic function. People with severe PAD have poorer peroneal nerve conduction velocity compared to people with mild PAD or no PAD. The degree of ischemia-related pathophysiologic changes in lower extremity muscles and peripheral nerves of people with PAD are associated with the degree of functional impairment. New interventions are needed to improve functional performance and prevent mobility loss in the large number of PAD patients, including in those who are asymptomatic or who have exertional leg symptoms other than claudication. PMID:25908727

  11. The Toll of Vascular Insufficiency: Implications for the Management of Peripheral Arterial Disease

    PubMed Central

    Xu, Jun; Sachdev, Ulka

    2016-01-01

    Peripheral artery disease (PAD) can result in limb loss within six months of diagnosis in a subset of patients who cannot undergo endovascular or surgical revascularization yet continues to maintain a marginal position in cardiovascular research. While a body of literature continues to grow describing the role of danger signaling and innate immunity in cardiac biology, the role of these pathways in the ischemic myopathy associated with PAD has not been extensively studied. The following report will review the current literature on the role of Toll-like receptor (TLR) signaling in cardiovascular biology as well as in nonischemic myopathy. While attenuation of TLR signaling has not been shown to be clinically useful in the treatment of infectious inflammation, it may show promise in the management of severe arterial insufficiency. PMID:26998496

  12. 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

  13. Productive Infection of Human Peripheral Blood Mononuclear Cells by Feline Immunodeficiency Virus: Implications for Vector Development

    PubMed Central

    Johnston, James; Power, Christopher

    1999-01-01

    Feline immunodeficiency virus (FIV) is a lentivirus causing immune suppression and neurological disease in cats. Like primate lentiviruses, FIV utilizes the chemokine receptor CXCR4 for infection. In addition, FIV gene expression has been demonstrated in immortalized human cell lines. To investigate the extent and mechanism by which FIV infected primary and immortalized human cell lines, we compared the infectivity of two FIV strains, V1CSF and Petaluma, after cell-free infection. FIV genome was detected in infected human peripheral blood mononuclear cells (PBMC) and macrophages at 21 and 14 days postinfection, respectively. Flow cytometry analysis of FIV-infected human PBMC indicated that antibodies to FIV p24 recognized 12% of the cells. Antibodies binding the CCR3 chemokine receptor maximally inhibited infection of human PBMC by both FIV strains compared to antibodies to CXCR4 or CCR5. Reverse transcriptase levels increased in FIV-infected human PBMC, with detection of viral titers of 101.3 to 102.1 50% tissue culture infective doses/106 cells depending on the FIV strain examined. Cell death in human PBMC infected with either FIV strain was significantly elevated relative to uninfected control cultures. These findings indicate that FIV can productively infect primary human cell lines and that viral strain specificity should be considered in the development of an FIV vector for gene therapy. PMID:9971834

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

    PubMed Central

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

    2013-01-01

    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 of limb-state 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. PMID:21878419

  15. 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. PMID:24332017

  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. 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

  18. Nonclassical patrolling monocyte function in the vasculature.

    PubMed

    Thomas, Graham; Tacke, Robert; Hedrick, Catherine C; Hanna, Richard N

    2015-06-01

    Nonclassical patrolling monocytes are characterized by their unique ability to actively patrol the vascular endothelium under homeostatic and inflammatory conditions. Patrolling monocyte subsets (CX3CR1(high)Ly6C(-) in mouse and CX3CR1(high)CD14(dim)CD16(+) in humans) are distinct from the classical monocyte subsets (CCR2(high)Ly6C(+) in mouse and CCR2(high)CD14(+)CD16(-) in humans) and exhibit unique functions in the vasculature and inflammatory disease. Patrolling monocytes function in several 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

  19. Peripheral Neuropathy

    MedlinePlus

    ... Enhancing Diversity Find People About NINDS NINDS Peripheral Neuropathy Information Page Condensed from Peripheral Neuropathy Fact Sheet ... Español Additional resources from MedlinePlus What is Peripheral Neuropathy? Peripheral neuropathy describes damage to the peripheral nervous ...

  20. Developmental conditioning of the vasculature.

    PubMed

    Clough, Geraldine F

    2015-01-01

    There is increasing evidence from epidemiological and experimental animal studies that the early life environment, of which nutrition is a key component, acts through developmental adaptive responses to set the capacity of cardiovascular and metabolic pathways to respond to physiological and pathophysiological challenges in later life. One finding that is consistent to both population studies and animal models is the propensity for such effects to induce endothelial dysfunction throughout the vascular tree, including the microvasculature. Obesity, type 2 diabetes and hypertension are associated with changes in microvascular function affecting multiple tissues and organs. These changes may be detected early, often before the onset of macrovascular disease and the development of end organ damage. Suboptimal maternal nutrition and fetal growth result in reduced microvascular perfusion and functional dilator capacity in the offspring, which together with microvascular rarefaction and remodeling serve to limit capillary recruitment, reduce exchange capacity and increase diffusion distances of metabolic substrates; they also increase local and overall peripheral resistance. This article explores how a developmentally conditioned disadvantageous microvascular phenotype may represent an important and additional risk factor for increased susceptibility to the development of cardio-metabolic disease in adult life and considers the cell signaling pathways associated with microvascular dysfunction that may be "primed" by the maternal environment. As the microvasculature has been shown to be a potential target for early therapeutic and lifestyle intervention, this article also considers evidence for the efficacy of such strategies in humans and in animal models of the developmental origins of health and disease. PMID:25589274

  1. Functional implications of the localization and activity of acid-sensitive channels in rat peripheral nervous system

    PubMed Central

    Alvarez de la Rosa, Diego; Zhang, Ping; Shao, Deren; White, Fletcher; Canessa, Cecilia M.

    2002-01-01

    Acid-sensitive ion channels (ASIC) are proton-gated ion channels expressed in neurons of the mammalian central and peripheral nervous systems. The functional role of these channels is still uncertain, but they have been proposed to constitute mechanoreceptors and/or nociceptors. We have raised specific antibodies for ASIC1, ASIC2, ASIC3, and ASIC4 to examine the distribution of these proteins in neurons from dorsal root ganglia (DRG) and to determine their subcellular localization. Western blot analysis demonstrates that all four ASIC proteins are expressed in DRG and sciatic nerve. Immunohistochemical experiments and functional measurements of unitary currents from the ASICs with the patch–clamp technique indicate that ASIC1 localizes to the plasma membrane of small-, medium-, and large-diameter cells, whereas ASIC2 and ASIC3 are preferentially in medium to large cells. Neurons coexpressing ASIC2 and ASIC3 form predominantly heteromeric ASIC2–3 channels. Two spliced forms, ASIC2a and ASIC2b, colocalize in the same population of DRG neurons. Within cells, the ASICs are present mainly on the plasma membrane of the soma and cellular processes. Functional studies indicate that the pH sensitivity for inactivation of ASIC1 is much higher than the one for activation; hence, increases in proton concentration will inactivate the channel. These functional properties and localization in DRG have profound implications for the putative functional roles of ASICs in the nervous system. PMID:11842212

  2. Functional implications of the localization and activity of acid-sensitive channels in rat peripheral nervous system.

    PubMed

    Alvarez de la Rosa, Diego; Zhang, Ping; Shao, Deren; White, Fletcher; Canessa, Cecilia M

    2002-02-19

    Acid-sensitive ion channels (ASIC) are proton-gated ion channels expressed in neurons of the mammalian central and peripheral nervous systems. The functional role of these channels is still uncertain, but they have been proposed to constitute mechanoreceptors and/or nociceptors. We have raised specific antibodies for ASIC1, ASIC2, ASIC3, and ASIC4 to examine the distribution of these proteins in neurons from dorsal root ganglia (DRG) and to determine their subcellular localization. Western blot analysis demonstrates that all four ASIC proteins are expressed in DRG and sciatic nerve. Immunohistochemical experiments and functional measurements of unitary currents from the ASICs with the patch-clamp technique indicate that ASIC1 localizes to the plasma membrane of small-, medium-, and large-diameter cells, whereas ASIC2 and ASIC3 are preferentially in medium to large cells. Neurons coexpressing ASIC2 and ASIC3 form predominantly heteromeric ASIC2-3 channels. Two spliced forms, ASIC2a and ASIC2b, colocalize in the same population of DRG neurons. Within cells, the ASICs are present mainly on the plasma membrane of the soma and cellular processes. Functional studies indicate that the pH sensitivity for inactivation of ASIC1 is much higher than the one for activation; hence, increases in proton concentration will inactivate the channel. These functional properties and localization in DRG have profound implications for the putative functional roles of ASICs in the nervous system. PMID:11842212

  3. Peripheral neuropathy

    MedlinePlus

    Peripheral neuritis; Neuropathy - peripheral; Neuritis - peripheral; Nerve disease; Polyneuropathy ... Neuropathy is very common. There are many types and causes. Often, no cause can be found. Some ...

  4. 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

  5. Experimental splenosis in the liver and lung spread through the vasculature.

    PubMed

    Seguchi, S; Yue, F; Asanuma, K; Sasaki, K

    2015-05-01

    To demonstrate that intra-organ splenosis can engraft and develop after being distributed through the vasculature, tiny fragments of splenic tissues were injected into the inferior vena cava or the portal vein to induce intrapulmonary and intrahepatic splenosis in rats. After 1 month, splenic autograft structures in the lung and liver were assessed for structure by histology, for immunologic compartments by immunohistochemistry, for phagocytic function by carbon uptake and for vascular formation by Microfil (a silicon rubber compound) injection. Intrapulmonary and intrahepatic splenoses were indeed able to spread through the vasculature. The intrapulmonary splenic autografts were trapped and spread out in the interstitium, without forming a capsule. White pulp was markedly developed, showing lymphocyte aggregations that consisted in B cells surrounding the dilated vessel. Splenic sinuses were not definitively observed. Although macrophages were detected by immunohistochemistry, they showed no indication of having phagocytized carbon particles from the vessels, implying a closed circulation. In contrast, intrahepatic splenic autografts formed well-developed capsules, trabeculae and red pulp with splenic sinuses. Macrophages detected by immunohistochemistry were observed capturing carbon particles, which clearly revealed an open system circulation, as seen in normal rat spleen. The development of white pulp was poor and lymphocytes consisting in B cells aggregated in the peripheral margins. These results demonstrate that intra-organ splenosis can spread through the vasculature and that the morphologic and immunologic structures formed in these regenerated autografts are influenced by the organ vasculature and extracellular matrix wherein the tissue fragments settled. PMID:25526699

  6. Popliteal vasculature injuries in paediatric trauma patients.

    PubMed

    Jones, S A; Roberts, D C; Clarke, N M P

    2012-10-01

    Popliteal-artery injuries in the paediatric-trauma patient are uncommon, difficult to diagnose and with prolonged ischaemia lead to substantial complications. We report three cases of popliteal-vasculature injury in paediatric-trauma patients with diverse mechanisms of injury: blunt trauma, penetrating injury and a Salter-Harris I fracture. We present a range of the significant sequelae that can result from paediatric popliteal-artery injury, both physically and psychologically. It is imperative that clinicians have a high index of suspicion when confronted with paediatric patients with trauma around the knee and that popliteal-vasculature injuries are diagnosed early. If insufficiencies are detected, further imaging should be considered, but surgical exploration should not be delayed in the presence of ischaemia. PMID:22776610

  7. Diagnostic angiography of the cerebrospinal vasculature.

    PubMed

    Rabinov, James D; Leslie-Mazwi, Thabele M; Hirsch, Joshua A

    2016-01-01

    Diagnostic catheter angiography remains the gold standard for evaluation of vascular lesions of the brain, head and neck, and spine. It is often combined with cross-sectional and functional imaging to provide a complete anatomic and physiologic workup of patients. Such data are combined with clinical information to help make treatment decisions. This chapter describes the specific techniques for arterial access and catheter navigation of the cerebrospinal vasculature. Discussion of patient positioning, injection rates, and basic anatomy of arterial and venous systems is included. Finally, important safety issues related to contrast allergy, renal failure, and complications are considered. PMID:27432664

  8. Regulation of the ovarian follicular vasculature

    PubMed Central

    Fraser, Hamish M

    2006-01-01

    Angiogenesis is associated with follicular development and is regulated independently within each follicle potentially making the functioning of its vasculature critically important in determining its fate. This review examines the various ways in which follicular angiogenesis may be monitored, describes the follicular localisation and changes in pro- and anti-angiogenic factors that may regulate the process and how antagonists may be used to elucidate their physiological role in vivo. Thus, inhibition of vascular endothelial growth factor (VEGF), VEGF receptor-2, vascular endothelial cell cadherin or interference with the angiopoietin system can inhibit follicular development or prevent ovulation. PMID:16611363

  9. 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. PMID:27028849

  10. Role of vasculature in atopic dermatitis.

    PubMed

    Steinhoff, Martin; Steinhoff, Antje; Homey, Bernhard; Luger, Thomas A; Schneider, Stefan W

    2006-07-01

    Atopic dermatitis (AD) lesions are characterized by differences in the activation state of endothelial cells and vascular smooth muscle cells and the release of inflammatory mediators by and toward the vasculature. The vascular system, including endothelial cells and smooth muscle cells, is ultimately involved in clinical symptoms of AD, such as erythema, edema, leukocyte recruitment, and white dermographism. Various mediators and bidirectional neurovascular interactions regulate the inflammatory response during AD. T cell-endothelial cell interactions are a crucial component to establish acute AD. Various immune cells, including monocytes and mast cells, communicate with the endothelium by releasing inflammatory mediators, thereby stimulating inflammatory mediator release from activated endothelial cells. The process of adhesion, tethering, and transmigration of infiltrating cells is a highly regulated and an active communication process between endothelial cells and leukocytes. Endothelial cells play a pivotal role in the pathophysiology of AD and represent future targets for the treatment of AD. PMID:16815154

  11. 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

  12. 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

  13. 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

  14. Effector lymphocyte-induced lymph node-like vasculature enables naïve T-cell entry into tumors and enhanced anti-tumor immunity

    PubMed Central

    Peske, J. David; Thompson, Elizabeth D.; Gemta, Lelisa; Baylis, Richard A.; Fu, Yang-Xin; Engelhard, Victor H.

    2015-01-01

    The presence of lymph node (LN)-like vasculature in tumors, characterized by expression of peripheral node addressin and chemokine CCL21, is correlated with T-cell infiltration and positive prognosis in breast cancer and melanoma patients. However, mechanisms controlling the development of LN-like vasculature and how it might contribute to a beneficial outcome for cancer patients are unknown. Here we demonstrate that LN-like vasculature is present in murine models of melanoma and lung carcinoma. It enables infiltration by naïve T-cells that significantly delay tumor outgrowth after intratumoral activation. Development of this vasculature is controlled by a mechanism involving effector CD8 T-cells and NK cells that secrete LTα3 and IFNγ. LN-like vasculature is also associated with organized aggregates of B-lymphocytes and gp38+ fibroblasts that resemble tertiary lymphoid organs that develop in models of chronic inflammation. These results establish LN-like vasculature as both a consequence of and key contributor to anti-tumor immunity. PMID:25968334

  15. Effector lymphocyte-induced lymph node-like vasculature enables naive T-cell entry into tumours and enhanced anti-tumour immunity.

    PubMed

    Peske, J David; Thompson, Elizabeth D; Gemta, Lelisa; Baylis, Richard A; Fu, Yang-Xin; Engelhard, Victor H

    2015-01-01

    The presence of lymph node (LN)-like vasculature in tumours, characterized by expression of peripheral node addressin and chemokine CCL21, is correlated with T-cell infiltration and positive prognosis in breast cancer and melanoma patients. However, mechanisms controlling the development of LN-like vasculature and how it might contribute to a beneficial outcome for cancer patients are unknown. Here we demonstrate that LN-like vasculature is present in murine models of melanoma and lung carcinoma. It enables infiltration by naive T cells that significantly delay tumour outgrowth after intratumoral activation. Development of this vasculature is controlled by a mechanism involving effector CD8 T cells and NK cells that secrete LTα3 and IFNγ. LN-like vasculature is also associated with organized aggregates of B lymphocytes and gp38(+) fibroblasts, which resemble tertiary lymphoid organs that develop in models of chronic inflammation. These results establish LN-like vasculature as both a consequence of and key contributor to anti-tumour immunity. PMID:25968334

  16. The choroid plexus is modulated by various peripheral stimuli: implications to diseases of the central nervous system

    PubMed Central

    Marques, Fernanda; Sousa, João C.

    2015-01-01

    The blood brain barrier (BBB) and the blood cerebrospinal fluid barrier (BCSFB) form the barriers of the brain. These barriers are essential not only for the protection of the brain, but also in regulating the exchange of cells and molecules in and out of the brain. The choroid plexus (CP) epithelial cells and the arachnoid membrane form the BCSFB. The CP is structurally divided into two independent compartments: one formed by a unique and continuous line of epithelial cells that rest upon a basal lamina; and, a second consisting of a central core formed by connective and highly vascularized tissue populated by diverse cell types (fibroblasts, macrophages and dendritic cells). Here, we review how the CP transcriptome and secretome vary depending on the nature and duration of the stimuli to which the CP is exposed. Specifically, when the peripheral stimulation is acute the CP response is rapid, strong and transient, whereas if the stimulation is sustained in time the CP response persists but it is weaker. Furthermore, not all of the epithelium responds at the same time to peripheral stimulation, suggesting the existence of a synchrony system between individual CP epithelial cells. PMID:26236190

  17. 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. PMID:26114426

  18. Mathematical modeling of light-mediated HPA axis activity and downstream implications on the entrainment of peripheral clock genes.

    PubMed

    Mavroudis, Panteleimon D; Corbett, Siobhan A; Calvano, Steven E; Androulakis, Ioannis P

    2014-10-15

    In this work we propose a semimechanistic model that describes the photic signal transduction to the hypothalamic-pituitary-adrenal (HPA) axis that ultimately regulates the synchronization of peripheral clock genes (PCGs). Our HPA axis model predicts that photic stimulation induces a type-1 phase response curve to cortisol's profile with increased cortisol sensitivity to light exposure in its rising phase, as well as the shortening of cortisol's period as constant light increases (Aschoff's first rule). Furthermore, our model provides insight into cortisol's phase and amplitude dependence on photoperiods and reveals that cortisol maintains highest amplitude variability when it is entrained by a balanced schedule of light and dark periods. Importantly, by incorporating the links between HPA axis and PCGs we were able to investigate how cortisol secretion impacts the entrainment of a population of peripheral cells and show that disrupted light schedules, leading to blunted cortisol secretion, fail to synchronize a population of PCGs which further signifies the loss of circadian rhythmicity in the periphery of the body. PMID:25073602

  19. Cocaine Constrictor Mechanisms of the Cerebral Vasculature.

    PubMed

    Rapoport, Robert M; Yoon, SeongHun; Zuccarello, Mario

    2016-05-01

    Cocaine constriction of the cerebral vasculature is thought to contribute to the ischemia associated with cocaine use. However, the mechanisms whereby cocaine elicits relevant vasoconstriction remain elusive. Indeed, proposed intra- and intercellular mechanisms based on over 3 decades of ex vivo vascular studies are, for the most part, of questionable relevancy due to the generally low contractile efficacy of cocaine combined with the use of nonresistance-type vessels. Furthermore, the significance attached to mechanisms derived from in vivo animal studies may be limited by the inability to demonstrate cocaine-induced decreased cerebral blood flow, as observed in (awake) humans. Despite these apparent limitations, we surmise that the vasoconstriction relevant to cocaine-induced ischemia is elicited by inhibition of dilator and activation of constrictor pathways because of cocaine action on the neurovascular unit (neuron, astrocyte, and vessel) and on vessels outside the unit. Furthermore, previous cocaine exposure, that is, conditions present in human subjects, downregulates and sensitizes these dilator and constrictor pathways, respectively, thereby enhancing constriction to acute cocaine. Identification of specific intra- and intercellular mechanisms requires investigations in the isolated microvasculature and the neurovascular unit from species chronically exposed to cocaine and in which cocaine decreases cerebral blood flow. PMID:26771152

  20. MR for the investigation of murine vasculature.

    PubMed

    Jacoby, Christoph; Flögel, Ulrich

    2011-01-01

    The investigation of alterations in vessel morphology of transgenic mouse models generally requires time-consuming and laborious planimetry of histological sections. This postmortem analysis is per se restricted to endpoint studies and, furthermore, may reflect the situation in vivo to a limited degree only. For the repetitive and noninvasive monitoring of dynamic changes in the murine vasculature, several protocols for high-resolution 3D MR angiography (MRA) at a vertical 9.4 T system are described. These protocols are based on flow-compensated 3D gradient echo sequences with application-dependent spatial resolution, resulting in voxel sizes between 1 and 13 nL. To ensure constant physiological conditions, particular attention is paid to minimize the acquisition time. All measurements are carried out without a contrast agent to avoid temporal inconstancy of the contrast-to-noise-ratio (CNR) as well as toxic side effects. Moreover, metabolic alterations as a consequence of disturbed vascularization and blood supply are monitored by (31)P MR spectroscopy. PMID:21874492

  1. 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.

  2. Thioaptamer Conjugated Liposomes for Tumor Vasculature Targeting

    PubMed Central

    Mann, Aman P.; Bhavane, Rohan C.; Somasunderam, Anoma; Montalvo-Ortiz, Brenda Liz; Ghaghada, Ketan B.; Volk, David; Nieves-Alicea, René; Suh, K. Stephen; Ferrari, Mauro; Annapragada, Ananth; Gorenstein, David G.; Tanaka, Takemi

    2011-01-01

    Recent developments in multi-functional nanoparticles offer a great potential for targeted delivery of therapeutic compounds and imaging contrast agents to specific cell types, in turn, enhancing therapeutic effect and minimizing side effects. Despite the promise, site specific delivery carriers have not been translated into clinical reality. In this study, we have developed long circulating liposomes with the outer surface decorated with thioated oligonucleotide aptamer (thioaptamer) against E-selectin (ESTA) and evaluated the targeting efficacy and PK parameters. In vitro targeting studies using Human Umbilical Cord Vein Endothelial Cell (HUVEC) demonstrated efficient and rapid uptake of the ESTA conjugated liposomes (ESTA-lip). In vivo, the intravenous administration of ESTA-lip resulted in their accumulation at the tumor vasculature of breast tumor xenografts without shortening the circulation half-life. The study presented here represents an exemplary use of thioaptamer for targeting and opens the door to testing various combinations of thioaptamer and nanocarriers that can be constructed to target multiple cancer types and tumor components for delivery of both therapeutics and imaging agents. PMID:21666286

  3. 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

  4. 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.

  5. SCN9A Variants May be Implicated in Neuropathic Pain Associated With Diabetic Peripheral Neuropathy and Pain Severity

    PubMed Central

    Cheng, Peter; Favis, Reyna; Wickenden, Alan; Romano, Gary; Wang, Hao

    2015-01-01

    Objectives: Previous studies have established the role of SCN9A in various pain conditions, including idiopathic small fiber neuropathy. In the present study, we interrogate the relationship between common and rare variants in SCN9A gene and chronic neuropathic pain associated with diabetic peripheral neuropathy. Design: Using a cohort of 938 patients of European ancestry with chronic neuropathic pain associated with diabetic peripheral neuropathy enrolled in 6 clinical studies and 2 controls (POPRES, n=2624 and Coriell, n=1029), we examined the relationship between SCN9A variants and neuropathic pain in a case-control study using a 2-stage design. The exonic regions of SCN9A were sequenced in a subset of 244 patients with neuropathic pain, and the variants discovered were compared with POPRES control (stage 1). The top associated variants were followed up by genotyping in the entire case collection and Coriell controls restricting the analysis to the matching patients from the United States and Canada only (stage 2). Results: Seven variants were found to be associated with neuropathic pain at the sequencing stage. Four variants (Asp1908Gly, Val991Leu/Met932Leu, and an intronic variant rs74449889) were confirmed by genotyping to occur at a higher frequency in cases than controls (odds ratios ∼2.1 to 2.6, P=0.05 to 0.009). Val991Leu/Met932Leu was also associated with the severity of pain as measured by pain score Numeric Rating Scale (NRS-11, P=0.047). Val991Leu/Met932Leu variants were in complete linkage disequilibrium and previously shown to cause hyperexcitability in dorsal root ganglia neurons. Conclusions: The association of SCN9A variants with neuropathic pain and pain severity suggests a role of SCN9A in the disease etiology of neuropathic pain. PMID:25585270

  6. Simultaneous segmentation and anatomical labeling of the cerebral vasculature.

    PubMed

    Robben, David; Türetken, Engin; Sunaert, Stefan; Thijs, Vincent; Wilms, Guy; Fua, Pascal; Maes, Frederik; Suetens, Paul

    2016-08-01

    We present a novel algorithm for the simultaneous segmentation and anatomical labeling of the cerebral vasculature. Unlike existing approaches that first attempt to obtain a good segmentation and then perform labeling, we optimize for both by simultaneously taking into account the image evidence and the prior knowledge about the geometry and connectivity of the vasculature. This is achieved by first constructing an overcomplete graph capturing the vasculature, and then selecting and labeling the subset of edges that most likely represents the true vasculature. We formulate the latter problem as an Integer Program (IP), which can be solved efficiently to provable optimality. We evaluate our approach on a publicly available dataset of 50 cerebral MRA images, and demonstrate that it compares favorably against state-of-the-art methods. PMID:27131026

  7. Non-Physiologic Blood Flow Triggers Endothelial and Arterial Remodeling In Vivo: Implications for Novel LVADs with a Peripheral Anastomosis

    PubMed Central

    Bartoli, Carlo R.; Spence, Paul A.; Siess, Thorsten; Raess, Daniel H.; Koenig, Steven C.; Dowling, Robert D.

    2014-01-01

    Introduction Less-invasive circulatory support devices have been developed that require anastomosis to a peripheral artery. The Symphony Heart Assist System is a volume displacement pump sewn to the subclavian artery to provide partial circulatory support. The surgical configuration produces non-physiologic blood pressure and bidirectional flow in the subclavian artery. Our objective was to identify effects of altered hemodynamics on arterial structure and function. Methods In calves (n=23, 80-100kg), the Symphony pump was sewn end-to-side to the carotid artery. Acutely, carotid blood pressure and flow were recorded to evaluate hemodynamic changes. After medium-term support (1-4 weeks), carotid artery cross sections were studied. Histology and molecular assays evaluated architectural changes. Quantitative real-time PCR evaluated gene expression of matrix metalloproteinase (MMP)-2 and MMP-9 and connective tissue growth factor (CTGF). In vitro carotid arterial-ring studies evaluated physiological responses. Results During Symphony support, carotid arterial pressure was 200/15mmHg. Antegrade flow increased significantly (p<0.05) from 1.40±0.32 to 4.29±0.33L/min. Flow during native cardiac diastole reversed completely from 0.25±0.05 to -4.15±0.38L/min in carotid artery proximal to the anastomosis. After medium-term support, the carotid artery was significantly dilated with significantly thinner tunica media and thicker tunica adventitia versus controls. MMP-9 gene expression decreased significantly, CTGF gene expression increased significantly, and collagen, elastin, and total extracellular matrix increased significantly. Endothelial cells were significantly hypertrophied and produced significantly more von Willebrand factor. Endothelial apoptosis increased significantly. Platelet-endothelial interactions decreased significantly. Endothelial-independent contraction decreased significantly, whereas endothelial-dependant relaxation increased modestly. Conclusions

  8. Comparison of the function of the serotonin transporter in the vasculature of male and female rats.

    PubMed

    Linder, Aurea Elizabeth; Davis, Robert Patrick; Burnett, Robert; Watts, Stephanie W

    2011-05-01

    1. The serotonin transporter (SERT) handles serotonin (5-hydroxytryptamine (5-HT)) and is blocked by the antidepressant SERT inhibitors fluoxetine and fluvoxamine. Although the importance of SERT in the central nervous system is clear, SERT also functions in the peripheral vasculature. In the present study, we tested the hypothesis that the vasculature from female rats has increased SERT function compared with male rats because females are more responsive to SERT inhibitors. 2. In addition to in vitro experiments, in vivo experiments were used to evaluate how male and female rats handle chronically elevated levels of 5-HT. Wild-type (WT) and SERT-knockout (SERT-KO) rats were infused with 5-HT (25 μg/kg per min) for 7 days by minipump. 3. Using HPLC analysis, we demonstrated that blood vessels (aorta, carotid artery, jugular vein and vena cava) from naïve, non-infused female rats took up 5-HT acutely in vitro in a SERT-dependent manner. In in vitro experiments, SERT affected the contractility of aortas from female rats, as evidenced by an eightfold increase in potency of 5-HT in fluvoxamine (1 μmol/L)-incubated WT aortas compared with control. Fluvoxamine did not alter 5-HT-induced contraction in aortas from SERT-KO female rats. 4. Infusion of 5-HT resulted in an increase in tissue 5-HT that was reduced to a larger extent in blood vessels from female than male SERT-KO rats. Aortic contractions to 5-HT were abolished in aortas from male and female 5-HT-infused SERT-KO rats compared with WT rats. 5. Collectively, these data suggest that SERT function, when challenged with 5-HT, is modestly more important in the vasculature of the female compared with male rat. PMID:21371073

  9. Antibody drug-conjugates targeting the tumor vasculature

    PubMed Central

    Gerber, Hans-Peter; Senter, Peter D

    2009-01-01

    Reducing the blood supply of tumors is one modality to combat cancer. Monoclonal antibodies are now established as a key therapeutic approach for a range of diseases. Owing to the ability of antibodies to selectively target endothelial cells within the tumor vasculature, vascular targeting programs have become a mainstay in oncology drug development. However, the antitumor activity of single agent administration of conventional anti-angiogenic compounds is limited and the improvements in patient survival are most prominent in combinations with chemotherapy. Furthermore, prolonged treatment with conventional anti-angiogenic drugs is associated with toxicity and drug resistance. These circumstances provide a strong rationale for novel approaches to enhance the efficacy of mAbs targeting tumor vasculature such as antibody-drug conjugates (ADCs). Here, we review trends in the development of ADCs targeting tumor vasculature with the aim of informing future research and development of this class of therapeutics. PMID:20069754

  10. 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

  11. Pulmonary vasculature and critical asthma syndromes: a comprehensive review.

    PubMed

    Avdalovic, Mark

    2015-02-01

    One of the important factors and consequences in persistent asthma is the change in the vasculature of the airways and lung parenchyma. These changes could contribute to worsening asthma control and predispose asthmatics to critical asthma syndromes. For many years, the contribution of vasculature to severe asthma was limited to discussion of small and medium vessel vasculitis commonly referred to as Churg-Strauss syndrome. This comprehensive review will explore the known mechanisms that are associated with remodeling of the vasculature in a variety of critical asthma presentations. Inflammation of pulmonary and bronchial small blood vessels may contribute significantly but silently to asthma pathobiology. Inflammation in the vasculature of the lung parenchyma can decrease lung capacity while inflammation in airway vasculature can decrease airflow. This review will provide a modern perspective on Churg-Strauss syndromes with a focus on phenotyping, mechanism, and ultimately modern therapeutic approaches. Vascular remodeling and airway remodeling are not mutually exclusive concepts in understanding the progression of asthma and frequency of acute exacerbations. Furthermore, the contribution of vascular leak, particularly in the parenchymal vasculature, has become an increasingly recognized component of certain presentations of poorly controlled, severe persistent asthmatic and during exacerbations. We highlight how these mechanisms can contribute to some the severe presentations of influenza infection in patients with a history of asthma. The ultimate aim of this review is to summarize the current literature concerning vasculitis and the contribution of airway and parenchymal vascular remodeling to presentation of persistent asthma and its consequences during acute exacerbations and critical asthma syndromes. PMID:24752370

  12. A survey on the visualization and reconstruction of vasculatures

    NASA Astrophysics Data System (ADS)

    Hong, Qingqi

    2014-01-01

    Visualization and reconstruction of blood vessel from standard medical datasets play an important role in many clinical situations. This paper presents a survey on the visualization and reconstruction of vascular structures. Firstly, the visualization techniques of vasculatures are introduced, which includes volume rendering and surface rendering of vasculatures. Then, we focus on the reconstruction techniques of vascular structures, which can be classified into two categories: explicit reconstruction and implicit reconstruction of vascular structures. With reconstructed vascular geometry, it is quite easy to produce smooth visualization of vessel surfaces. In addition, finding the accurate geometric representation of vascular structures is crucial in developing computer aided vascular surgery systems.

  13. Peripheral Neuropathy

    MedlinePlus

    ... can be associated with peripheral neuropathy. Metabolic and endocrine disorders impair the body’s ability to transform nutrients into ... to neuropathies as a result of chemical imbalances. Endocrine disorders that lead to hormonal imbalances can disturb normal ...

  14. 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

    2010-01-01

    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-([(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

  15. 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. PMID:27088921

  16. MR Molecular Imaging of Tumor Vasculature and Vascular Targets

    PubMed Central

    Pathak, Arvind P.; Penet, Marie-France; Bhujwalla, Zaver M.

    2016-01-01

    Tumor angiogenesis and the ability of cancer cells to induce neovasculature continue to be a fascinating area of research. As the delivery network that provides substrates and nutrients, as well as chemotherapeutic agents to cancer cells, but allows cancer cells to disseminate, the tumor vasculature is richly primed with targets and mechanisms that can be exploited for cancer cure or control. The spatial and temporal heterogeneity of tumor vasculature, and the heterogeneity of response to targeting, make noninvasive imaging essential for understanding the mechanisms of tumor angiogenesis, tracking vascular targeting, and detecting the efficacy of antiangiogenic therapies. With its noninvasive characteristics, exquisite spatial resolution and range of applications, magnetic resonance imaging (MRI) techniques have provided a wealth of functional and molecular information on tumor vasculature in applications spanning from “bench to bedside”. The integration of molecular biology and chemistry to design novel imaging probes ensures the continued evolution of the molecular capabilities of MRI. In this review, we have focused on developments in the characterization of tumor vasculature with functional and molecular MRI. PMID:20807600

  17. Effect of Ergot Alkaloids on Bovine Foregut Vasculature

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  18. 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

  19. 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 ...

  20. Small GTPase Rap1 Is Essential for Mouse Development and Formation of Functional Vasculature

    PubMed Central

    Chrzanowska-Wodnicka, Magdalena; White, Gilbert C.; Quilliam, Lawrence A.; Whitehead, Kevin J.

    2015-01-01

    Background Small GTPase Rap1 has been implicated in a number of basic cellular functions, including cell-cell and cell-matrix adhesion, proliferation and regulation of polarity. Evolutionarily conserved, Rap1 has been studied in model organisms: yeast, Drosophila and mice. Mouse in vivo studies implicate Rap1 in the control of multiple stem cell, leukocyte and vascular cell functions. In vitro, several Rap1 effectors and regulatory mechanisms have been proposed. In particular, Rap1 has been implicated in maintaining epithelial and endothelial cell junction integrity and linked with cerebral cavernous malformations. Rationale How Rap1 signaling network controls mammalian development is not clear. As a first step in addressing this question, we present phenotypes of murine total and vascular-specific Rap1a, Rap1b and double Rap1a and Rap1b (Rap1) knockout (KO) mice. Results and Conclusions The majority of total Rap1 KO mice die before E10.5, consistent with the critical role of Rap1 in epithelial morphogenesis. At that time point, about 50% of Tie2-double Rap1 KOs appear grossly normal and develop normal vasculature, while the remaining 50% suffer tissue degeneration and show vascular abnormalities, including hemorrhages and engorgement of perineural vessels, albeit with normal branchial arches. However, no Tie2-double Rap1 KO embryos are present at E15.5, with hemorrhages a likely cause of death. Therefore, at least one Rap1 allele is required for development prior to the formation of the vascular system; and in endothelium–for the life-supporting function of the vasculature. PMID:26714318

  1. Enhanced Vascular PI3K/Akt-NOX Signaling Underlies the Peripheral NMDAR-Mediated Pressor Response in Conscious Rats

    PubMed Central

    McGee, Marie A.; Abdel-Rahman, Abdel A.

    2014-01-01

    The molecular mechanisms for peripheral N-Methyl-D-Aspartate receptor (NMDAR)-mediated vascular oxidative stress and pressor response are not known. We conducted integrative (in vivo) and ex vivo biochemical studies to test the hypothesis that ROS-dependent calcium influx, triggered by activation of vascular kinases, underlies the NMDAR-mediated pressor response. Pharmacological inhibition of PI3K/Akt (Wortmannin; 15 μg/kg), PKC (Chelerythrine; 5 mg/kg, i.v.), Ca2+ influx (nifedipine; 0.35 or 0.75 mg/kg) or NOX (apocynin; 5 mg/kg) attenuated the peripheral NMDAR-mediated pressor response in conscious male Sprague-Dawley rats. NMDAR activation enhanced the phosphorylation of Akt, ERK1, JNK and p38 (Western blot) and NADPH oxidase (NOX) activity in vascular tissues collected during the pressor response caused by NMDA infusion (180 μg/kg/min, 30 min). Further, ex vivo studies showed that wortmannin, chelerythrine or apocynin abrogated the NMDAR-mediated vascular NO and ROS generation and NOX activation in the vasculature. These findings implicate vascular PI3K/Akt-PKC signaling in the peripheral NMDAR-mediated increases in vascular NO and NOX activation (ROS), which ultimately lead to calcium influx and pressor response in conscious rats. PMID:24336015

  2. Lipopolysaccharide-induced early response genes in bovine peripheral blood mononuclear cells implicate GLG1/E-selectin as a key ligand–receptor interaction

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study uses a systems biology approach, integrating global gene expression information and knowledge of the regulatory events in cells to identify transcription networks controlling peripheral blood mononuclear cells’ (PBMCs) immune response to lipopolysaccharide (LPS) and to identify the molecu...

  3. Role of taurine in the vasculature: an overview of experimental and human studies

    PubMed Central

    Abebe, Worku; Mozaffari, Mahmood S

    2011-01-01

    Taurine is a sulfur-containing amino acid-like endogenous compound found in substantial amounts in mammalian tissues. It exerts a diverse array of biological effects, including cardiovascular regulation, antioxidation, modulation of ion transport, membrane stabilization, osmoregulation, modulation of neurotransmission, bile acid conjugation, hypolipidemia, antiplatelet activity and modulation of fetal development. This brief review summarizes the role of taurine in the vasculature and modulation of blood pressure, based on experimental and human studies. Oral supplementation of taurine induces antihypertensive effects in various animal models of hypertension. These effects of taurine have been shown to be both centrally and peripherally mediated. Consistent with this, taurine produces endothelium-dependent and independent relaxant effects in isolated vascular tissue preparations. Oral administration of taurine also ameliorates impairment of vascular reactivity, intimal thickening, arteriosclerosis, endothelial apoptosis, oxidative stress and inflammation, associated primarily with diabetes and, to a lesser extent with obesity, hypertension and nicotine-induced vascular adverse events. In rat aortic vascular smooth muscle cells (VSMCs), taurine acts as an antiproliferative and antioxidant agent. In endothelial cells, taurine inhibits apoptosis, inflammation, oxidative stress and cell death while increasing NO generation. Oral taurine in hypertensive human patients alleviates the symptoms of hypertension and also reverses arterial stiffness and brachial artery reactivity in type 1 diabetic patients. However, despite these favorable findings, there is a need to further establish certain aspects of the reported results and also consider addressing unresolved related issues. In addition, the molecular mechanism (s) involved in the vascular effects of taurine is largely unknown and requires further investigations. Elucidation of the mechanisms through which taurine

  4. Angiography reveals novel features of the retinal vasculature in healthy and diabetic mice.

    PubMed

    McLenachan, Samuel; Magno, Aaron Len; Ramos, David; Catita, Joana; McMenamin, Paul G; Chen, Fred Kuanfu; Rakoczy, Elizabeth Piroska; Ruberte, Jesus

    2015-09-01

    The mouse retina is a commonly used animal model for the study of pathogenesis and treatment of blinding retinal vascular diseases such as diabetic retinopathy. In this study, we aimed to characterize normal and pathological variations in vascular anatomy in the mouse retina using fluorescein angiography visualized with scanning laser ophthalmoscopy and optical coherence tomography (SLO-OCT). We examined eyes from C57BL/6J wild type mice as well as the Ins2(Akita) and Akimba mouse models of diabetic retinopathy using the Heidelberg Retinal Angiography (HRA) and OCT system. Angiography was performed on three focal planes to examine distinct vascular layers. For comparison with angiographic data, ex vivo analyses, including Indian ink angiography, histology and 3D confocal scanning laser microscopy were performed in parallel. All layers of the mouse retinal vasculature could be readily visualized during fluorescein angiography by SLO-OCT. Blood vessel density was increased in the deep vascular plexus (DVP) compared with the superficial vascular plexus (SVP). Arteriolar and venular typologies were established and structural differences were observed between venular types. Unexpectedly, the hyaloid artery was found to persist in 15% of C57BL/6 mice, forming anastomoses with peripheral retinal capillaries. Fluorescein leakage was easily detected in Akimba retinae by angiography, but was not observed in Ins2(Akita) mice. Blood vessel density was increased in the DVP of 6 month old Ins2(Akita) mice, while the SVP displayed reduced branching in precapillary arterioles. In summary, we present the first comprehensive characterization of the mouse retinal vasculature by SLO-OCT fluorescein angiography. Using this clinical imaging technique, we report previously unrecognized variations in C57BL/6J vascular anatomy and novel features of vascular retinopathy in the Ins2(Akita) mouse model of diabetes. PMID:26122048

  5. 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

  6. 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.

  7. Interrelationships between the Retinal Neuroglia and Vasculature in Diabetes

    PubMed Central

    2014-01-01

    For years, diabetic retinopathy has been defined based on vascular lesions, and neural abnormalities were not regarded as important. This review summarizes evidence that the neural retina has important effects on the retinal vasculature under normal conditions, and the interaction between the retinal neuroglial cells and vascular function is altered in diabetes. Importantly, new evidence raises a possibility that abnormalities within retinal neuroglial cells (notably photoreceptors) might actually be causing or initiating the vascular disease in diabetic retinopathy. PMID:25003068

  8. 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.

  9. Molecular Changes in the Vasculature of Injured Tissues

    PubMed Central

    Järvinen, Tero A.H.; Ruoslahti, Erkki

    2007-01-01

    We have explored molecular specialization of the vasculature of regenerating wound tissue in the skin and tendons to identify a different repertoire of markers from that obtained by studying tumor vasculature. We screened a phage-displayed peptide library for peptides that home to wounds in mice and identified two peptides that selectively target phage to skin and tendon wounds: CARSKNKDC (CAR) and CRKDKC (CRK). CAR is homologous to heparin-binding sites in various proteins and binds to cell surface heparan sulfate and heparin. CRK is similar to a segment in thrombospondin type 1 repeat. Intravenously injected CAR and CRK phage, as well as fluorescein-labeled CAR and CRK peptides, selectively accumulated at wound sites, where they partially co-localized with blood vessels. The CAR peptide showed a preference for early stages of wound healing, whereas the CRK favored wounds at later stages of healing. The CAR peptide was internalized into the target cells and delivered the fluorescent label into the cell nuclei. These results identify new molecular markers in wound tissues and show that the expression of these markers in wound vasculature changes as healing progresses. The peptides recognizing these markers may be useful in delivering treatments into regenerating tissues. PMID:17600129

  10. Combinatorial function of ETS transcription factors in the developing vasculature

    PubMed Central

    Pham, Van N.; Lawson, Nathan D.; Mugford, Joshua W.; Dye, Louis; Castranova, Daniel; Lo, Brigid; Weinstein, Brant M.

    2007-01-01

    Members of the ETS family of transcription factors are among the first genes expressed in the developing vasculature, but loss-of-function experiments for individual ETS factors in mice have not uncovered important early functional roles for these genes. However, multiple ETS factors are expressed in spatially and temporally overlapping patterns in the developing vasculature, suggesting possible functional overlap. We have taken a comprehensive approach to exploring the function of these factors during vascular development by employing the genetic and experimental tools available in the zebrafish to analyze four ETS family members expressed together in the zebrafish vasculature; fli1, fli1b, ets1, and etsrp. We isolated and characterized an ENU-induced mutant with defects in trunk angiogenesis and positionally cloned the defective gene from this mutant, etsrp. Using the etsrp morpholinos targeting each of the four genes, we show that the four ETS factors function combinatorially during vascular and hematopoietic development. Reduction of etsrp or any of the other genes alone results in either partial or no defects in endothelial differentiation, while combined reduction in the function of all four genes causes dramatic loss of endothelial cells. Our results demonstrate that combinatorial ETS factor function is essential for early endothelial specification and differentiation. PMID:17125762

  11. 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. PMID:27165833

  12. 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.

  13. 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.

  14. 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.

  15. 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. PMID:26888065

  16. Anatomic Eponyms in Neuroradiology: Brain, Cerebral Vasculature, and Calvarium.

    PubMed

    Bunch, Paul M; Zamani, Amir A

    2016-06-01

    Medical eponyms are ubiquitous, numerous, and at times controversial. They are often useful for succinctly conveying complex concepts, and familiarity with eponyms is important for proper usage and appropriate communication. In this historical review, we identify 18 anatomic eponyms used to describe structures of the brain, cerebral vasculature, and calvarium. For each structure, we first offer a biographical sketch of the individual for whom the structure is named. This is followed by a description of the anatomic structure and a brief discussion of its clinical relevance. PMID:26916250

  17. 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

  18. Osmotic Drug Delivery to Ischemic Hindlimbs and Perfusion of Vasculature with Microfil for Micro-Computed Tomography Imaging

    PubMed Central

    Pan, Su; Yang, Zhongwei; Willerson, James T.; Dixon, Richard A. F.; Liu, Qi

    2013-01-01

    Preclinical research in animal models of peripheral arterial disease plays a vital role in testing the efficacy of therapeutic agents designed to stimulate microcirculation. The choice of delivery method for these agents is important because the route of administration profoundly affects the bioactivity and efficacy of these agents1,2. In this article, we demonstrate how to locally administer a substance in ischemic hindlimbs by using a catheterized osmotic pump. This pump can deliver a fixed volume of aqueous solution continuously for an allotted period of time. We also present our mouse model of unilateral hindlimb ischemia induced by ligation of the common femoral artery proximal to the origin of profunda femoris and epigastrica arteries in the left hindlimb. Lastly, we describe the in vivo cannulation and ligation of the infrarenal abdominal aorta and perfusion of the hindlimb vasculature with Microfil, a silicone radiopaque casting agent. Microfil can perfuse and fill the entire vascular bed (arterial and venous), and because we have ligated the major vascular conduit for exit, the agent can be retained in the vasculature for future ex vivo imaging with the use of small specimen micro-CT3. PMID:23852145

  19. High spatial and temporal resolution imaging of the arterial vasculature of the lower extremity with contrast enhanced MR angiography.

    PubMed

    Mostardi, Petrice M; Haider, Clifton R; Glockner, James F; Young, Phillip M; Riederer, Stephen J

    2011-05-01

    Vascular imaging can be essential in the diagnosis, monitoring, and planning and assessment of treatment of patients with peripheral vascular disease. The purpose of this work is to describe a recently developed three-dimensional (3D) time-resolved contrast-enhanced MR angiography (CE-MRA) technique, Cartesian Acquisition with Projection Reconstruction-like sampling (CAPR), and its application to imaging of the vasculature of the lower legs and feet. CAPR implements accelerated imaging techniques and uses specialized multielement imaging coil arrays to achieve high temporal and high spatial resolution imaging. Volunteer and patient studies of the vasculature of the lower legs and feet have been performed. Temporal resolution of 4.9-6.5 sec and spatial resolution less than or equal to 1 mm in all directions allow for the depiction of progressive arterial filling and complex flow patterns as well as sharp visualization of vascular structure as small as the fine muscular branches. High-quality diagnostic imaging is made possible with CAPR's advanced acquisition and reconstruction techniques and the use of specialized coil arrays. PMID:21509813

  20. High Spatial and Temporal Resolution Imaging of the Arterial Vasculature of the Lower Extremity With Contrast Enhanced MR Angiography

    PubMed Central

    MOSTARDI, PETRICE M.; HAIDER, CLIFTON R.; GLOCKNER, JAMES F.; YOUNG, PHILLIP M.; RIEDERER, STEPHEN J.

    2011-01-01

    Vascular imaging can be essential in the diagnosis, monitoring, and planning and assessment of treatment of patients with peripheral vascular disease. The purpose of this work is to describe a recently developed three-dimensional (3D) time-resolved contrast-enhanced MR angiography (CE-MRA) technique, Cartesian Acquisition with Projection Reconstruction-like sampling (CAPR), and its application to imaging of the vasculature of the lower legs and feet. CAPR implements accelerated imaging techniques and uses specialized multielement imaging coil arrays to achieve high temporal and high spatial resolution imaging. Volunteer and patient studies of the vasculature of the lower legs and feet have been performed. Temporal resolution of 4.9–6.5 sec and spatial resolution less than or equal to 1 mm in all directions allow for the depiction of progressive arterial filling and complex flow patterns as well as sharp visualization of vascular structure as small as the fine muscular branches. High-quality diagnostic imaging is made possible with CAPR’s advanced acquisition and reconstruction techniques and the use of specialized coil arrays. PMID:21509813

  1. Architecture of GnRH-Gonadotrope-Vasculature Reveals a Dual Mode of Gonadotropin Regulation in Fish.

    PubMed

    Golan, Matan; Zelinger, Einat; Zohar, Yonathan; Levavi-Sivan, Berta

    2015-11-01

    The function and components of the hypothalamic-pituitary axis are conserved among vertebrates; however, in fish, a neuroglandular mode of delivery (direct contact between axons and endocrine cells) was considered dominant, whereas in tetrapods hypothalamic signals are relayed to their targets via the hypophysial portal blood system (neurovascular delivery mode). By using a transgenic zebrafish model we studied the functional and anatomical aspects of gonadotrope regulation thus revisiting the existing model. FSH cells were found to be situated close to the vasculature whereas the compact organization of LH cells prevented direct contact of all cells with the circulation. GnRH3 fibers formed multiple boutons upon reaching the pituitary, but most of these structures were located in the neurohypophysis rather than adjacent to gonadotropes. A close association was observed between FSH cells and GnRH3 boutons, but only a fifth of the LH cells were in direct contact with GnRH3 axons, suggesting that FSH cells are more directly regulated than LH cells. GnRH3 fibers closely followed the vasculature in the neurohypophysis and formed numerous boutons along these tracts. These vessels were found to be permeable to relatively large molecules, suggesting the uptake of GnRH3 peptides. Our findings have important implications regarding the differential regulation of LH and FSH and contradict the accepted notion that fish pituitary cells are mostly regulated directly by hypothalamic fibers. Instead, we provide evidence that zebrafish apply a dual mode of gonadotrope regulation by GnRH3 that combines both neuroglandular and neurovascular components. PMID:26261873

  2. Alterations of Retinal Vasculature in Cystathionine–β-Synthase Heterozygous Mice

    PubMed Central

    Tawfik, Amany; Markand, Shanu; Al-Shabrawey, Mohamed; Mayo, Jamie N.; Reynolds, Jason; Bearden, Shawn E.; Ganapathy, Vadivel; Smith, Sylvia B.

    2015-01-01

    Mild to moderate hyperhomocysteinemia is prevalent in humans and is implicated in neurovascular diseases, including recently in certain retinal diseases. Herein, we used hyperhomocysteinemic mice deficient in the Cbs gene encoding cystathionine–β-synthase (Cbs+/−) to evaluate retinal vascular integrity. The Cbs+/+ (wild type) and Cbs+/− (heterozygous) mice (aged 16 to 52 weeks) were subjected to fluorescein angiography and optical coherence tomography to assess vasculature in vivo. Retinas harvested for cryosectioning or flat mount preparations were subjected to immunofluorescence microscopy to detect blood vessels (isolectin-B4), angiogenesis [anti-vascular endothelial growth factor (VEGF) and anti-CD105], gliosis [anti-glial fibrillary acidic protein (GFAP)], pericytes (anti-neural/glial antigen 2), blood-retinal barrier [anti–zonula occludens protein 1 (ZO-1) and anti-occludin], and hypoxia [anti–pimonidazole hydrochloride (Hypoxyprobe-1)]. Levels of VEGF, GFAP, ZO-1, and occludin were determined by immunoblotting. Results of these analyses showed a mild vascular phenotype in young mice, which progressed with age. Fluorescein angiography revealed progressive neovascularization and vascular leakage in Cbs+/− mice; optical coherence tomography confirmed new vessels in the vitreous by 1 year. Immunofluorescence microscopy demonstrated vascular patterns consistent with ischemia, including a capillary-free zone centrally and new vessels with capillary tufts midperipherally in older mice. This was associated with increased VEGF, CD105, and GFAP and decreased ZO-1/occludin levels in the Cbs+/− retinas. Retinal vein occlusion was observed in some Cbs+/− mouse retinas. We conclude that mild to moderate elevation of homocysteine in Cbs+/− mice is accompanied by progressive alterations in retinal vasculature characterized by ischemia, neovascularization, incompetent blood-retinal barrier, and vascular occlusion. PMID:25016930

  3. Targeting tumor vasculature through oncolytic virotherapy: recent advances

    PubMed Central

    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.

  4. Control of the Adaptive Immune Response by Tumor Vasculature

    PubMed Central

    Mauge, Laetitia; Terme, Magali; Tartour, Eric; Helley, Dominique

    2014-01-01

    The endothelium is nowadays described as an entire organ that regulates various processes: vascular tone, coagulation, inflammation, and immune cell trafficking, depending on the vascular site and its specific microenvironment as well as on endothelial cell-intrinsic mechanisms like epigenetic changes. In this review, we will focus on the control of the adaptive immune response by the tumor vasculature. In physiological conditions, the endothelium acts as a barrier regulating cell trafficking by specific expression of adhesion molecules enabling adhesion of immune cells on the vessel, and subsequent extravasation. This process is also dependent on chemokine and integrin expression, and on the type of junctions defining the permeability of the endothelium. Endothelial cells can also regulate immune cell activation. In fact, the endothelial layer can constitute immunological synapses due to its close interactions with immune cells, and the delivery of co-stimulatory or co-inhibitory signals. In tumor conditions, the vasculature is characterized by an abnormal vessel structure and permeability, and by a specific phenotype of endothelial cells. All these abnormalities lead to a modulation of intra-tumoral immune responses and contribute to the development of intra-tumoral immunosuppression, which is a major mechanism for promoting the development, progression, and treatment resistance of tumors. The in-depth analysis of these various abnormalities will help defining novel targets for the development of anti-tumoral treatments. Furthermore, eventual changes of the endothelial cell phenotype identified by plasma biomarkers could secondarily be selected to monitor treatment efficacy. PMID:24734218

  5. 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

  6. Interplay of macrophages and T cells in the lung vasculature.

    PubMed

    Gerasimovskaya, Evgenia; Kratzer, Adelheid; Sidiakova, Asya; Salys, Jonas; Zamora, Martin; Taraseviciene-Stewart, Laimute

    2012-05-15

    In severe pulmonary arterial hypertension (PAH), vascular lesions are composed of phenotypically altered vascular and inflammatory cells that form clusters or tumorlets. Because macrophages are found in increased numbers in intravascular and perivascular space in human PAH, here we address the question whether macrophages play a role in pulmonary vascular remodeling and whether accumulation of macrophages in the lung vasculature could be compromised by the immune system. We used the mouse macrophage cell line RAW 264.7 because these cells are resistant to apoptosis, have high proliferative capacity, and resemble cells in the plexiform lesions that tend to pile up instead of maintaining a monolayer. Cells were characterized by immunocytochemistry with cell surface markers (Lycopersicon Esculentum Lectin, CD117, CD133, FVIII, CD31, VEGFR-2, and S100). Activated, but not quiescent, T cells were able to suppress RAW 264.7 cell proliferative and migration activity in vitro. The carboxyfluorescein diacetate-labeled RAW 264.7 cells were injected into the naïve Sprague Dawley (SD) rat and athymic nude rat. Twelve days later, cells were found in the lung vasculature of athymic nude rats that lack functional T cells, contributing to vascular remodeling. No labeled RAW 264.7 cells were detected in the lungs of immune-competent SD rats. Our data demonstrate that T cells can inhibit in vitro migration and in vivo accumulation of macrophage-like cells. PMID:22387295

  7. Three-dimensional vasculature reconstruction of tumour microenvironment via local clustering and classification

    PubMed Central

    Zhu, Yanqiao; Li, Fuhai; Vadakkan, Tegy J.; Zhang, Mei; Landua, John; Wei, Wei; Ma, Jinwen; Dickinson, Mary E.; Rosen, Jeffrey M.; Lewis, Michael T.; Zhan, Ming; Wong, Stephen T. C.

    2013-01-01

    The vasculature inside breast cancers is one important component of the tumour microenvironment. The investigation of its spatial morphology, distribution and interactions with cancer cells, including cancer stem cells, is essential for elucidating mechanisms of tumour development and treatment response. Using confocal microscopy and fluorescent markers, we have acquired three-dimensional images of vasculature within mammary tumours and normal mammary gland of mouse models. However, it is difficult to segment and reconstruct complex vasculature accurately from the in vivo three-dimensional images owing to the existence of uneven intensity and regions with low signal-to-noise ratios (SNR). To overcome these challenges, we have developed a novel three-dimensional vasculature segmentation method based on local clustering and classification. First, images of vasculature are clustered into local regions, whose boundaries well delineate vasculature even in low SNR and uneven intensity regions. Then local regions belonging to vasculature are identified by applying a semi-supervised classification method based on three informative features of the local regions. Comparison of results using simulated and real vasculature images, from mouse mammary tumours and normal mammary gland, shows that the new method outperforms existing methods, and can be used for three-dimensional images with uneven background and low SNR to achieve accurate vasculature reconstruction. PMID:24511379

  8. Three-dimensional vasculature reconstruction of tumour microenvironment via local clustering and classification.

    PubMed

    Zhu, Yanqiao; Li, Fuhai; Vadakkan, Tegy J; Zhang, Mei; Landua, John; Wei, Wei; Ma, Jinwen; Dickinson, Mary E; Rosen, Jeffrey M; Lewis, Michael T; Zhan, Ming; Wong, Stephen T C

    2013-08-01

    The vasculature inside breast cancers is one important component of the tumour microenvironment. The investigation of its spatial morphology, distribution and interactions with cancer cells, including cancer stem cells, is essential for elucidating mechanisms of tumour development and treatment response. Using confocal microscopy and fluorescent markers, we have acquired three-dimensional images of vasculature within mammary tumours and normal mammary gland of mouse models. However, it is difficult to segment and reconstruct complex vasculature accurately from the in vivo three-dimensional images owing to the existence of uneven intensity and regions with low signal-to-noise ratios (SNR). To overcome these challenges, we have developed a novel three-dimensional vasculature segmentation method based on local clustering and classification. First, images of vasculature are clustered into local regions, whose boundaries well delineate vasculature even in low SNR and uneven intensity regions. Then local regions belonging to vasculature are identified by applying a semi-supervised classification method based on three informative features of the local regions. Comparison of results using simulated and real vasculature images, from mouse mammary tumours and normal mammary gland, shows that the new method outperforms existing methods, and can be used for three-dimensional images with uneven background and low SNR to achieve accurate vasculature reconstruction. PMID:24511379

  9. 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.

  10. 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

  11. I. Embryonal vasculature formation recapitulated in transgenic mammary tumor spheroids implanted pseudo-orthotopicly into mouse dorsal skin fold: the organoblasts concept

    PubMed Central

    Witkiewicz, Halina

    2013-01-01

    Inadequate understanding of cancer biology is a problem. This work focused on cellular mechanisms of tumor vascularization. According to earlier studies, the tumor vasculature derives from host endothelial cells (angiogenesis) or their precursors of bone marrow origin circulating in the blood (neo-vasculogenesis) unlike in embryos. In this study, we observed the neo-vasculature form in multiple ways from local precursor cells. Recapitulation of primitive as well as advanced embryonal stages of vasculature formation followed co-implantation of avascular ( in vitro cultured) N202 breast tumor spheroids and homologous tissue grafts into mouse dorsal skin chambers. Ultrastructural and immunocytochemical analysis of tissue sections exposed the interactions between the tumor and the graft tissue stem cells. It revealed details of vasculature morphogenesis not seen before in either tumors or embryos. A gradual increase in complexity of the vascular morphogenesis at the tumor site reflected a range of steps in ontogenic evolution of the differentiating cells. Malignant- and surgical injury repair-related tissue growth prompted local cells to initiate extramedullar erythropoiesis and vascular patterning. The new findings included: interdependence between the extramedullar hematopoiesis and assembly of new vessels (both from the locally differentiating precursors); nucleo-cytoplasmic conversion (karyolysis) as the mechanism of erythroblast enucleation; the role of megakaryocytes and platelets in vascular pattern formation before emergence of endothelial cells; lineage relationships between hematopoietic and endothelial cells; the role of extracellular calmyrin in tissue morphogenesis; and calmyrite, a new ultrastructural entity associated with anaerobic energy metabolism. The central role of the extramedullar erythropoiesis in the formation of new vasculature (blood and vessels) emerged here as part of the tissue building process including the lymphatic system and nerves

  12. 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. PMID:25323627

  13. 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. PMID:26930260

  14. [(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. PMID:24861611

  15. Endurance Exercise Mobilizes Developmentally Early Stem Cells into Peripheral Blood and Increases Their Number in Bone Marrow: Implications for Tissue Regeneration.

    PubMed

    Marycz, Krzysztof; Mierzejewska, Katarzyna; Śmieszek, Agnieszka; Suszynska, Ewa; Malicka, Iwona; Kucia, Magda; Ratajczak, Mariusz Z

    2016-01-01

    Endurance exercise has been reported to increase the number of circulating hematopoietic stem/progenitor cells (HSPCs) in peripheral blood (PB) as well as in bone marrow (BM). We therefore became interested in whether endurance exercise has the same effect on very small embryonic-like stem cells (VSELs), which have been described as a population of developmentally early stem cells residing in BM. Mice were run daily for 1 hour on a treadmill for periods of 5 days or 5 weeks. Human volunteers had trained in long-distance running for one year, six times per week. FACS-based analyses and RT-PCR of murine and human VSELs and HSPCs from collected bone marrow and peripheral blood were performed. We observed that endurance exercise increased the number of VSELs circulating in PB and residing in BM. In parallel, we observed an increase in the number of HSPCs. These observations were subsequently confirmed in young athletes, who showed an increase in circulating VSELs and HSPCs after intensive running exercise. We provide for the first time evidence that endurance exercise may have beneficial effects on the expansion of developmentally early stem cells. We hypothesize that these circulating stem cells are involved in repairing minor exercise-related tissue and organ injuries. PMID:26664409

  16. 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. PMID:15822811

  17. 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.

  18. Pharmacology of transient receptor potential melastatin channels in the vasculature

    PubMed Central

    Zholos, Alexander

    2010-01-01

    Mammalian transient receptor potential melastatin (TRPM) non-selective cation channels, the largest TRP subfamily, are widely expressed in excitable and non-excitable cells where they perform diverse functions ranging from detection of cold, taste, osmolarity, redox state and pH to control of Mg2+ homeostasis and cell proliferation or death. Recently, TRPM gene expression has been identified in vascular smooth muscles with dominance of the TRPM8 channel. There has been in parallel considerable progress in decoding the functional roles of several TRPMs in the vasculature. This research on native cells is aided by the knowledge of the activation mechanisms and pharmacological properties of heterologously expressed TRPM subtypes. This paper summarizes the present state of knowledge of vascular TRPM channels and outlines several anticipated directions of future research in this area. PMID:20233227

  19. New ways to successfully target tumor vasculature in ovarian cancer

    PubMed Central

    Yang, Xiaoyun; Shen, Fangrong; Hu, Wei; Coleman, Robert L.; Sood, Anil K.

    2015-01-01

    Purpose of review The aim of this paper was to review the recent literature on potential therapeutic strategies for overcoming resistance to anti-VEGF drugs in ovarian cancer. Recent findings Although clinical benefits of anti-VEGF therapy were observed in ovarian cancer treatment trials, this use yielded only modest improvement in progression-free survival, and with the exception of cediranib no effect on overall survival. Adaptive resistance and escape from anti-angiogenesis therapy is likely a multifactorial process, including induction of hypoxia, vascular modulators and the immune response. New drugs targeting the tumor vasculature or other components of the surrounding microenvironment have shown promising results. Summary When to start and end antiangiogenesis therapy and the choice of optimal treatment combinations remain controversial. Further evaluation of personalized novel angiogenesis-based therapy is warranted. Defining the critical interaction of these agents and pathways and the appropriate predictive markers will become an increasingly important objective for effective treatment. PMID:25502429

  20. 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

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

    PubMed

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

    2016-01-01

    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. PMID:27033295

  2. 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

  3. 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

  4. 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

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

    PubMed Central

    Pan, Xiao; Ji, Zuoquan; Xue, Jiang

    2016-01-01

    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/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. PMID:27389933

  6. 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

  7. 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

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

    PubMed

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

    2015-10-01

    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

  9. 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.

  10. Angiotensin antagonists with increased specificity for the renal vasculature.

    PubMed Central

    Taub, K J; Caldicott, W J; Hollenberg, N K

    1977-01-01

    This study was designed to ascertain whether renal vascular angiotensin receptors differ from other systemic angiotensin receptors and whether, on that basis, antagonists with greater specificity for the renal vasculature can be defined. Femoral and renal blood flow and their responses to angiotensin II (AII) and its heptapeptide analogue, 1-des Asp AII (AIII), were measured with an electromagnetic flowmeter in 26 dogs. For the kidney, the threshold doses of AII and AIII were identical (2.5+/-0.27 vs. 2.3+/-0.35 pmol/100 ml renal blood flow, with similar dose-response curves. In contrast, AII had a greater pressor effect (P less than 0.001) and produced more femoral vasoconstriction (P less than 0.001) than AIII. All four antagonists studied (1-Sar, 8-Ala AII [P113]; 8-Ala AII; 1-des Asp, 8-Ala AII; 1-des Asp, 8-Ile AII) induced parallel shifts in the renal blood flow response to AII and AIII. P113 induced greater blockade than 8-Ala AII (P less than 0.001) which, in turn, was more effective than 1-des Asp, 8-Ala AII (P less than 0.001). 1-des Asp, 8-Ile AII was as effective as P113. Each analogue induced an identical inhibition of the renal vascular response to AII and AIII. In addition, AII and AIII induced cross-tachyphylaxis. All lines of evidence suggested that AII and AIII act on a single receptor in the kidney, which differs at least functionally from other systemic vascular receptors. The possibility that heptapeptide analogues represent angiotensin antagonists with greater specificity for the renal vasculature was pursued in a model in which the renin-angiotensin system is activated. Acute, partial thoracic inferior vena caval occlusion was induced in an additional 16 dogs. P113 induced progressive, dose-related hypotension and a limited increase in renal blood flow in this model. The 1-des Asp, 8-Ile AII analogue, conversely, induced a consistent, larger, dose-related renal blood flow increase, with significantly less hypotension over a wide dose range

  11. 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

  12. 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

  13. 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

  14. 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

  15. Chemokine-guided angiogenesis directs coronary vasculature formation in zebrafish.

    PubMed

    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

    2015-05-26

    Interruption of the coronary blood supply severely impairs heart function with often fatal consequences for 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

  16. 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

  17. 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

  18. Multiple variations in the pelvic vasculature - a case report.

    PubMed

    Nayak, Satheesha B; Shetty, Surekha D; Sirasanagandla, Srinivasa Rao; P, Vasanthakumar; Jetti, Raghu

    2015-02-01

    A thorough knowledge of possible variations of pelvic vasculature is very useful for surgeons, gynaecologists, radiologists, urologists and orthopaedic surgeons. We report multiple vascular variations in the left half of the pelvis of an adult male cadaver. Iliolumbar artery arose from the main trunk of the internal iliac artery. Posterior division of the internal iliac artery gave two lateral sacral arteries and a superior gluteal artery. The anterior division of the internal iliac artery gave origin to superior vesical, inferior vesical, inferior gluteal and internal pudendal arteries. The internal pudendal artery gave origin to a common trunk before leaving the pelvis. The common trunk divided into middle rectal artery and deep artery of the penis. The obturator artery took origin from the inferior epigastric artery and descended downward to the pelvis and left the pelvis by passing through the obturator foramen. Most of the other veins accompanying the arteries joined to form a plexus on the superior surface of the pelvic diaphragm. This plexus condensed to form anterior and posterior divisions of the internal iliac vein. Apart from this, the posterior part of the plexus drained directly into the common iliac vein through a large unnamed vein. PMID:25859441

  19. 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.

  20. Endothelial cell metabolism in normal and diseased vasculature.

    PubMed

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

    2015-03-27

    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) 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 affects 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

  1. Developmental regression of hyaloid vasculature is triggered by neurons.

    PubMed

    Yoshikawa, Yusuke; Yamada, Toru; Tai-Nagara, Ikue; Okabe, Keisuke; Kitagawa, Yuko; Ema, Masatsugu; Kubota, Yoshiaki

    2016-06-27

    Vascular development involves not only vascular growth, but also regression of transient or unnecessary vessels. Hyaloid vasculature is the temporary circulatory system in fetal eyes, which spontaneously degenerates when the retinal blood vessels start to grow. Failure of the hyaloid vessels to regress leads to disease in humans, persistent hyperplastic primary vitreous, which causes severe intraocular hemorrhage and impairs visual function. However, the mechanism underlying the endogenous program that mediates spontaneous regression of the hyaloid vessels is not well understood. In this study, we identify a robust switch triggering this program directed by neurons in mice. Marked up-regulation of vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) occurs in retinal neurons just after birth via distal-multipotent-mesodermal enhancer, a hemangioblast-specific enhancer of VEGFR2. Genetic deletion of neuronal VEGFR2 interrupts this program, resulting in massive hyaloid vessels that persist even during late postnatal days. This abnormality is caused by excessive VEGF proteins in the vitreous cavity as a result of impairment in the neuronal sequestration of VEGF. Collectively, our data indicate that neurons trigger transition from the fetal to the postnatal circulatory systems in the retina. PMID:27325890

  2. 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

  3. Peripheral Nerve Disorders

    MedlinePlus

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

  4. Natriuretic peptide C receptor signalling in the heart and vasculature

    PubMed Central

    Rose, Robert A; Giles, Wayne R

    2008-01-01

    Natriuretic peptides (NPs), including atrial, brain and C-type natriuretic peptides (ANP, BNP and CNP), bind two classes of cell surface receptors: the guanylyl cyclase-linked A and B receptors (NPR-A and NPR-B) and the C receptor (NPR-C). The biological effects of NPs have been mainly attributed to changes in intracellular cGMP following their binding to NPR-A and NPR-B. NPR-C does not include a guanylyl cyclase domain. It has been denoted as a clearance receptor and is thought to bind and internalize NPs for ultimate degradation. However, a substantial body of biochemical work has demonstrated the ability of NPR-C to couple to inhibitory G proteins (Gi) and cause inhibition of adenylyl cyclase and activation of phospholipase-C. Recently, novel physiological effects of NPs, mediated specifically by NPR-C, have been discovered in the heart and vasculature. We have described the ability of CNP, acting via NPR-C, to selectively inhibit L-type calcium currents in atrial and ventricular myocytes, as well as in pacemaker cells (sinoatrial node myocytes). In contrast, our studies of the electrophysiological effects of CNP on cardiac fibroblasts demonstrated an NPR-C–Gi–phospholipase-C-dependent activation of a non-selective cation current mediated by transient receptor potential (TRP) channels. It is also known that CNP and BNP have important anti-proliferative effects in cardiac fibroblasts that appear to involve NPR-C. In the mammalian resistance vessels, including mesenteric and coronary arteries, CNP has been found to function as an NPR-C-dependent endothelium-derived hyperpolarizing factor that regulates local blood flow and systemic blood pressure by hyperpolarizing smooth muscle cells. In this review we highlight the role of NPR-C in mediating these NP effects in myocytes and fibroblasts from the heart as well as in vascular smooth muscle cells. PMID:18006579

  5. 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

  6. Caloric restriction: powerful protection for the aging heart and vasculature

    PubMed Central

    Fontana, Luigi

    2011-01-01

    Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Research has shown that the majority of the cardiometabolic alterations associated with an increased risk of CVD (e.g., insulin resistance/type 2 diabetes, abdominal obesity, dyslipidemia, hypertension, and inflammation) can be prevented, and even reversed, with the implementation of healthier diets and regular exercise. Data from animal and human studies indicate that more drastic interventions, i.e., calorie restriction with adequate nutrition (CR), may have additional beneficial effects on several metabolic and molecular factors that are modulating cardiovascular aging itself (e.g., cardiac and arterial stiffness and heart rate variability). The purpose of this article is to review the current knowledge on the effects of CR on the aging of the cardiovascular system and CVD risk in rodents, monkeys, and humans. Taken together, research shows that CR has numerous beneficial effects on the aging cardiovascular system, some of which are likely related to reductions in inflammation and oxidative stress. In the vasculature, CR appears to protect against endothelial dysfunction and arterial stiffness and attenuates atherogenesis by improving several cardiometabolic risk factors. In the heart, CR attenuates age-related changes in the myocardium (i.e., CR protects against fibrosis, reduces cardiomyocyte apoptosis, prevents myosin isoform shifts, etc.) and preserves or improves left ventricular diastolic function. These effects, in combination with other benefits of CR, such as protection against obesity, diabetes, hypertension, and cancer, suggest that CR may have a major beneficial effect on health span, life span, and quality of life in humans. PMID:21841020

  7. Histamine-induced vasodilatation in the human forearm vasculature

    PubMed Central

    Sandilands, Euan A; Crowe, Jane; Cuthbert, Hayley; Jenkins, Paul J; Johnston, Neil R; Eddleston, Michael; Bateman, D Nicholas; Webb, David J

    2013-01-01

    Aim To investigate the mechanism of action of intra-arterial histamine in the human forearm vasculature. Methods Three studies were conducted to assess changes in forearm blood flow (FBF) using venous occlusion plethysmography in response to intra-brachial histamine. First, the dose–response was investigated by assessing FBF throughout a dose-escalating histamine infusion. Next, histamine was infused at a constant dose to assess acute tolerance. Finally, a four way, double-blind, randomized, placebo-controlled crossover study was conducted to assess FBF response to histamine in the presence of H1- and H2-receptor antagonists. Flare and itch were assessed in all studies. Results Histamine caused a dose-dependent increase in FBF, greatest with the highest dose (30 nmol min−1) infused [mean (SEM) infused arm vs. control: 26.8 (5.3) vs. 2.6 ml min−1 100 ml−1; P < 0.0001]. Dose-dependent flare and itch were demonstrated. Acute tolerance was not observed, with an increased FBF persisting throughout the infusion period. H2-receptor antagonism significantly reduced FBF (mean (95% CI) difference from placebo at 30 nmol min−1 histamine: −11.9 ml min−1 100 ml−1 (−4.0, −19.8), P < 0.0001) and flare (mean (95% CI) difference from placebo: −403.7 cm2 (−231.4, 576.0), P < 0.0001). No reduction in FBF or flare was observed in response to the H1-receptor antagonist. Itch was unaffected by the treatments. Histamine did not stimulate vascular release of tissue plasminogen activator or von Willebrand factor. Conclusion Histamine causes dose-dependent vasodilatation, flare and itch in the human forearm. H2-receptors are important in this process. Our results support further exploration of combined H1- and H2-receptor antagonist therapy in acute allergic syndromes. PMID:23488545

  8. An imaging-based stochastic model for simulation of tumour vasculature

    PubMed Central

    Adhikarla, Vikram; Jeraj, Robert

    2013-01-01

    A mathematical model which reconstructs the structure of existing vasculature using patient-specific anatomical, functional and molecular imaging as input was developed. The vessel structure is modelled according to empirical vascular parameters, such as the mean vessel branching angle. The model is calibrated such that the resultant oxygen map modelled from the simulated microvasculature stochastically matches the input oxygen map to a high degree of accuracy (R2 ≈ 1). The calibrated model was successfully applied to preclinical imaging data. Starting from the anatomical vasculature image (obtained from contrast-enhanced computed tomography), a representative map of the complete vasculature was stochastically simulated as determined by the oxygen map (obtained from hypoxia [64Cu]Cu-ATSM positron emission tomography). The simulated microscopic vasculature and the calculated oxygenation map successfully represent the imaged hypoxia distribution (R2 = 0.94). The model elicits the parameters required to simulate vasculature consistent with imaging and provides a key mathematical relationship relating the vessel volume to the tissue oxygen tension. Apart from providing an excellent framework for visualizing the imaging gap between the microscopic and macroscopic imagings, the model has the potential to be extended as a tool to study the dynamics between the tumour and the vasculature in a patient-specific manner and has an application in the simulation of anti-angiogenic therapies. PMID:22971525

  9. Optical coherence tomography for longitudinal monitoring of vasculature in scars treated with laser fractionation.

    PubMed

    Gong, Peijun; Es'haghian, Shaghayegh; Harms, Karl-Anton; Murray, Alexandra; Rea, Suzanne; Kennedy, Brendan F; Wood, Fiona M; Sampson, David D; McLaughlin, Robert A

    2016-06-01

    This study presents the first in vivo longitudinal assessment of scar vasculature in ablative fractional laser treatment using optical coherence tomography (OCT). A method based on OCT speckle decorrelation was developed to visualize and quantify the scar vasculature over the treatment period. Through reliable co-location of the imaging field of view across multiple imaging sessions, and compensation for motion artifact, the study was able to track the same scar tissue over a period of several months, and quantify changes in the vasculature area density. The results show incidences of occlusion of individual vessels 3 days after the first treatment. The subsequent responses ˜20 weeks after the initial treatment show differences between immature and mature scars. Image analysis showed a distinct decrease (25 ± 13%, mean ± standard deviation) and increase (19 ± 5%) of vasculature area density for the immature and mature scars, respectively. This study establishes the feasibility of OCT imaging for quantitative longitudinal monitoring of vasculature in scar treatment. En face optical coherence tomography vasculature images pre-treatment (top) and ˜20 weeks after the first laser treatment (bottom) of a mature burn scar. Arrows mark the same vessel pattern. PMID:26260918

  10. Propylthiouracil and peripheral neuropathy.

    PubMed

    Van Boekel, V; Godoy, J M; Lamy, L A; Assuf, S; Meyer Neto, J G; Balassiano, S L; Prata, L E

    1992-06-01

    Peripheral neuropathy is a rare manifestation in hyperthyroidism. We describe the neurological manifestations of a 38 year old female with Graves' disease who developed peripheral neuropathy in the course of her treatment with propylthiouracil. After the drug was tapered off, the neurological signs disappeared. Therefore, we call attention for a possible toxic effect on peripheral nervous system caused by this drug. PMID:1339201

  11. Evaluating Peripheral Displays

    NASA Astrophysics Data System (ADS)

    Matthews, Tara; Hsieh, Gary; Mankoff, Jennifer

    Although peripheral displays have been a domain of inquiry for over a decade now, evaluation criteria and techniques for this area are still being created. Peripheral display evaluation is an acknowledged challenge in a field setting. This chapter first describes models and methods that have been tailored specifically to evaluating peripheral displays (measuring how well they achieve their goals). Then, we present evaluation criteria used in past evaluations of peripheral displays, ranging from issues such as learnability to distraction. After explaining how these criteria have been assessed in the past, we present a case study evaluation of two e-mail peripheral displays that demonstrates the pros and cons of various evaluation techniques.

  12. [Colonic Crohn's disease complicated with peripheral neuropathy].

    PubMed

    Chaoui, F; Hellal, H; Balamane, M; Boudhane, M; Mikol, J; Masmoudi, A

    1990-01-01

    The association of Crohn's disease and peripheral neuropathy is a rare event and the pathogenic factors often implicated are vitamin B12 deficiency or metronidazole treatment. We report a case of severe axonal polyneuropathy associated with Crohn's disease and unrelated to vitamin deficiency or metronidazole treatment. This represents a very rare extra-digestive manifestation of Crohn's disease. PMID:2125951

  13. In-vivo imaging of retinal nerve fiber layer vasculature: imaging - histology comparison

    PubMed Central

    Scoles, Drew; Gray, Daniel C; Hunter, Jennifer J; Wolfe, Robert; Gee, Bernard P; Geng, Ying; Masella, Benjamin D; Libby, Richard T; Russell, Stephen; Williams, David R; Merigan, William H

    2009-01-01

    Background Although it has been suggested that alterations of nerve fiber layer vasculature may be involved in the etiology of eye diseases, including glaucoma, it has not been possible to examine this vasculature in-vivo. This report describes a novel imaging method, fluorescence adaptive optics (FAO) scanning laser ophthalmoscopy (SLO), that makes possible for the first time in-vivo imaging of this vasculature in the living macaque, comparing in-vivo and ex-vivo imaging of this vascular bed. Methods We injected sodium fluorescein intravenously in two macaque monkeys while imaging the retina with an FAO-SLO. An argon laser provided the 488 nm excitation source for fluorescence imaging. Reflectance images, obtained simultaneously with near infrared light, permitted precise surface registration of individual frames of the fluorescence imaging. In-vivo imaging was then compared to ex-vivo confocal microscopy of the same tissue. Results Superficial focus (innermost retina) at all depths within the NFL revealed a vasculature with extremely long capillaries, thin walls, little variation in caliber and parallel-linked structure oriented parallel to the NFL axons, typical of the radial peripapillary capillaries (RPCs). However, at a deeper focus beneath the NFL, (toward outer retina) the polygonal pattern typical of the ganglion cell layer (inner) and outer retinal vasculature was seen. These distinguishing patterns were also seen on histological examination of the same retinas. Furthermore, the thickness of the RPC beds and the caliber of individual RPCs determined by imaging closely matched that measured in histological sections. Conclusion This robust method demonstrates in-vivo, high-resolution, confocal imaging of the vasculature through the full thickness of the NFL in the living macaque, in precise agreement with histology. FAO provides a new tool to examine possible primary or secondary role of the nerve fiber layer vasculature in retinal vascular disorders and

  14. 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.

  15. Vegfa signaling promotes zebrafish intestinal vasculature development through endothelial cell migration from the posterior cardinal vein.

    PubMed

    Koenig, Andrew L; Baltrunaite, Kristina; Bower, Neil I; Rossi, Andrea; Stainier, Didier Y R; Hogan, Benjamin M; Sumanas, Saulius

    2016-03-01

    The mechanisms underlying organ vascularization are not well understood. The zebrafish intestinal vasculature forms early, is easily imaged using transgenic lines and in-situ hybridization, and develops in a stereotypical pattern thus making it an excellent model for investigating mechanisms of organ specific vascularization. Here, we demonstrate that the sub-intestinal vein (SIV) and supra-intestinal artery (SIA) form by a novel mechanism from angioblasts that migrate out of the posterior cardinal vein and coalesce to form the intestinal vasculature in an anterior to posterior wave with the SIA forming after the SIV. We show that vascular endothelial growth factor aa (vegfaa) is expressed in the endoderm at the site where intestinal vessels form and therefore likely provides a guidance signal. Vegfa/Vegfr2 signaling is required for early intestinal vasculature development with mutation in vegfaa or loss of Vegfr2 homologs causing nearly complete inhibition of the formation of the intestinal vasculature. Vegfc and Vegfr3 function, however, are dispensable for intestinal vascularization. Interestingly, ubiquitous overexpression of Vegfc resulted in an overgrowth of the SIV, suggesting that Vegfc is sufficient to induce SIV development. These results argue that Vegfa signaling directs endothelial cells to migrate out of existing vasculature and coalesce to form the intestinal vessels. It is likely that a similar mechanism is utilized during vascularization of other organs. PMID:26769101

  16. Insulin Resistance and Skeletal Muscle Vasculature: Significance, Assessment and Therapeutic Modulators

    PubMed Central

    Manrique, Camila; Sowers, James R.

    2014-01-01

    Overnutrition and sedentarism are closely related to the alarming incidence of obesity and type 2 diabetes mellitus (DM2) in the Western world. Resistance to the actions of insulin is a common occurrence in conditions such as obesity, hypertension and DM2. In the skeletal muscle vasculature, insulin promotes vasodilation and its own transport across the vascular wall to reach its target tissue. Furthermore, insulin resistance (IR) in the skeletal muscle vasculature results in impaired skeletal muscle glucose uptake and altered whole-body glucose homeostasis. The development of different invasive and noninvasive techniques has allowed the characterization of the actions of insulin and other vasoactive hormones in the skeletal muscle vasculature in both health and disease. Current treatment strategies for DM2 do not necessarily address the impaired effect of insulin in the vasculature. Understanding the effects of insulin and other metabolically active hormones in the vasculature should facilitate the development of new therapeutic strategies targeted at the modulation of IR and improvement of whole-body glucose tolerance. PMID:25737689

  17. 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. PMID:26443964

  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. The vasculature of nurse cells infected with non-encapsulated Trichinella species.

    PubMed

    Khositharattanakool, Pathamet; Morakote, Nimit; Uparanukraw, Pichart

    2013-07-01

    The vasculature surrounding the nurse cells of encapsulated Trichinella spiralis has been described previously. It has been postulated the function of these vessels is to support the growth of the parasite. We describe here for the first time the vasculature surrounding the nurse cells of non-encapsulated T. pseudospiralis and T. papuae. Similar to the vasculature of uninfected muscle cells, the vessels surrounding non-encapsulated Trichinella nurse cells are dense and branched longitudinally along the long axis of the muscle cells; they also appear to be similar in diameter. The netting pattern of enlarged vessels found around T. spiralis (encapsulated) nurse cells is not present in non-encapsulated Trichinella infections. The vessels surrounding non-encapsulated Trichinella nurse cells seem to exist prior to parasite invasion of the muscle cell. PMID:24050088

  20. Dual-beam-scan Doppler optical coherence angiography for birefringence-artifact-free vasculature imaging.

    PubMed

    Makita, Shuichi; Jaillon, Franck; Yamanari, Masahiro; Yasuno, Yoshiaki

    2012-01-30

    Dual-beam-scan Doppler optical coherence angiography (DB-OCA) enables high-speed, high-sensitivity blood flow imaging. However, birefringence of biological tissues is an obstacle to vasculature imaging. Here, the influence of polarization and birefringence on DB-OCA imaging was analyzed. A DB-OCA system without birefringence artifact has been developed by introducing a Faraday rotator. The performance was confirmed in vitro using chicken muscle and in vivo using the human eye. Birefringence artifacts due to birefringent tissues were suppressed. Micro-vasculatures in the lamina cribrosa and nerve fiber layer of human eyes were visualized in vivo. High-speed and high-sensitivity micro-vasculature imaging involving birefringent tissues is available with polarization multiplexing DB-OCA. PMID:22330505

  1. Topical anaesthetic effects on skin vasculature with potential implications for laser treatment.

    PubMed

    Tollan, Clare Josephine; MacLaren, William; Mackay, Iain R

    2016-05-01

    Laser treatment of vascular lesions is affected by parameters including the diameter and depth of the vessels and flow within the vessels. Topical anaesthetics are in common use prior to laser treatment but may have effects on vessel parameters and, subsequently, the efficacy of laser treatment. Eleven patients with capillary vascular malformations were investigated for vessel diameter before and after elective application of a topical anaesthetic, Eutectic Mixture of Local Anaesthetics (EMLA) (AstraZeneca) or Ametop (S&N Health), prior to pulsed dye laser treatment. EMLA contains 2.5% lidocaine ad 2.5% prilocaine, and Ametop gel contains 4% tetracaine. Patients' capillary malformations were assessed using confocal laser scanning microscopy (CLSM) (Vivascope 1500 Mavig GmbH, Munich). Six of the 11 patients recruited had EMLA topical anaesthetic, and five had Ametop. Four hundred twenty-one diameters were measured. The mean vessel diameter was 50.87 μm. Previous laser treatments undergone by each patient were noted to exclude this as a confounding variable, and no significant difference was found between topical anaesthetic groups. Statistical calculations were made using GenStat and Minitab. There is no evidence that Ametop affects mean diameter (p value is 0.361). EMLA reduces the mean diameter of vessels (p = 0.002), with a 27% reduction in post-EMLA diameter. This study demonstrates that the use of EMLA cream has a statistically significant reduction vessel diameter. As it is known that vessel diameter is important for the response of laser treatment, the use of EMLA may affect outcome. PMID:26861976

  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. Observation of vasculature alternation by intense pulsed light combined with physicochemical methods.

    PubMed

    Son, Taeyoon; Kang, Heesung; Jung, Byungjo

    2016-05-01

    Intense pulsed light (IPL) with low energy insufficient to completely destroy a vasculature was applied to rabbit ears to investigate vasculature alteration. Glycerol was combined with IPL to enhance the transfer efficacy of IPL energy. Both trans-illumination and laser speckle contrast images were obtained and analyzed after treatment. The application of IPL and glycerol combination induced vasodilation and improvement in blood flow. Moreover, such phenomenon was maintained over time. IPL may be applied to treat blood circulatory diseases by inducing vasodilation and to improve blood flow. PMID:26776941

  4. In vivo TRPC functions in the cardiopulmonary vasculature.

    PubMed

    Dietrich, Alexander; Kalwa, Hermann; Fuchs, Beate; Grimminger, Friedrich; Weissmann, Norbert; Gudermann, Thomas

    2007-08-01

    Cardiovascular diseases are the leading cause of death in the industrialized countries. The cardiovascular system includes the systemic blood circulation, the heart and the pulmonary circulation providing sufficient blood flow and oxygen to peripheral tissues and organs according to their metabolic demand. This review focuses on three major cell types of the cardiovascular system: myocytes of the heart as well as smooth muscle cells and endothelial cells from the systemic and pulmonary circulation. Ion channels initiate and regulate contraction in all three cell types, and the identification of their genes has significantly improved our knowledge of signal transduction pathways in these cells. Among the ion channels expressed in smooth muscle cells, cation channels of the TRPC family allow for the entry of Na(+) and Ca(2+). Physiological functions of TRPC1, TRPC3, TRPC4, TRPC5, TRPC6 and TRPC7 in the cardiovascular system, dissected by down-regulating channel activity in isolated tissues or by the analysis of gene-deficient mouse models, are reviewed. Possible functional roles and physiological regulation of TRPCs as homomeric or heteromeric channels in these cell types are discussed. Moreover, TRP channels may also be responsible for pathophysiological processes of the cardiovascular system like hypertension as well as cardiac hypertrophy and increased endothelial permeability. PMID:17433435

  5. Peripheral giant cell granuloma.

    PubMed

    Adlakha, V K; Chandna, P; Rehani, U; Rana, V; Malik, P

    2010-01-01

    Peripheral giant cell granuloma is a benign reactive lesion of gingiva. It manifests as a firm, soft, bright nodule or as a sessile or pedunculate mass. This article reports the management of peripheral giant cell granuloma in a 12-year-old boy by surgical excision. PMID:21273719

  6. Peripheral Color Demo

    PubMed Central

    2015-01-01

    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. PMID:27551354

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  8. Peripheral Neuropathy: Symptoms and Signs

    MedlinePlus

    ... Research News Make a Difference Symptoms of Peripheral Neuropathy Print This Page Peripheral Neuropathy symptoms usually start ... slowly over many years. The symptoms of peripheral neuropathy often include: A sensation of wearing an invisible “ ...

  9. 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…

  10. Occlusive Peripheral Arterial Disease

    MedlinePlus

    ... artery. Such people should seek medical care immediately. Did You Know... When people suddenly develop a painful, ... In This Article Animation 1 Peripheral Arterial Disease Did You Know 1 Did You Know... Figure 1 ...

  11. Peripheral Vascular Disease

    MedlinePlus

    ... Information Center Back to previous page En español Aneurysms and Dissections Angina Arrhythmia Bundle Branch Block Cardiomyopathy ... blockage including peripheral artery disease or PAD Aortic aneurysms Buerger's Disease Raynaud's Phenomenon Disease of the veins ...

  12. 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, ...

  13. Peripheral artery bypass - leg

    MedlinePlus

    ... P. Peripheral arterial diseases. In: Mann DL, Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald's ... noncoronary obstructive vascular disease.In: Mann DL, Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald's ...

  14. Peripheral Artery Disease (PAD)

    MedlinePlus

    ... changes and medication . View an animation of atherosclerosis Atherosclerosis and PAD Atherosclerosis is a disease in which plaque builds up ... of an artery. PAD is usually caused by atherosclerosis in the peripheral arteries (or outer regions away ...

  15. 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

  16. Permanent Peripheral Neuropathy

    PubMed Central

    Higgins, Elizabeth

    2014-01-01

    The health risks and side effects of fluoroquinolone use include the risk of tendon rupture and myasthenia gravis exacerbation, and on August 15, 2013, the Food and Drug Administration updated its warning to include the risk of permanent peripheral neuropathy. We present a case of fluoroquinolone-induced peripheral neuropathy in a patient treated for clinically diagnosed urinary tract infection with ciprofloxacin antibiotic. PMID:26425618

  17. Nf1 Loss and Ras Hyperactivation in Oligodendrocytes Induce NOS-Driven Defects in Myelin and Vasculature

    PubMed Central

    Mayes, Debra A.; Rizvi, Tilat A.; Titus-Mitchell, Haley; Oberst, Rachel; Ciraolo, Georgianne M.; Vorhees, Charles V.; Robinson, Andrew P.; Miller, Stephen D.; Cancelas, Jose A.; Stemmer-Rachamimov, Anat O.; Ratner, Nancy

    2014-01-01

    SUMMARY Patients with neurofibromatosis type 1 (NF1) and Costello syndrome Rasopathy have behavioral deficits. In NF1 patients, these may correlate with white matter enlargement and aberrant myelin. To model these features, we induced Nf1 loss or HRas hyperactivation in mouse oligodendrocytes. Enlarged brain white matter tracts correlated with myelin decompaction, downregulation of claudin-11, and mislocalization of connexin-32. Surprisingly, non-cell-autonomous defects in perivascular astrocytes and the blood-brain barrier (BBB) developed, implicating a soluble mediator. Nitric oxide (NO) can disrupt tight junctions and gap junctions, and NO and NO synthases (NOS1–NOS3) were upregulated in mutant white matter. Treating mice with the NOS inhibitor NG-nitro-L-arginine methyl ester or the antioxidant N-acetyl cysteine corrected cellular phenotypes. CNP-HRasG12V mice also displayed locomotor hyperactivity, which could be rescued by antioxidant treatment. We conclude that Nf1/Ras regulates oligodendrocyte NOS and that dysregulated NO signaling in oligodendrocytes can alter the surrounding vasculature. The data suggest that anti-oxidants may improve some behavioral deficits in Rasopathy patients. PMID:24035394

  18. 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

  19. Peripheral tissue homing receptor control of naïve, effector, and memory CD8 T cell localization in lymphoid and non-lymphoid tissues.

    PubMed

    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

  20. 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.

  1. 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

  2. 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.

  3. 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. PMID:25449784

  4. 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

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

    PubMed

    Chen, Feng; Hong, Hao; Goel, Shreya; Graves, Stephen A; Orbay, Hakan; Ehlerding, Emily B; Shi, Sixiang; Theuer, Charles P; Nickles, Robert J; Cai, Weibo

    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

  6. [A peripheral osteoma].

    PubMed

    Mizbah, K; Soehardi, A; Maal, T J J; Weijs, W L J; Merkx, M A W; Barkhuysen, R

    2012-02-01

    A 43-year-old man appeared with a painless, asymptomatic swelling on the left side of his neck, which had existed for years and had slowly been progressing. After surgical removal, it became clear that it had to do with a peripheral osteoma. This is a benign lesion with a low incidence. Generally, complete surgical removal leads to cure, although recurrence is possible. A peripheral osteoma is mostly located in the mandible, although peripheral osteomata in the frontal or maxillary sinus have been described. The aetiology is unknown. Trauma in the patient's history has been described on occasion. The presence of multiple osteomata in the jawbones is characteristic of Gardner's syndrome. PMID:22428273

  7. Painful Peripheral Neuropathies

    PubMed Central

    Marchettini, P; Lacerenza, M; Mauri, E; Marangoni, C

    2006-01-01

    Peripheral neuropathies are a heterogeneous group of diseases affecting peripheral nerves. The causes are multiple: hereditary, metabolic, infectious, inflammatory, toxic, traumatic. The temporal profile includes acute, subacute and chronic conditions. The majority of peripheral neuropathies cause mainly muscle weakness and sensory loss, positive sensory symptoms and sometimes pain. When pain is present, however, it is usually extremely intense and among the most disabling symptoms for the patients. In addition, the neurological origin of the pain is often missed and patients receive inadequate or delayed specific treatment. Independently of the disease causing the peripheral nerve injury, pain originating from axonal pathology or ganglionopathy privileges neuropathies affecting smaller fibres, a clinical observation that points towards abnormal activity within nociceptive afferents as a main generator of pain. Natural activation of blood vessels or perineurial nociceptive network by pathology also causes intense pain. Pain of this kind, i.e. nerve trunk pain, is among the heralding symptoms of inflammatory or ischemic mononeuropathy and for its intensity represents itself a medical emergency. Neuropathic pain quality rekindles the psychophysical experience of peripheral nerves intraneural microstimulation i.e. a combination of large and small fibres sensation temporally distorted compared to physiological perception evoked by natural stimuli. Pins and needles, burning, cramping mixed with numbness, and tingling are the wording most used by patients. Nociceptive pain instead is most often described as aching, deep and dull. Good command of peripheral nerve anatomy and pathophysiology allows timely recognition of the different pain components and targeted treatment, selected according to intensity, type and temporal profile of the pain. PMID:18615140

  8. AECHL-1, a novel triterpenoid, targets tumor neo-vasculature and impairs the endothelial cell cytoskeleton.

    PubMed

    Dasgupta, Aparajita; Sawant, Mithila A; Lavhale, Manish S; Krishnapati, Lakshmi-Surekha; Ghaskadbi, Surendra; Sitasawad, Sandhya L

    2015-07-01

    Tumor angiogenesis is characterized by abnormal vessel morphology leading to erratic and insufficient delivery of chemotherapeutics and oxygen, making the tumor core not only highly hypoxic but also unresponsive toward treatment. Such hypoxic conditions promote tumor aggressiveness, leading to the establishment of metastatic disease. Most anti-angiogenic treatments aim toward the destruction of tumor vasculature, which proves countereffective by further increasing its aggressive nature. Hence, developing drugs which target or regulate these processes might lead to a better delivery of chemotherapeutics resulting in tumor shrinkage. Plant-derived natural compounds having a bioactive ingredient, especially triterpenoids, have been known to possess anticancer properties. AECHL-1, a recently isolated novel triterpenoid with proven anticancer potential, is seemingly noncytotoxic toward HEK 293 and HUVECs. Also, cytotoxicity was absent during in vivo studies involving intraperitoneal injections with 5 µg/kg body weight AECHL-1 on SCID mice. When used at subtoxic doses, it was found to be effective in suppression of neo-vessel formation as demonstrated in the chick chorioallantoic membrane, rat aortic rings, Matrigel plugs and xenograft tumors implanted in SCID mice. Tumor vasculature from AECHL-1-treated mice showed greater mural cell coverage and relatively normalized architecture. Investigations into the molecular mechanisms responsible for these observations revealed an effect on the actin cytoskeleton of stimulated HUVECs as well as the VEGFR2-mediated MAPK pathway. AECHL-1 could effectively distinguish between stimulated and nonstimulated endothelial cells. AECHL-1 could also downregulate HIF-1α expression and VEGF secretion under hypoxic conditions, thus reducing the fears of unnecessarily aggravating tumor metastasis as a result of anti-angiogenic therapy. Results obtained from the aforementioned studies make it clear that though AECHL-1 shows promise in

  9. Sensitivity of CFD Based Hemodynamic Results in Rabbit Aneurysm Models to Idealizations in Surrounding Vasculature

    PubMed Central

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

    2010-01-01

    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

  10. 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

  11. 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

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

    PubMed

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

    2016-04-12

    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

  13. Selective targeting of bioengineered platelets to prostate cancer vasculature: new paradigm for therapeutic modalities.

    PubMed

    Montecinos, Viviana P; Morales, Claudio H; Fischer, Thomas H; Burns, Sarah; San Francisco, Ignacio F; Godoy, Alejandro S; Smith, Gary J

    2015-07-01

    Androgen deprivation therapy (ADT) provides palliation for most patients with advanced prostate cancer (CaP); however, greater than 80% subsequently fail ADT. ADT has been indicated to induce an acute but transient destabilization of the prostate vasculature in animal models and humans. Human re-hydrated lyophilized platelets (hRL-P) were investigated as a prototype for therapeutic agents designed to target selectively the tumour-associated vasculature in CaP. The ability of hRL-P to bind the perturbed endothelial cells was tested using thrombin- and ADP-activated human umbilical vein endothelial cells (HUVEC), as well as primary xenografts of human prostate tissue undergoing acute vascular involution in response to ADT. hRL-P adhered to activated HUVEC in a dose-responsive manner. Systemically administered hRL-P, and hRL-P loaded with super-paramagnetic iron oxide (SPIO) nanoparticles, selectively targeted the ADT-damaged human microvasculature in primary xenografts of human prostate tissue. This study demonstrated that hRL-P pre-loaded with chemo-therapeutics or nanoparticles could provide a new paradigm for therapeutic modalities to prevent the rebound/increase in prostate vasculature after ADT, inhibiting the transition to castration-recurrent growth. PMID:25736582

  14. 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.

  15. Reconstruction and representation of caudal vasculature of zebrafish embryo from confocal scanning laser fluorescence microscopic images.

    PubMed

    Feng, Jun; Cheng, Shuk Han; Chan, Po K; Ip, Horace H S

    2005-12-01

    Three-dimensional (3D) reconstruction from a series of sections is an important technique in medical imaging, particularly for visualization of blood vessels from angiography. Here, we present a framework for automatic segmentation and registration of different kind of blood vessels from 2-day-old zebrafish embryos. Series of optical sections were acquired from confocal microscopy with the blood vessels labeled by fluorescent microbeads (0.02 microm) injected into blood stream of 2-day-old zebrafish embryos. Blood vessels were extracted and their morphological parameters, including length and diameter, were calculated. At the same time, individual blood vessels were registered automatically. Vasculature was represented by attributed vessel represent graph (AVRG), which contained morphological data and connectivity of every blood vessel. Using AVRG to represent a vasculature made the comparison between vasculatures of different embryos more easy. Visualization, as well as quantification, of reconstructed 3D model of AVRG was presented in an interactive interface. The framework was implemented by Visual C++ as Windows-based program. PMID:16263106

  16. Retinal Vasculature of Adult Zebrafish: In Vivo Imaging Using Confocal Scanning Laser Ophthalmoscopy

    PubMed Central

    Bell, Brent A.; Xie, Jing; Yuan, Alex; Kaul, Charles; Hollyfield, Joe G.; Anand-Apte, Bela

    2014-01-01

    Over the past 3 decades the zebrafish (Danio rerio) has become an important biomedical research species. As their use continues to grow additional techniques and tools will be required to keep pace with ongoing research using this species. In this paper we describe a novel method for in vivo imaging of the retinal vasculature in adult animals using a commercially available confocal scanning laser ophthalmoscope (SLO). With this instrumentation, we demonstrate the ability to distinguish diverse vascular phenotypes in different transgenic GFP lines. In addition this technology allows repeated visualization of the vasculature in individual zebrafish over time to document vascular leakage progression and recovery induced by intraocular delivery of proteins that induce vascular permeability. SLO of the retinal vasculature was found to be highly informative, providing images of high contrast and resolution that were capable of resolving individual vascular endothelial cells. Finally, the procedures required to acquire SLO images from zebrafish are non-invasive, simple to perform and can be achieved with low animal mortality, allowing repeated imaging of individual fish. PMID:25447564

  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. 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

  19. 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

  20. 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.

  1. 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

  2. Peripheral Artery Disease and Diabetes

    MedlinePlus

    ... High Blood Pressure Tools & Resources Stroke 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 ...

  3. 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 - ...

  4. Impaired Nitric Oxide Mediated Vasodilation In The Peripheral Circulation In The R6/2 Mouse Model Of Huntington's Disease.

    PubMed

    Kane, Andrew D; Niu, Youguo; Herrera, Emilio A; Morton, A Jennifer; Giussani, Dino A

    2016-01-01

    Recent evidence shows that the Huntington's disease (HD) extends beyond the nervous system to other sites, including the cardiovascular system. Further, the cardiovascular pathology pre-dates neurological decline, however the mechanisms involved remain unclear. We investigated in the R6/2 mouse model of HD nitric oxide (NO) dependent and independent endothelial mechanisms. Femoral artery reactivity was determined by wire myography in wild type (WT) and R6/2 mice at 12 and 16 weeks of adulthood. WT mice showed increased endothelial relaxation between 12 and 16 weeks (Rmax: 72 ± 7% vs. 97 ± 13%, P < 0.05). In contrast, R6/2 mice showed enhanced endothelial relaxation already by 12 weeks (Rmax at 12w: 72 ± 7% vs. 94 ± 5%, WT vs. R6/2, P < 0.05) that declined by 16 weeks compared with WT mice (Rmax at 16w: 97 ± 13% vs. 68 ± 7%, WT vs. R6/2, P < 0.05). In WT mice, the increase in femoral relaxation between 12 and 16 weeks was due to enhanced NO dependent mechanisms. By 16 weeks of adult age, the R6/2 mouse developed overt endothelial dysfunction due to an inability to increase NO dependent vasodilation. The data add to the growing literature of non-neural manifestations of HD and implicate NO depletion as a key mechanism underlying the HD pathophysiology in the peripheral vasculature. PMID:27181166

  5. 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

  6. 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. PMID:26602549

  7. [Ganglia of peripheral nerves].

    PubMed

    Tatagiba, M; Penkert, G; Samii, M

    1993-01-01

    The authors present two different types of ganglion affecting the peripheral nerves: extraneural and intraneural ganglion. Compression of peripheral nerves by articular ganglions is well known. The surgical management involves the complete removal of the lesion with preservation of most nerve fascicles. Intraneural ganglion is an uncommon lesion which affects the nerve diffusely. The nerve fascicles are usually intimately involved between the cysts, making complete removal of all cysts impossible. There is no agreement about the best surgical management to be applied in these cases. Two possibilities are available: opening of the epineural sheath lengthwise and pressing out the lesion; or resection of the affected part of the nerve and performing a nerve reconstruction. While in case of extraneural ganglion the postoperative clinical evolution is very favourable, only long follow up studies will reveal in case of intraneural ganglion the best surgical approach. PMID:8128785

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. Fibroblast growth factor-2 facilitates rapid anastomosis formation between bioengineered human vascular networks and living vasculature

    PubMed Central

    Lin, Ruei-Zeng; Melero-Martin, Juan M.

    2012-01-01

    Many common diseases involve the injury, loss, or death of organ tissues. For these patients, organ transplantation is often the only viable solution. Nonetheless, organ transplantation is seriously limited by the relative scarcity of living and non-living donors, a situation that is worsening with aging of the world population. Tissue Engineering (TE) is a research discipline in regenerative medicine that aims to generate tissues in the laboratory that can replace diseased and damaged tissues in patients. Crucially, engineered tissues must have a vascular network that guarantees adequate nutrient supply, gas exchange, and elimination of waste products. Therefore, the search for clinically relevant sources of vasculogenic cells and the subsequent development of methods to achieve rapid vascularization is of utmost importance. We and others have previously shown that human blood-derived endothelial colony-forming cells (ECFCs) have the required vasculogenic capacity to form functional vascular networks in vivo. These studies demonstrated that, in the presence of an appropriate source of perivascular cells, ECFCs can self-assemble into microvascular networks and connect to the host vasculature, a process that takes approximately 7 days in vivo. The prospect is to incorporate these vascular networks into future engineered tissues. However, engineered tissues must have a functional vasculature immediately after implantation in order to preserve viability and function. Thus, it is critical to further develop strategies for rapid formation of perfused vascular network in vivo. Here, we describe a methodology to deliver ECFCs and bone marrow-derived mesenchymal stem cells (MSCs) subcutaneously into immunodeficient mice in the presence of fibroblast growth factor-2 (FGF-2). This approach significantly reduces the time needed to achieve functional anastomoses between bioengineered human blood vessels and the host vasculature. This methodology includes (1) isolation

  14. Metabolism and bioenergetics in the right ventricle and pulmonary vasculature in pulmonary hypertension

    PubMed Central

    Archer, Stephen L.; Fang, Yong-Hu; Ryan, John J.; Piao, Lin

    2013-01-01

    Pulmonary arterial hypertension (PAH) is a syndrome in which pulmonary vascular cross sectional area and compliance are reduced by vasoconstriction, vascular remodeling, and inflammation. Vascular remodeling results in part from increased proliferation and impaired apoptosis of vascular cells. The resulting increase in afterload promotes right ventricular hypertrophy (RVH) and RV failure. Recently identified mitochondrial-metabolic abnormalities in PAH, notably pyruvate dehydrogenase kinase-mediated inhibition of pyruvate dehydrogenase (PDH), result in aerobic glycolysis in both the lung vasculature and RV. This glycolytic shift has diagnostic importance since it is detectable early in experimental PAH by increased lung and RV uptake of 18F-fluorodeoxyglucose on positron emission tomography. The metabolic shift also has pathophysiologic and therapeutic relevance. In RV myocytes, the glycolytic switch reduces contractility while in the vasculature it renders cells hyperproliferative and apoptosis-resistant. Reactivation of PDH can be achieved directly by PDK inhibition (using dichloroacetate), or indirectly via activating the Randle cycle, using inhibitors of fatty acid oxidation (FAO), trimetazidine and ranolazine. In experimental PAH and RVH, PDK inhibition increases glucose oxidation, enhances RV function, regresses pulmonary vascular disease by reducing proliferation and enhancing apoptosis, and restores cardiac repolarization. FAO inhibition increases RV glucose oxidation and RV function in experimental RVH. The trigger for metabolic remodeling in the RV and lung differ. In the RV, metabolic remodeling is likely triggered by ischemia (due to microvascular rarefaction and/or reduced coronary perfusion pressure). In the vasculature, metabolic changes result from redox-mediated activation of transcription factors, including hypoxia-inducible factor 1α, as a consequence of epigenetic silencing of SOD2 and/or changes in mitochondrial fission/fusion. Randomized

  15. 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.

  16. Variation in the Obturator Vasculature During Routine Anatomy Dissection of a Cadaver.

    PubMed

    Deshmukh, Vishwajit; Singh, Seema; Sirohi, Neerja; Baruhee, Divya

    2016-08-01

    The obturator artery normally originates from the internal iliac artery while the obturator vein drains into the internal iliac vein. During a routine gross anatomy dissection class for undergraduate students at the All India Institute of Medical Sciences, New Delhi, India, in 2016, a rare unilateral variation in the obturator vasculature was found in a female cadaver of approximately 55 years of age. In this case, the left obturator artery originated from the superior gluteal artery and the left obturator vein drained into the external iliac vein. Knowledge of such variations is necessary during hernia procedures, ligation of the internal iliac artery and muscle graft surgeries. PMID:27606118

  17. Variation in the Obturator Vasculature During Routine Anatomy Dissection of a Cadaver

    PubMed Central

    Deshmukh, Vishwajit; Singh, Seema; Sirohi, Neerja; Baruhee, Divya

    2016-01-01

    The obturator artery normally originates from the internal iliac artery while the obturator vein drains into the internal iliac vein. During a routine gross anatomy dissection class for undergraduate students at the All India Institute of Medical Sciences, New Delhi, India, in 2016, a rare unilateral variation in the obturator vasculature was found in a female cadaver of approximately 55 years of age. In this case, the left obturator artery originated from the superior gluteal artery and the left obturator vein drained into the external iliac vein. Knowledge of such variations is necessary during hernia procedures, ligation of the internal iliac artery and muscle graft surgeries. PMID:27606118

  18. An alternative tool for intraoperative assessment of renal vasculature after revascularization of a transplanted kidney.

    PubMed

    Sawada, Tokihiko; Solly, Mizrahi; Kita, Junji; Shimoda, Mitsugi; Kubota, Keiichi

    2010-06-01

    Intraoperative assessment of flow in the renal artery and vein after reconstruction is a crucial matter in kidney transplantation. Conventional Doppler ultrasound detects blood flow only in a limited area. The authors report a newly developed device that noninvasively visualizes the condition of perfusion of an entire allograft at one time from any angle and also clearly detects the state of anastomosis of the renal vessels. This near-infrared camera system provides the opportunity for the intraoperative assessment of the vasculature of renal allografts. PMID:20409513

  19. [Chemotherapy induced peripheral neuropathy].

    PubMed

    Kolak, Agnieszka; Starosławska, Elzbieta; Kubiatowski, Tomasz; Kieszko, Dariusz; Cisek, Paweł; Patyra, Krzysztof Ireneusz; Surdyka, Dariusz; Mocarska, Agnieszka; Burdan, Franciszek

    2013-11-01

    Modern cancer therapy prolongs patients life but commonly increases incidence of treatment-related complications. One of such adverse effect is a neurotoxicity, which usually manifestates as peripheral neuropathies (CIPN), characterised by various sensory (tingling, numbness, pain), motor (foot and hands drop, fastening buttons difficulties) and autonomic (constipation, arythmia) abnormalities as well as pain. Despite of intensive epidemiological and clinical studies, standardized diagnostic criteria and methods of the neuropathy prevention and treatment have not been fully established. The most commonly used form of treatment is symptomatic therapy, including anticonvulsant and antidepressant drugs. Proper education of patients and their families of symptoms and neuropathy consequences is desirable to reduce anxiety and stress. PMID:24575651

  20. Renal oxygenation: preglomerular vasculature is an unlikely contributor to renal oxygen shunting.

    PubMed

    Olgac, Ufuk; Kurtcuoglu, Vartan

    2015-04-01

    The primary aim of this study was to assess the plausibility of preglomerular arterial-to-venous oxygen shunting in the kidney. To this end, we have developed a segment-wise three-dimensional computational model that takes into account transport processes in arteries, veins, cortical tissue, and capillaries. Our model suggests that the amount of preglomerular oxygen shunting is negligible. Consequently, it is improbable that preglomerular shunting contributes to the hypothesized regulation of renal oxygenation. Cortical tissue oxygenation is more likely determined by the interplay between oxygen supply, either from the preglomerular vasculature or from capillaries, and oxygen consumption. We show that reported differences in permeability to oxygen between perfused and unperfused tissue may be explained by what we refer to as advection-facilitated diffusion. We further show that the preglomerular vasculature is the primary source of oxygen for the tissue when cortical consumption is high or renal arterial blood is highly oxygenated, i.e., under hyperoxemic conditions. Conversely, when oxygen demand in the tissue is decreased, or under hypoxemic conditions, oxygen is supplied predominantly by capillaries. PMID:25503734

  1. Generation of a functional liver tissue mimic using adipose stromal vascular fraction cell-derived vasculatures

    PubMed Central

    Nunes, S. S.; Maijub, J. G.; Krishnan, L.; Ramakrishnan, V. M.; Clayton, L. R.; Williams, S. K.; Hoying, J. B.; Boyd, N. L.

    2013-01-01

    One of the major challenges in cell implantation therapies is to promote integration of the microcirculation between the implanted cells and the host. We used adipose-derived stromal vascular fraction (SVF) cells to vascularize a human liver cell (HepG2) implant. We hypothesized that the SVF cells would form a functional microcirculation via vascular assembly and inosculation with the host vasculature. Initially, we assessed the extent and character of neovasculatures formed by freshly isolated and cultured SVF cells and found that freshly isolated cells have a higher vascularization potential. Generation of a 3D implant containing fresh SVF and HepG2 cells formed a tissue in which HepG2 cells were entwined with a network of microvessels. Implanted HepG2 cells sequestered labeled LDL delivered by systemic intravascular injection only in SVF-vascularized implants demonstrating that SVF cell-derived vasculatures can effectively integrate with host vessels and interface with parenchymal cells to form a functional tissue mimic. PMID:23828203

  2. Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination

    PubMed Central

    Anderberg, Charlotte; Cunha, Sara I.; Zhai, Zhenhua; Cortez, Eliane; Pardali, Evangelia; Johnson, Jill R.; Franco, Marcela; Páez-Ribes, Marta; Cordiner, Ross; Fuxe, Jonas; Johansson, Bengt R.; Goumans, Marie-José; Casanovas, Oriol; ten Dijke, Peter; Arthur, Helen M.

    2013-01-01

    Therapy-induced resistance remains a significant hurdle to achieve long-lasting responses and cures in cancer patients. We investigated the long-term consequences of genetically impaired angiogenesis by engineering multiple tumor models deprived of endoglin, a co-receptor for TGF-β in endothelial cells actively engaged in angiogenesis. Tumors from endoglin-deficient mice adapted to the weakened angiogenic response, and refractoriness to diminished endoglin signaling was accompanied by increased metastatic capability. Mechanistic studies in multiple mouse models of cancer revealed that deficiency for endoglin resulted in a tumor vasculature that displayed hallmarks of endothelial-to-mesenchymal transition, a process of previously unknown significance in cancer biology, but shown by us to be associated with a reduced capacity of the vasculature to avert tumor cell intra- and extravasation. Nevertheless, tumors deprived of endoglin exhibited a delayed onset of resistance to anti-VEGF (vascular endothelial growth factor) agents, illustrating the therapeutic utility of combinatorial targeting of multiple angiogenic pathways for the treatment of cancer. PMID:23401487

  3. 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.

  4. 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

  5. The role of RNA interference in the developmental separation of blood and lymphatic vasculature

    PubMed Central

    2014-01-01

    Background Dicer is an RNase III enzyme that cleaves double stranded RNA and generates functional interfering RNAs that act as important regulators of gene and protein expression. Dicer plays an essential role during mouse development because the deletion of the dicer gene leads to embryonic death. In addition, dicer-dependent interfering RNAs regulate postnatal angiogenesis. However, the role of dicer is not yet fully elucidated during vascular development. Methods In order to explore the functional roles of the RNA interference in vascular biology, we developed a new constitutive Cre/loxP-mediated inactivation of dicer in tie2 expressing cells. Results We show that cell-specific inactivation of dicer in Tie2 expressing cells does not perturb early blood vessel development and patterning. Tie2-Cre; dicerfl/fl mutant embryos do not show any blood vascular defects until embryonic day (E)12.5, a time at which hemorrhages and edema appear. Then, midgestational lethality occurs at E14.5 in mutant embryos. The developing lymphatic vessels of dicer-mutant embryos are filled with circulating red blood cells, revealing an impaired separation of blood and lymphatic vasculature. Conclusion Thus, these results show that RNA interference perturbs neither vasculogenesis and developmental angiogenesis, nor lymphatic specification from venous endothelial cells but actually provides evidence for an epigenetic control of separation of blood and lymphatic vasculature. PMID:24690185

  6. The cadaveric perfusion and angiography as a teaching tool: imaging the intracranial vasculature in cadavers.

    PubMed

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

    2014-12-01

    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

  7. 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

  8. Modelling the Role of the Coronary Vasculature During External Field Stimulation

    PubMed Central

    Bishop, Martin J.; Boyle, Patrick M.; Plank, Gernot; Welsh, Donald G.; Vigmond, Edward J.

    2010-01-01

    The exact mechanisms by which defibrillation shocks excite cardiac tissue far from both the electrodes and heart surfaces require elucidation. Bidomain theory explains this phenomena through the existence of intramural virtual electrodes (VEs), caused by discontinuities in myocardial tissue structure. In this study, we assess the modelling components essential in constructing a finite element cardiac tissue model including blood vessels from high resolution MR data and investigate the specific role played by coronary vasculature in VE formation, which currently remains largely unknown. We use a novel method for assigning histologically-based fibre architecture around intramural structures and include an experimentally-derived vessel lumen wall conductance within the model. Shock-tissue interaction in the presence of vessels was assessed through comparison with a simplified model lacking intramural structures. Results indicate that VEs form around blood vessels for shocks > 8 V/cm. The magnitude of induced polarisations is attenuated by realistic representation of fibre negotiation around vessel cavities, as well as the insulating effects of the vessel lumen wall. Furthermore, VEs formed around large sub-epicardial vessels reduce epicardial polarisation levels. In conclusion, we have found that coronary vasculature acts as an important substrate for VE formation, which may help interpretation of optical mapping data. PMID:20542762

  9. 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.

  10. Effects of CXC chemokines on neutrophil activation and sequestration in hepatic vasculature.

    PubMed

    Bajt, M L; Farhood, A; Jaeschke, H

    2001-11-01

    The initiating step of neutrophil-induced cytotoxicity in the liver is the recruitment of these phagocytes into sinusoids. The aim of our study was to compare the efficacy of systemic exposure with individual inflammatory mediators on neutrophil activation and sequestration in the hepatic vasculature of C3Heb/FeJ mice as assessed by flow cytometry and histochemistry, respectively. The CXC chemokine macrophage inflammatory protein-2 (MIP-2; 20 microg/kg) induced a time-dependent upregulation of Mac-1 (318% at 4 h) and shedding of L-selectin (41% at 4 h). MIP-2 treatment caused a temporary increase of sinusoidal neutrophil accumulation at 0.5 h [97 +/- 6 polymorphonuclear leukocytes (PMN)/50 high-power fields (HPF)], which declined to baseline (8 +/- 2) at 4 h. The CXC chemokine KC was largely ineffective in activating neutrophils or recruiting them into the liver. Cytokines (tumor necrosis factor-alpha and interleukin-1alpha) and cobra venom factor substantially increased Mac-1 expression and L-selectin shedding on neutrophils and caused stable sinusoidal neutrophil accumulation (170-220 PMN/50 HPF). Only cytokines induced venular neutrophil margination. Thus CXC chemokines in circulation are less effective than cytokines or complement in activation of neutrophils and their recruitment into the hepatic vasculature in vivo. PMID:11668027

  11. Automatic anatomical labeling of the complete cerebral vasculature in mouse models.

    PubMed

    Ghanavati, Sahar; Lerch, Jason P; Sled, John G

    2014-07-15

    Study of cerebral vascular structure broadens our understanding of underlying variations, such as pathologies that can lead to cerebrovascular disorders. The development of high resolution 3D imaging modalities has provided us with the raw material to study the blood vessels in small animals such as mice. However, the high complexity and 3D nature of the cerebral vasculature make comparison and analysis of the vessels difficult, time-consuming and laborious. Here we present a framework for automated segmentation and recognition of the cerebral vessels in high resolution 3D images that addresses this need. The vasculature is segmented by following vessel center lines starting from automatically generated seeds and the vascular structure is represented as a graph. Each vessel segment is represented as an edge in the graph and has local features such as length, diameter, and direction, and relational features representing the connectivity of the vessel segments. Using these features, each edge in the graph is automatically labeled with its anatomical name using a stochastic relaxation algorithm. We have validated our method on micro-CT images of C57Bl/6J mice. A leave-one-out test performed on the labeled data set demonstrated the recognition rate for all vessels including major named vessels and their minor branches to be >75%. This automatic segmentation and recognition methods facilitate the comparison of blood vessels in large populations of subjects and allow us to study cerebrovascular variations. PMID:24680868

  12. 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.

  13. Diverse roles of the vasculature within the neural stem cell niche

    PubMed Central

    Goldberg, Joshua S; Hirschi, Karen K

    2010-01-01

    An interdependent relationship between the vascular and nervous systems begins during the earliest stages of development and persists through the mammalian lifespan. Accordingly, the process of adult neurogenesis involves the coordinated response of both systems to maintain a specialized microenvironment (niche) that tips the scale towards maintenance or regeneration, as needed. Understanding the nature and regulation of this balance will provide a foundation on which the potential for molecular-and stem cell-based therapies can be developed to treat prevalent CNS diseases and disorders. The vasculature is cited as a prominent feature within the adult subventricular zone and subgranular zone, known adult neural stem cell niches, helping to retain neural stem and progenitor cell potential. The vascular compartment within the neural stem cell niche has the unique opportunity to not only regulate neural stem and progenitor cells through direct contact with, and paracrine signaling from, endothelial and mural cells that make up blood vessels, but also integrates systemic signals into the local microenvironment via distribution of soluble factors from blood circulation to regulate stem cell niche behavior. Understanding the intricate role that the vasculature plays to influence neural stem cells in the context of niche regulation will help to bridge the gap from bench to bedside for the development of regeneration-based therapies for the CNS. PMID:19903006

  14. Characterization of an Isolated Kidney's Vasculature for Use in Bio-Thermal Modeling

    NASA Astrophysics Data System (ADS)

    Payne, Allison H.; Parker, Dennis L.; Moellmer, Jeff; Roemer, Robert B.; Clifford, Sarah

    2007-05-01

    Accurate bio-thermal modeling requires site-specific modeling of discrete vascular anatomy. Presented herewith are several steps that have been developed to describe the vessel network of isolated canine and bovine kidneys. These perfused, isolated kidneys provide an environment to repeatedly test and improve acquisition methods to visualize the vascular anatomy, as well as providing a method to experimentally validate discrete vasculature thermal models. The organs are preserved using a previously developed methodology that keeps the vasculature intact, allowing for the organ to be perfused. It also allows for the repeated fixation and re-hydration of the same organ, permitting the comparison of various methods and models. The organ extraction, alcohol preservation, and perfusion of the organ are described. The vessel locations were obtained through a high-resolution time-of-flight (TOF) magnetic resonance angiography (MRA) technique. Sequential improvements of both the experimental setup used for this acquisition, as well as MR sequence development are presented. The improvements in MR acquisition and experimental setup improved the number of vessels seen in both the raw data and segmented images by 50%. An automatic vessel centerline extraction algorithm describes both vessel location and genealogy. Centerline descriptions also allows for vessel diameter and flow rate determination, providing valuable input parameters for the discrete vascular thermal model. Characterized vessels networks of both canine and bovine kidneys are presented. While these tools have been developed in an ex vivo environment, all steps can be applied to in vivo applications.

  15. Tumor endothelial marker 1–specific DNA vaccination targets tumor vasculature

    PubMed Central

    Facciponte, John G.; Ugel, Stefano; De Sanctis, Francesco; Li, Chunsheng; Wang, Liping; Nair, Gautham; Sehgal, Sandy; Raj, Arjun; Matthaiou, Efthymia; Coukos, George; Facciabene, Andrea

    2014-01-01

    Tumor endothelial marker 1 (TEM1; also known as endosialin or CD248) is a protein found on tumor vasculature and in tumor stroma. Here, we tested whether TEM1 has potential as a therapeutic target for cancer immunotherapy by immunizing immunocompetent mice with Tem1 cDNA fused to the minimal domain of the C fragment of tetanus toxoid (referred to herein as Tem1-TT vaccine). Tem1-TT vaccination elicited CD8+ and/or CD4+ T cell responses against immunodominant TEM1 protein sequences. Prophylactic immunization of animals with Tem1-TT prevented or delayed tumor formation in several murine tumor models. Therapeutic vaccination of tumor-bearing mice reduced tumor vascularity, increased infiltration of CD3+ T cells into the tumor, and controlled progression of established tumors. Tem1-TT vaccination also elicited CD8+ cytotoxic T cell responses against murine tumor-specific antigens. Effective Tem1-TT vaccination did not affect angiogenesis-dependent physiological processes, including wound healing and reproduction. Based on these data and the widespread expression of TEM1 on the vasculature of different tumor types, we conclude that targeting TEM1 has therapeutic potential in cancer immunotherapy. PMID:24642465

  16. VEGF165b in the developing vasculatures of the fetal human eye

    PubMed Central

    Baba, Takayuki; McLeod, D. Scott; Edwards, Malia M.; Merges, Carol; Sen, Tanusree; Sinha, Debasish; Lutty, Gerard A.

    2016-01-01

    VEGF165b is an anti-angiogenic form of VEGF165 produced by alternative splicing. The localization of pro-angiogenic VEGF165 and anti-angiogenic VEGF165b was investigated during development of the vasculatures in fetal human eyes from 7 to 21 weeks gestation (WG). The fetal vasculature of vitreous, which includes tunica vasculosa lentis (TVL), had moderate VEGF165 immunoreactivity at 7WG and very little VEGF165b. Both forms were elevated at 12WG. VEGF165 then decreased around 17WG when the TVL regresses but VEGF165b remained elevated. In choroid, VEGF165 was present in forming choriocapillaris (CC) and retinal pigment epithelium (RPE) at 7WG while VEGF165b was present in CC and mesenchymal precursors within the choroidal stroma. By 21WG, both forms were elevated in RPE and choroidal blood vessels but VEGF165b was apical and VEGF165 basal in RPE. Diffuse VEGF165 immunoreactivity was prominent in 12WG innermost retina where blood vessels will form while VEGF165b was present in most CXCR4+ progenitors in the inner neuroblastic layer and migrating angioblasts in the putative nerve fiber layer. By 21WG, VEGF165 was present in nerve fibers and VEGF165b in inner Muller cell process. The localization of VEGF165b was distinctly different from VEGF165 both spatially and temporally and it was often associated with nucleus in progenitors. PMID:22275161

  17. 3D Light-Sheet Fluorescence Microscopy of Cranial Neurons and Vasculature during Zebrafish Embryogenesis

    PubMed Central

    Park, Ok Kyu; Kwak, Jina; Jung, Yoo Jung; Kim, Young Ho; Hong, Hyun-Seok; Hwang, Byung Joon; Kwon, Seung-Hae; Kee, Yun

    2015-01-01

    Precise 3D spatial mapping of cells and their connections within living tissues is required to fully understand developmental processes and neural activities. Zebrafish embryos are relatively small and optically transparent, making them the vertebrate model of choice for live in vivo imaging. However, embryonic brains cannot be imaged in their entirety by confocal or two-photon microscopy due to limitations in optical range and scanning speed. Here, we use light-sheet fluorescence microscopy to overcome these limitations and image the entire head of live transgenic zebrafish embryos. We simultaneously imaged cranial neurons and blood vessels during embryogenesis, generating comprehensive 3D maps that provide insight into the coordinated morphogenesis of the nervous system and vasculature during early development. In addition, blood cells circulating through the entire head, vagal and cardiac vasculature were also visualized at high resolution in a 3D movie. These data provide the foundation for the construction of a complete 4D atlas of zebrafish embryogenesis and neural activity. PMID:26429501

  18. Peripheral neuropathies during biologic therapies.

    PubMed

    Yagita, Masato; Hamano, Toshiaki; Hatachi, Saori; Fujita, Masaaki

    2016-01-01

    Peripheral neuropathies should be recognized as the adverse effects of biological agents, especially anti-TNF agents. However, no solid clinical databases for biological agent-associated peripheral neuropathies (BAPN) have been established in Japan. Here we report two cases of peripheral neuropathy associated with anti-TNF agents. One was peroneal motor neuropathy. The other case was chronic inflammatory demyelinating polyradiculoneuropathy. In addition, we summarize the previous reports on BAPN and discuss their prevalence rate, pathogenesis and management. PMID:24313920

  19. Noise-immune complex correlation for vasculature imaging based on standard and Jones-matrix optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Makita, Shuichi; Kurokawa, Kazuhiro; Hong, Young-Joo; Li, En; Miura, Masahiro; Yasuno, Yoshiaki

    2016-03-01

    A new optical coherence angiography (OCA) method, called correlation mapping OCA (cmOCA), is presented by using the SNR-corrected complex correlation. An SNR-correction theory for the complex correlation calculation is presented. The method also integrates a motion-artifact-removal method for the sample motion induced decorrelation artifact. The theory is further extended to compute more reliable correlation by using multi- channel OCT systems, such as Jones-matrix OCT. The high contrast vasculature imaging of in vivo human posterior eye has been obtained. Composite imaging of cmOCA and degree of polarization uniformity indicates abnormalities of vasculature and pigmented tissues simultaneously.

  20. The use of microangiography in detecting aberrant vasculature in zebrafish embryos exposed to cadmium.

    PubMed

    Cheng, S H; Chan, P K; Wu, R S

    2001-03-01

    Embryonic vascular patterns in zebrafish (Danio rerio) could be visualised by confocal microscopy coupled with microinjected fluorescent microbeads. This microangiographic technique was adopted here, for the first time, to study the effects of cadmium on cardiovascular development in zebrafish embryos. Zebrafish embryos were incubated in culture medium containing 100 microM cadmium from 5 h post fertilisation (hpf) to 48 hpf. At 48 hpf, embryos were examined for viability and occurrence of malformations. The 100 microM cadmium caused 32.21 +/- 3.65% mortality and 20.33 +/- 4.04% visible malformations in surviving embryos. In the remaining embryos with no visible signs of malformations, further assessments for less obvious abnormalities were performed. Assessments on craniofacial development were made by digital measurements on areas of brains and eyes. Cardiac development was assessed by immunostaining the heart with the antibody MF20 specific for myosin heavy chain. Body lengths of the embryos were also measured. Embryonic development of brains, eyes, hearts and body lengths of visibly healthy embryos in the cadmium treatment group showed no significant difference from the controls. Embryonic vasculature of these visibly healthy embryos was then studied by microinjecting fluorescent microbeads of diameter 0.02 microm into the circulation. All the cadmium treated embryos showed localised vascular defects in the dorsal aortae, segmental and cranial vessels while none of the control embryos showed any aberrant patterns in the networking of the vasculature. Improved image analyses on the anterior regions revealed that cadmium treated embryos had markedly less complex networks of cranial vessels with fewer vessels perfusing the craniofacial regions. The number of branch points in the vascular network was counted. In untreated embryos, there were 135.6 +/- 51 branches in the vasculature in entire body. In the cadmium treated embryos, there were 64.5+/-31 branches. The

  1. 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

  2. Peripherally Silylated Porphyrins.

    PubMed

    Kato, Kenichi; Fujimoto, Keisuke; Yorimitsu, Hideki; Osuka, Atsuhiro

    2015-09-21

    Silylation of peripherally lithiated porphyrins with silyl electrophiles has realized the first synthesis of a series of directly silyl-substituted porphyrins. The meso-silyl group underwent facile protodesilylation, whereas the β-silyl group was entirely compatible with standard work-up and purification on silica gel. The meso-silyl group caused larger substituent effects to the porphyrin compared with the β-silyl group. Silylation of β-lithiated porphyrins with 1,2-dichlorodisilane furnished β-to-β disilane-bridged porphyrin dimers. A doubly β-to-β disilane-bridged Ni(II)-porphyrin dimer was also synthesized from a β,β-dilithiated Ni(II)-porphyrin and characterized by X-ray crystallographic analysis to take a steplike structure favorable for interporphyrinic interaction. Denickelation of β-silylporphyrins was achieved upon treatment with a 4-tolylmagnesium bromide to yield the corresponding freebase porphyrins. PMID:26356498

  3. Autoimmune peripheral neuropathies.

    PubMed

    Bourque, Pierre R; Chardon, Jodi Warman; Massie, Rami

    2015-09-20

    Peripheral nervous system axons and myelin have unique potential protein, proteolipid, and ganglioside antigenic determinants. Despite the existence of a blood-nerve barrier, both humoral and cellular immunity can be directed against peripheral axons and myelin. Molecular mimicry may be triggered at the systemic level, as was best demonstrated in the case of bacterial oligosaccharides. The classification of immune neuropathy has been expanded to take into account specific syndromes that share unique clinical, electrophysiological, prognostic and serological features. Guillain-Barré syndrome encompasses a classical syndrome of acute demyelinating polyradiculoneuropathy and many variants: axonal motor and sensory, axonal motor, Miller-Fisher, autonomic, and sensory. Similarly, chronic immune neuropathy is composed of classic chronic inflammatory demyelinating polyradiculoneuropathy and variants characterized as multifocal (motor or sensorimotor), sensory, distal symmetric, and syndromes associated with monoclonal gammopathy. Among putative biomarkers, myelin associated glycoprotein and several anti-ganglioside autoantibodies have shown statistically significant associations with specific neuropathic syndromes. Currently, the strongest biomarker associations are those linking Miller-Fisher syndrome with anti-GQ1b, multifocal motor neuropathy with anti-GM1, and distal acquired symmetric neuropathy with anti-MAG antibodies. Many other autoantibody associations have been proposed, but presently lack sufficient specificity and sensitivity to qualify as biomarkers. This field of research has contributed to the antigenic characterization of motor and sensory functional systems, as well as helping to define immune neuropathic syndromes with widely different clinical presentation, prognosis and response to therapy. Serologic biomarkers are likely to become even more relevant with the advent of new targeted forms of immunotherapy, such as monoclonal antibodies. PMID:25748038

  4. Automated Protein Localization of Blood Brain Barrier Vasculature in Brightfield IHC Images.

    PubMed

    Soans, Rajath E; Lim, Diane C; 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

  5. 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

  6. 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.

  7. 3D-printed fluidic networks as vasculature for engineered tissue.

    PubMed

    Kinstlinger, Ian S; Miller, Jordan S

    2016-05-24

    Fabrication of vascular networks within engineered tissue remains one of the greatest challenges facing the fields of biomaterials and tissue engineering. Historically, the structural complexity of vascular networks has limited their fabrication in tissues engineered in vitro. Recently, however, key advances have been made in constructing fluidic networks within biomaterials, suggesting a strategy for fabricating the architecture of the vasculature. These techniques build on emerging technologies within the microfluidics community as well as on 3D printing. The freeform fabrication capabilities of 3D printing are allowing investigators to fabricate fluidic networks with complex architecture inside biomaterial matrices. In this review, we examine the most exciting 3D printing-based techniques in this area. We also discuss opportunities for using these techniques to address open questions in vascular biology and biophysics, as well as for engineering therapeutic tissue substitutes in vitro. PMID:27173478

  8. 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.

  9. Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature.

    PubMed

    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

  10. 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.

  11. Imaging and graphing of cortical vasculature using dynamically focused optical coherence microscopy angiography

    NASA Astrophysics Data System (ADS)

    Leahy, Conor; Radhakrishnan, Harsha; Bernucci, Marcel; Srinivasan, Vivek J.

    2016-02-01

    Recently, optical coherence tomography (OCT) angiography has enabled label-free imaging of vasculature based on dynamic scattering in vessels. However, quantitative volumetric analysis of the vascular networks depicted in OCT angiography data has remained challenging. Multiple-scattering tails (artifacts specific to the imaging geometry) make automated assessment of vascular morphology problematic. We demonstrate that dynamically focused optical coherence microscopy (OCM) angiography with a high numerical aperture, chosen so the scattering length greatly exceeds the depth-of-field, significantly reduces the deleterious effect of multiple-scattering tails in synthesized angiograms. Capitalizing on the improved vascular image quality, we devised and tailored a self-correcting automated graphing approach that achieves a reconstruction of cortical microvasculature from OCM angiography data sets with accuracy approaching that attained by trained operators. The automated techniques described here will facilitate more widespread study of vascular network topology in health and disease.

  12. 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

  13. [Tumor vasculature as a therapeutic target in non-small cell lung cancer].

    PubMed

    Döme, Balázs; Magyar, Melinda

    2008-09-01

    Despite developments in conventional (chemo)radiotherapy and surgery, survival of non-small cell lung cancer (NSCLC) patients remains poor. Treatments with targeted molecular drugs offer novel therapeutic strategies. Bevacizumab, a recombinant anti-vascular endothelial growth factor (VEGF) antibody, is the antiangiogenic drug at the most advanced stage of development in the therapy of NSCLC. However, a number of questions and future challenges relating to the use of bevacizumab in NSCLC remain. Furthermore, novel agents targeting the pre-existing NSCLC vasculature (i.e. vascular disrupting agents, VDAs) or multiple tyrosine kinase inhibitors have emerged as unique drug classes delivering promising results in several preclinical and clinical studies. Herein, we review the most recent data using these novel targeted agents either alone or in combination with chemotherapy in NSCLC. PMID:18845495

  14. Vascular reactivity to vasoconstrictors in aorta and renal vasculature of hyperthyroid and hypothyroid rats.

    PubMed

    Sabio, J M; Rodriguez-Maresca, M; Luna, J D; García del Río, C; Vargas, F

    1994-10-01

    Vascular reactivity to vasoconstrictors in relation to altered thyroid function was studied in two preparations: aortic strips and the isolated perfused kidney. To assess whether the possible alterations in vascular reactivity were restricted to a specific agonist or whether they involved the contractile system, receptor-mediated and nonspecific smooth muscle stimulants were used. Male Wistar rats were divided into three groups: control, hyperthyroid and hypothyroid rats. Aortic strips from hypothyroid rats were less sensitive to phenylephrine and KCl when the data were expressed in absolute values or as percentages of the maximum responses. Sensitivity and reactivity in strips from hyperthyroid rats were similar to those observed in control strips. Renal vasculature obtained from hypothyroid rats also showed a markedly reduced sensitivity to phenylephrine, with normal maximal responses. The response to vasopressin at 3-10(-11) mol/l was also decreased, as was the reactivity to barium chloride. In contrast, renal vasculature of hyperthyroid rats showed markedly enhanced reactivity to all agonists: the concentration-response curves were characterized by a similar threshold and a greater maximal response. These results demonstrate that hypothyroidism is accompanied by a marked decrease in sensitivity to vasoconstrictors in large arteries as well as in resistance vessels. This decrease may be secondary to a generalized alteration in the contractile system of vascular smooth muscle cells and may play a role in the decreased blood pressure in these animals. In contrast, isolated perfused kidneys of hyperthyroid rats showed increased vascular reactivity to vasoconstrictors, which may play a role in the maintenance of elevated blood pressure in these animals. PMID:7831389

  15. Immune consequences of decreasing tumor vasculature with antiangiogenic tyrosine kinase inhibitors in combination with therapeutic vaccines.

    PubMed

    Farsaci, Benedetto; Donahue, Renee N; Coplin, Michael A; Grenga, Italia; Lepone, Lauren M; Molinolo, Alfredo A; Hodge, James W

    2014-11-01

    This study investigated the effects on the tumor microenvironment (TME) of combining antiangiogenic tyrosine kinase inhibitors (TKI) with therapeutic vaccines, and in particular, how vascular changes affect tumor-infiltrating immune cells. We conducted studies using a TKI (sunitinib or sorafenib) in combination with recombinant vaccines in two murine tumor models: colon carcinoma (MC38-CEA) and breast cancer (4T1). Tumor vasculature was measured by immunohistochemistry using three endothelial cell markers: CD31 (mature), CD105 (immature/proliferating), and CD11b (monocytic). We assessed oxygenation, tight junctions, compactness, and pressure within tumors, along with the frequency and phenotype of tumor-infiltrating lymphocytes (TIL), myeloid-derived suppressor cells (MDSC), and tumor-associated macrophages (TAM) following treatment with antiangiogenic TKIs alone, vaccine alone, or the combination of a TKI with vaccine. The combined regimen decreased tumor vasculature, compactness, tight junctions, and pressure, leading to vascular normalization and increased tumor oxygenation. This combination therapy also increased TILs, including tumor antigen-specific CD8 T cells, and elevated the expression of activation markers FAS-L, CXCL-9, CD31, and CD105 in MDSCs and TAMs, leading to reduced tumor volumes and an increase in the number of tumor-free animals. The improved antitumor activity induced by combining antiangiogenic TKIs with vaccine may be the result of activated lymphoid and myeloid cells in the TME, resulting from vascular normalization, decreased tumor-cell density, and the consequent improvement in vascular perfusion and oxygenation. Therapies that alter tumor architecture can, thus, have a dramatic impact on the effectiveness of cancer immunotherapy. PMID:25092771

  16. Nogo-B receptor deficiency causes cerebral vasculature defects during embryonic development in mice.

    PubMed

    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 E; Ramchandran, Ramani; Miao, Qing Robert

    2016-02-15

    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

  17. 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.

  18. Immune Consequences of Decreasing Tumor Vasculature with Antiangiogenic Tyrosine Kinase Inhibitors in Combination with Therapeutic Vaccines

    PubMed Central

    Farsaci, Benedetto; Donahue, Renee N.; Coplin, Michael A.; Grenga, Italia; Lepone, Lauren M.; Molinolo, Alfredo A.; Hodge, James W.

    2014-01-01

    This study investigated the effects on the tumor microenvironment of combining antiangiogenic tyrosine kinase inhibitors (TKI) with therapeutic vaccines, and in particular, how vascular changes affect tumor-infiltrating immune cells. We conducted studies using a TKI (sunitinib or sorafenib) in combination with recombinant vaccines in 2 murine tumor models: colon carcinoma (MC38-CEA) and breast cancer (4T1). Tumor vasculature was measured by immunohistochemistry using 3 endothelial cell markers: CD31 (mature), CD105 (immature/proliferating), and CD11b (monocytic). We assessed oxygenation, tight junctions, compactness, and pressure within tumors, along with the frequency and phenotype of tumor-infiltrating T lymphocytes (TIL), myeloid-derived suppressor cells (MDSC), and tumor-associated macrophages (TAM) following treatment with antiangiogenic TKIs alone, vaccine alone, or the combination of a TKI with vaccine. The combined regimen decreased tumor vasculature, compactness, tight junctions, and pressure, leading to vascular normalization and increased tumor oxygenation. This combination therapy also increased TILs, including tumor antigen-specific CD8 T cells, and elevated the expression of activation markers FAS-L, CXCL-9, CD31, and CD105 in MDSCs and TAMs, leading to reduced tumor volumes and an increase in the number of tumor-free animals. The improved antitumor activity induced by combining antiangiogenic TKIs with vaccine may be the result of activated lymphoid and myeloid cells in the tumor microenvironment, resulting from vascular normalization, decreased tumor-cell density, and the consequent improvement in vascular perfusion and oxygenation. Therapies that alter tumor architecture can thus have a dramatic impact on the effectiveness of cancer immunotherapy. PMID:25092771

  19. Computational Modeling of Tumor Response to Drug Release from Vasculature-Bound Nanoparticles

    PubMed Central

    Lowengrub, John; Decuzzi, Paolo; Frieboes, Hermann B.

    2015-01-01

    Systemically injected nanoparticle (NPs) targeting tumor vasculature offer a venue for anti-angiogenic therapies as well as cancer detection and imaging. Clinical application has been limited, however, due to the challenge of elucidating the complex interplay of nanotechnology, drug, and tumor parameters. A critical factor representing the likelihood of endothelial adhesion is the NP vascular affinity, a function of vascular receptor expression and NP size and surface-bound ligand density. We propose a theoretical framework to simulate the tumor response to vasculature-bound drug-loaded NPs and examine the interplay between NP distribution and accumulation as a function of NP vascular affinity, size, and drug loading and release characteristics. The results show that uniform spatial distribution coupled with high vascular affinity is achievable for smaller NPs but not for larger sizes. Consequently, small (100 nm) NPs with high vascular affinity are predicted to be more effective than larger (1000 nm) NPs with similar affinity, even though small NPs have lower drug loading and local drug release compared to the larger NPs. Medium vascular affinity coupled with medium or larger sized NPs is also effective due to a more uniform distribution with higher drug loading and release. Low vascular affinity hampered treatment efficacy regardless of NP size, with larger NPs additionally impeded by heterogeneous distribution and drug release. The results further show that increased drug diffusivity mainly benefits heterogeneously distributed NPs, and would negatively affect efficacy otherwise due to increased wash-out. This model system enables evaluation of efficacy for vascular-targeted drug-loaded NPs as a function of critical NP, drug, and tumor parameters. PMID:26660469

  20. 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

  1. The mitochondrial function of the cerebral vasculature in insulin-resistant Zucker obese rats.

    PubMed

    Merdzo, Ivan; Rutkai, Ibolya; Tokes, Tunde; Sure, Venkata N L R; Katakam, Prasad V G; Busija, David W

    2016-04-01

    Little is known about mitochondrial functioning in the cerebral vasculature during insulin resistance (IR). We examined mitochondrial respiration in isolated cerebral arteries of male Zucker obese (ZO) rats and phenotypically normal Zucker lean (ZL) rats using the Seahorse XFe24 analyzer. We investigated mitochondrial morphology in cerebral blood vessels as well as mitochondrial and nonmitochondrial protein expression levels in cerebral arteries and microvessels. We also measured reactive oxygen species (ROS) levels in cerebral microvessels. Under basal conditions, the mitochondrial respiration components (nonmitochondrial respiration, basal respiration, ATP production, proton leak, and spare respiratory capacity) showed similar levels among the ZL and ZO groups with the exception of maximal respiration, which was higher in the ZO group. We examined the role of nitric oxide by measuring mitochondrial respiration following inhibition of nitric oxide synthase withN(ω)-nitro-l-arginine methyl ester (l-NAME) and mitochondrial activation after administration of diazoxide (DZ). Both ZL and ZO groups showed similar responses to these stimuli with minor variations.l-NAME significantly increased the proton leak, and DZ decreased nonmitochondrial respiration in the ZL group. Other components were not affected. Mitochondrial morphology and distribution within vascular smooth muscle and endothelium as well as mitochondrial protein levels were similar in the arteries and microvessels of both groups. Endothelial nitric oxide synthase (eNOS) and ROS levels were increased in cerebral microvessels of the ZO. Our study suggests that mitochondrial function is not significantly altered in the cerebral vasculature of young ZO rats, but increased ROS production might be due to increased eNOS in the cerebral microcirculation during IR. PMID:26873973

  2. 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

  3. HIV peripheral neuropathy.

    PubMed

    Gabbai, Alberto Alain; Castelo, Adauto; Oliveira, Acary Souza Bulle

    2013-01-01

    Peripheral neuropathies are the most common neurological manifestations occurring in HIV-infected individuals. Distal symmetrical sensory neuropathy is the most common form encountered today and is one of the few that are specific to HIV infection or its treatment. The wide variety of other neuropathies is akin to the neuropathies seen in the general population and should be managed accordingly. In the pre-ART era, neuropathies were categorized according to the CD4 count and HIV viral load. In the early stages of HIV infection when CD4 count is high, the inflammatory demyelinating neuropathies predominate and in the late stages with the decline of CD4 count opportunistic infection-related neuropathies prevail. That scenario has changed with the present almost universal use of ART (antiretroviral therapy). Hence, HIV-associated peripheral neuropathies are better classified according to their clinical presentations: distal symmetrical polyneuropathy, acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), mononeuropathies, mononeuropathies multiplex and cranial neuropathies, autonomic neuropathy, lumbosacral polyradiculomyelopathy, and amyotrophic lateral sclerosis (ALS)-like motor neuropathy. Treated with ART, HIV-infected individuals are living longer and are at a higher risk of metabolic and age-related complications; moreover they are also prone to the potentially neurotoxic effects of ART. There are no epidemiological data regarding the incidence and prevalence of the peripheral neuropathies. In the pre-ART era, most data were from case reports, series of patients, and pooled autopsy data. At that time the histopathological evidence of neuropathies in autopsy series was almost 100%. In large prospective cohorts presently being evaluated, it has been found that 57% of HIV-infected individuals have distal symmetrical sensory neuropathy and 38% have neuropathic pain. It is now clear that

  4. Uptake of Fluorescent Gentamicin by Peripheral Vestibular Cells after Systemic Administration

    PubMed Central

    Liu, Jianping; Kachelmeier, Allan; Dai, Chunfu; Li, Hongzhe; Steyger, Peter S.

    2015-01-01

    Objective In addition to cochleotoxicity, systemic aminoglycoside pharmacotherapy causes vestibulotoxicity resulting in imbalance and visual dysfunction. The underlying trafficking routes of systemically-administered aminoglycosides from the vasculature to the vestibular sensory hair cells are largely unknown. We investigated the trafficking of systemically-administered gentamicin into the peripheral vestibular system in C56Bl/6 mice using fluorescence-tagged gentamicin (gentamicin-Texas-Red, GTTR) imaged by scanning laser confocal microscopy to determine the cellular distribution and intensity of GTTR fluorescence in the three semicircular canal cristae, utricular, and saccular maculae at 5 time points over 4 hours. Results Low intensity GTTR fluorescence was detected at 0.5 hours as both discrete puncta and diffuse cytoplasmic fluorescence. The intensity of cytoplasmic fluorescence peaked at 3 hours, while punctate fluorescence was plateaued after 3 hours. At 0.5 and 1 hour, higher levels of diffuse GTTR fluorescence were present in transitional cells compared to hair cells and supporting cells. Sensory hair cells typically exhibited only diffuse cytoplasmic fluorescence at all time-points up to 4 hours in this study. In contrast, non-sensory cells rapidly exhibited both intense fluorescent puncta and weaker, diffuse fluorescence throughout the cytosol. The numbers and size of fluorescent puncta in dark cells and transitional cells increased over time. There is no preferential GTTR uptake by the five peripheral vestibular organs’ sensory cells. Control vestibular tissues exposed to Dulbecco’s phosphate-buffered saline or hydrolyzed Texas Red had negligible fluorescence. Conclusions All peripheral vestibular cells rapidly take up systemically-administered GTTR, reaching peak intensity 3 hours after injection. Sensory hair cells exhibited only diffuse fluorescence, while non-sensory cells displayed both diffuse and punctate fluorescence. Transitional cells may

  5. Impaired Nitric Oxide Mediated Vasodilation In The Peripheral Circulation In The R6/2 Mouse Model Of Huntington’s Disease

    PubMed Central

    Kane, Andrew D.; Niu, Youguo; Herrera, Emilio A.; Morton, A. Jennifer; Giussani, Dino A.

    2016-01-01

    Recent evidence shows that the Huntington’s disease (HD) extends beyond the nervous system to other sites, including the cardiovascular system. Further, the cardiovascular pathology pre-dates neurological decline, however the mechanisms involved remain unclear. We investigated in the R6/2 mouse model of HD nitric oxide (NO) dependent and independent endothelial mechanisms. Femoral artery reactivity was determined by wire myography in wild type (WT) and R6/2 mice at 12 and 16 weeks of adulthood. WT mice showed increased endothelial relaxation between 12 and 16 weeks (Rmax: 72 ± 7% vs. 97 ± 13%, P < 0.05). In contrast, R6/2 mice showed enhanced endothelial relaxation already by 12 weeks (Rmax at 12w: 72 ± 7% vs. 94 ± 5%, WT vs. R6/2, P < 0.05) that declined by 16 weeks compared with WT mice (Rmax at 16w: 97 ± 13% vs. 68 ± 7%, WT vs. R6/2, P < 0.05). In WT mice, the increase in femoral relaxation between 12 and 16 weeks was due to enhanced NO dependent mechanisms. By 16 weeks of adult age, the R6/2 mouse developed overt endothelial dysfunction due to an inability to increase NO dependent vasodilation. The data add to the growing literature of non-neural manifestations of HD and implicate NO depletion as a key mechanism underlying the HD pathophysiology in the peripheral vasculature. PMID:27181166

  6. Quantitative investigation of the effect of the extra-cerebral vasculature in diffuse optical imaging: a simulation study

    PubMed Central

    Dehaes, Mathieu; Gagnon, Louis; Lesage, Frédéric; Pélégrini-Issac, Mélanie; Vignaud, Alexandre; Valabrègue, Romain; Grebe, Reinhard; Wallois, Fabrice; Benali, Habib

    2011-01-01

    Diffuse optical imaging (DOI) is a non invasive technique allowing the recovery of hemodynamic changes in the brain. Due to the diffusive nature of photon propagation in turbid media and the fact that cerebral tissues are located around 1.5 cm under the adult human scalp, DOI measurements are subject to partial volume errors. DOI measurements are also sensitive to large pial vessels because oxygenated and deoxygenated hemoglobin are the dominant chromophores in the near infrared window. In this study, the effect of the extra-cerebral vasculature in proximity of the sagittal sinus was investigated for its impact on DOI measurements simulated over the human adult visual cortex. Numerical Monte Carlo simulations were performed on two specific models of the human head derived from magnetic resonance imaging (MRI) scans. The first model included the extra-cerebral vasculature in which constant hemoglobin concentrations were assumed while the second did not. The screening effect of the vasculature was quantified by comparing recovered hemoglobin changes from each model for different optical arrays and regions of activation. A correction factor accounting for the difference between the recovered and the simulated hemoglobin changes was computed in each case. The results show that changes in hemoglobin concentration are better estimated when the extra-cerebral vasculature is modeled and the correction factors obtained in this case were at least 1.4-fold lower. The effect of the vasculature was also examined in a high-density diffuse optical tomography configuration. In this case, the difference between changes in hemoglobin concentration recovered with each model was reduced down to 10%. PMID:21412472

  7. Peripheral Mechanisms of Itch.

    PubMed

    Azimi, Ehsan; Xia, Jimmy; Lerner, Ethan A

    2016-01-01

    A multitude of exogenous environmental stimuli and endogenous molecular and cellular components interface directly or indirectly with the free nerve endings of sensory nerves in the skin. Environmental stimuli include substances derived from the microbiome and materials, such as allergens, that otherwise come in contact with the skin. Endogenous stimuli include components of or mediators derived from the epidermal barrier, keratinocytes, mast cells, and additional resident and skin-homing immune cells. The sensation of itch is ultimately provoked by mediators that interact with and activate pruriceptors on the sensory nerve fibers. These peripheral fibers convey signals from the skin to the dorsal root and trigeminal ganglia and on to the spinal cord and brain where central processing of the itch sensation occurs. A discussion of the nature and sources of itch stimuli and receptors in the periphery form the basis of this chapter. The development of drugs that target these processes is in the process of revolutionizing therapeutic approaches to itch. PMID:27578066

  8. Managing a peripheral ossifying fibroma.

    PubMed

    Kendrick, F; Waggoner, W F

    1996-01-01

    The Peripheral Ossifying Fibroma is an inflammatory lesion which most often appears in twenty-five to thirty-four-year-old females. It averages 1.0 cm at its greatest dimension. This case reports a seven-year-eight-month-old female who presented with a peripheral ossifying fibroma lesion which measured 2.7 cm by 1.5 cm by 1.0 cm. A review of peripheral ossifying fibroma, and the management and postsurgical sequelae of this child are discussed. PMID:8708123

  9. Malignant Peripheral Nerve Sheath Tumor.

    PubMed

    James, Aaron W; Shurell, Elizabeth; Singh, Arun; Dry, Sarah M; Eilber, Fritz C

    2016-10-01

    Malignant peripheral nerve sheath tumor (MPNST) is the sixth most common type of soft tissue sarcoma. Most MPNSTs arise in association with a peripheral nerve or preexisting neurofibroma. Neurofibromatosis type is the most important risk factor for MPNST. Tumor size and fludeoxyglucose F 18 avidity are among the most helpful parameters to distinguish MPNST from a benign peripheral nerve sheath tumor. The histopathologic diagnosis is predominantly a diagnosis of light microscopy. Immunohistochemical stains are most helpful to distinguish high-grade MPNST from its histologic mimics. Current surgical management of high-grade MPNST is similar to that of other high-grade soft tissue sarcomas. PMID:27591499

  10. Peripheral artery bypass - leg - discharge

    MedlinePlus

    ... P. Peripheral arterial diseases. In: Mann DL, Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald's ... noncoronary obstructive vascular disease. In: Mann DL, Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald's ...

  11. About Peripheral Artery Disease (PAD)

    MedlinePlus

    ... changes and medication . View an animation of atherosclerosis Atherosclerosis and PAD Atherosclerosis is a disease in which plaque builds up ... of an artery. PAD is usually caused by atherosclerosis in the peripheral arteries (or outer regions away ...

  12. Peripheral Neuropathy and Agent Orange

    MedlinePlus

    ... registry health exam . Research on peripheral neuropathy and herbicides The Health and Medicine Division (HMD) (formally known ... acute or subacute onset may be associated with herbicide exposure. Based on this evidence, VA presumed an ...

  13. Management of peripheral arterial disease.

    PubMed

    Gey, Daniela C; Lesho, Emil P; Manngold, Johannes

    2004-02-01

    Peripheral arterial disease is common, but the diagnosis frequently is overlooked because of subtle physical findings and lack of classic symptoms. Screening based on the ankle brachial index using Doppler ultrasonography may be more useful than physical examination alone. Noninvasive modalities to locate lesions include magnetic resonance angiography, duplex scanning, and hemodynamic localization. Major risk factors for peripheral arterial disease are cigarette smoking, diabetes mellitus, older age (older than 40 years), hypertension, hyperlipidemia, and hyperhomocystinemia. Nonsurgical therapy for intermittent claudication involves risk-factor modification, exercise, and pharmacologic therapy. Based on available evidence, a supervised exercise program is the most effective treatment. All patients with peripheral arterial disease should undergo aggressive control of blood pressure, sugar intake, and lipid levels. All available strategies to help patients quit smoking, such as counseling and nicotine replacement, should be used. Effective drug therapies for peripheral arterial disease include aspirin (with or without dipyridamole), clopidogrel, cilostazol, and pentoxifylline. PMID:14971833

  14. Evidence for reduced sympatholysis in leg resistance vasculature of healthy older women.

    PubMed

    Parker, Beth A; Smithmyer, Sandra L; Jarvis, Sara S; Ridout, Samuel J; Pawelczyk, James A; Proctor, David N

    2007-02-01

    Inhibition of a sympathetic stimulus (i.e., sympatholysis) during forearm exercise is reduced with age in women. This age-related alteration has not been characterized in the lower extremity vasculature of women, and the potential for blunting of the conduit artery dilatory response to a sudden increase in shear stress [flow-mediated dilation (FMD)] has not been examined in older adults of either sex. In the present study, we assessed popliteal artery diameter and velocity (Doppler ultrasound) in 16 young (23 +/- 1 yr) and 14 older (69 +/- 1 yr) women after 5 min of distal calf occlusion (FMD), 3 min of hand immersion in ice water [cold pressor test (CPT)], and 5 min of distal calf occlusion combined with hand immersion in ice water (FMD+CPT). Peak popliteal conductance after 5-min ischemia was not significantly different in young vs. older women. During the combined stimulus (FMD+CPT), the magnitude of vasoconstriction in the calf (reduction in peak popliteal artery conductance) was similar (5-8%), despite reduced resting adrenergic sensitivity to CPT [young (Y): -27.3 +/- 3.8%; older (O): -15.8 +/- 2.2%; P < 0.05] and blunted muscle sympathetic nerve activity responses to CPT (Y: 12.7 +/- 3.6 bursts/min; O: 7.8 +/- 2.5 bursts/min; P < 0.05) in older women. Popliteal FMD, normalized to the shear stimulus, was attenuated by 60-70% in older women. Peak popliteal diameter, measured during the combined stimulus (FMD+CPT), was blunted in young but not in older women (Y FMD: 5.5 +/- 0.1 mm; Y FMD+CPT: 5.4 +/- 0.1 mm; P = 0.03; O FMD: 5.8 +/- 0.2 mm; O FMD+CPT: 5.8 +/- 0.2 mm). These results confirm previous findings of diminished reactivity in the conduit arteries of older humans and provide the first evidence of reduced sympatholysis in the leg resistance vasculature of older women. PMID:17071730

  15. Heterogeneity of endothelial cell phenotype within and amongst conduit vessels of the swine vasculature.

    PubMed

    Simmons, Grant H; Padilla, Jaume; Laughlin, M Harold

    2012-09-01

    The purpose of this study was to investigate the extent of endothelial cell phenotypic heterogeneity throughout the swine vasculature, with a focus on the conduit vessels of the arterial and venous circulations. We tested the hypothesis that atheroprone arteries exhibit higher expression of markers of inflammation and oxidative stress than do veins and atheroresistant arteries. The study sample included tissues from 79 castrated, male swine. Immediately after the animals were killed, endothelial cells were mechanically scraped from isolated segments of the thoracic and abdominal aorta, carotid, brachial, femoral and renal arteries, and the vein regionally associated with each of these vessels, as well as the internal mammary and right coronary arteries. Cells were also taken from two regions of the aortic arch contrasted by atheroprone versus atherosusceptible haemodynamics. Endothelial cell phenotype was assessed by either immunoblotting or quantitative real-time PCR for a host of both pro- and anti-atherogenic markers (e.g. endothelial nitric oxide synthase, p67phox, cyclo-oxygenase-1 and superoxide dismutase 1). Marked heterogeneity across the vasculature was observed in the expression of both pro- and anti-atherogenic markers, at both the protein and transcriptional levels. In particular, the coronary vascular endothelium expressed higher levels of the oxidative stress marker p67phox (P < 0.05 versus other arteries). In addition, differential expression of endothelial nitric oxide synthase and KLF4 was evident between atheroprone and atherosusceptible regions of the aorta, while expression of endothelial nitric oxide synthase, KLF2, KLF4 and cyclo-oxygenase-1 was lower in both areas of the aortic arch compared with the internal mammary artery. Conduit arteries typically expressed higher levels of both pro- and anti-atherogenic markers relative to their associated veins. We show, for the first time, that endothelial cell phenotype is variable within vessels

  16. Risk of type 1 diabetes progression in islet autoantibody-positive children can be further stratified using expression patterns of multiple genes implicated in peripheral blood lymphocyte activation and function.

    PubMed

    Jin, Yulan; Sharma, Ashok; Bai, Shan; Davis, Colleen; Liu, Haitao; Hopkins, Diane; Barriga, Kathy; Rewers, Marian; She, Jin-Xiong

    2014-07-01

    There is tremendous scientific and clinical value to further improving the predictive power of autoantibodies because autoantibody-positive (AbP) children have heterogeneous rates of progression to clinical diabetes. This study explored the potential of gene expression profiles as biomarkers for risk stratification among 104 AbP subjects from the Diabetes Autoimmunity Study in the Young (DAISY) using a discovery data set based on microarray and a validation data set based on real-time RT-PCR. The microarray data identified 454 candidate genes with expression levels associated with various type 1 diabetes (T1D) progression rates. RT-PCR analyses of the top-27 candidate genes confirmed 5 genes (BACH2, IGLL3, EIF3A, CDC20, and TXNDC5) associated with differential progression and implicated in lymphocyte activation and function. Multivariate analyses of these five genes in the discovery and validation data sets identified and confirmed four multigene models (BI, ICE, BICE, and BITE, with each letter representing a gene) that consistently stratify high- and low-risk subsets of AbP subjects with hazard ratios >6 (P < 0.01). The results suggest that these genes may be involved in T1D pathogenesis and potentially serve as excellent gene expression biomarkers to predict the risk of progression to clinical diabetes for AbP subjects. PMID:24595351

  17. Risk of Type 1 Diabetes Progression in Islet Autoantibody-Positive Children Can Be Further Stratified Using Expression Patterns of Multiple Genes Implicated in Peripheral Blood Lymphocyte Activation and Function

    PubMed Central

    Jin, Yulan; Sharma, Ashok; Bai, Shan; Davis, Colleen; Liu, Haitao; Hopkins, Diane; Barriga, Kathy

    2014-01-01

    There is tremendous scientific and clinical value to further improving the predictive power of autoantibodies because autoantibody-positive (AbP) children have heterogeneous rates of progression to clinical diabetes. This study explored the potential of gene expression profiles as biomarkers for risk stratification among 104 AbP subjects from the Diabetes Autoimmunity Study in the Young (DAISY) using a discovery data set based on microarray and a validation data set based on real-time RT-PCR. The microarray data identified 454 candidate genes with expression levels associated with various type 1 diabetes (T1D) progression rates. RT-PCR analyses of the top-27 candidate genes confirmed 5 genes (BACH2, IGLL3, EIF3A, CDC20, and TXNDC5) associated with differential progression and implicated in lymphocyte activation and function. Multivariate analyses of these five genes in the discovery and validation data sets identified and confirmed four multigene models (BI, ICE, BICE, and BITE, with each letter representing a gene) that consistently stratify high- and low-risk subsets of AbP subjects with hazard ratios >6 (P < 0.01). The results suggest that these genes may be involved in T1D pathogenesis and potentially serve as excellent gene expression biomarkers to predict the risk of progression to clinical diabetes for AbP subjects. PMID:24595351

  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. 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.

  20. 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

  1. 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.

  2. The role of the renin-angiotensin and natriuretic peptide systems in the pulmonary vasculature.

    PubMed Central

    Cargill, R I; Lipworth, B J

    1995-01-01

    1. The role of vasoactive peptide systems in the pulmonary vasculature has been studied much less extensively than systemic vascular and endocrine effects. The current understanding of the role of the renin-angiotensin (RAS) and natriuretic peptide systems (NPS) in the pulmonary circulation is therefore reviewed. 2. Plasma concentrations of angiotensin II, the main vasoactive component of the RAS, are elevated in pulmonary hypertension and may interact with hypoxaemia to cause further pulmonary vasoconstriction. Pharmacological manipulation of angiotensin II can attenuate hypoxic pulmonary vasoconstriction but larger studies are needed to establish the efficacy of this therapeutic strategy in established pulmonary hypertension. 3. Although all the known natriuretic peptides, ANP, BNP and CNP are elevated in cor pulmonale, only ANP and BNP appear to have pulmonary vasorelaxant activity in humans. ANP and BNP can also attenuate hypoxic pulmonary vasoconstriction, suggesting a possible counter-regulatory role for these peptides. Inhibition of ANP/BNP metabolism by neutral endopeptidase has been shown to attenuate development of hypoxic pulmonary hypertension but this property has not been tested in humans. 4. It is also well established that there are potentially important endocrine and systemic circulatory interactions between the RAS and NPS. This also occurs in the pulmonary circulation and in humans, where at least BNP acts to attenuate angiotensin II induced pulmonary vasoconstriction. This interaction may be particularly relevant as a mechanism to counter-regulate overactivity of the RAS.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8527262

  3. Irradiation promotes Akt-targeting therapeutic gene delivery to the tumor vasculature

    SciTech Connect

    Sonveaux, Pierre; Frerart, Francoise; Bouzin, Caroline; Brouet, Agnes; Wever, Julie de; Jordan, Benedicte F.; Gallez, Bernard; Feron, Olivier . E-mail: feron@mint.ucl.ac.be

    2007-03-15

    Purpose: To determine whether radiation-induced increases in nitric oxide (NO) production can influence tumor blood flow and improve delivery of Akt-targeting therapeutic DNA lipocomplexes to the tumor. Methods and Materials: The contribution of NO to the endothelial response to radiation was identified using NO synthase (NOS) inhibitors and endothelial NOS (eNOS)-deficient mice. Reporter-encoding plasmids complexed with cationic lipids were used to document the tumor vascular specificity and the efficacy of in vivo lipofection after irradiation. A dominant-negative Akt gene construct was used to evaluate the facilitating effects of radiotherapy on the therapeutic transgene delivery. Results: The abundance of eNOS protein was increased in both irradiated tumor microvessels and endothelial cells, leading to a stimulation of NO release and an associated increase in tumor blood flow. Transgene expression was subsequently improved in the irradiated vs. nonirradiated tumor vasculature. This effect was not apparent in eNOS-deficient mice and could not be reproduced in irradiated cultured endothelial cells. Finally, we combined low-dose radiotherapy with a dominant-negative Akt gene construct and documented synergistic antitumor effects. Conclusions: This study offers a new rationale to combine radiotherapy with gene therapy, by directly exploiting the stimulatory effects of radiation on NO production by tumor endothelial cells. The preferential expression of the transgene in the tumor microvasculature underscores the potential of such an adjuvant strategy to limit the angiogenic response of irradiated tumors.

  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. 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.

  6. Mitochondrial regulation of reactive oxygen species (ROS) production-Unexpected observations in early postnatal cerebral vasculature.

    PubMed

    Wolf, S; Mattheis, A; Laufs, U; Meier, C; Tschernig, T

    2016-07-01

    Nicotinamide-nucleotide-transhydrogenase (Nnt) is a mitochondrial protein. It is altered and functionally lacking in the C57BL/6J sub-strain. This leads to the generation of more radical oxygen species than in the C57BL/6N sub-strain. During studies on the effect of Nnt in perinatal hypoxia the cerebral vasculature was investigated in postnatal day 9 mice using post mortem arterial filling with silicone rubber compounds. Surprisingly, the tiny vessels were no longer uniformly filled and a bleb-like pattern occurred in both sub-strains. Furthermore, considerably more bleb-like spots were observed in the C57Bl/6J sub-strain than in the C57Bl/6N sub-strain. These blebs might be the result of feathery vessels bursting. It remains unclear how the mechanisms in the used strains differ. Nnt might influence the vascular structure or its development and mechanisms and should be investigated further. PMID:26724498

  7. Aptamer-modified magnetic nanoprobe for molecular MR imaging of VEGFR2 on angiogenic vasculature

    NASA Astrophysics Data System (ADS)

    Kim, Bongjune; Yang, Jaemoon; Hwang, Myeonghwan; Choi, Jihye; Kim, Hyun-Ouk; Jang, Eunji; Lee, Jung Hwan; Ryu, Sung-Ho; Suh, Jin-Suck; Huh, Yong-Min; Haam, Seungjoo

    2013-09-01

    Nucleic acid-based aptamers have been developed for the specific delivery of diagnostic nanoprobes. Here, we introduce a new class of smart imaging nanoprobe, which is based on hybridization of a magnetic nanocrystal with a specific aptamer for specific detection of the angiogenic vasculature of glioblastoma via magnetic resonance (MR) imaging. The magnetic nanocrystal imaging core was synthesized using the thermal decomposition method and enveloped by carboxyl polysorbate 80 for water solubilization and conjugation of the targeting moiety. Subsequently, the surface of the carboxylated magnetic nanocrystal was modified with amine-functionalized aptamers that specifically bind to the vascular growth factor receptor 2 (VEGFR2) that is overexpressed on angiogenic vessels. To assess the targeted imaging potential of the aptamer-conjugated magnetic nanocrystal for VEGFR2 markers, the magnetic properties and MR imaging sensitivity were investigated using the orthotopic glioblastoma mouse model. In in vivo tests, the aptamer-conjugated magnetic nanocrystal effectively targeted VEGFR2 and demonstrated excellent MR imaging sensitivity with no cytotoxicity.

  8. 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. PMID:20876651

  9. 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

  10. Investigating the choriocapillaris and choroidal vasculature with new optical coherence tomography technologies.

    PubMed

    Ferrara, Daniela; Waheed, Nadia K; Duker, Jay S

    2016-05-01

    The body of knowledge of in vivo investigation of the choroid has been markedly enhanced by recent technological advances in optical coherence tomography (OCT). New insights elucidating the morphological features of the choriocapillaris and choroidal vasculature, in both physiological and pathological conditions, indicate that the choroid plays a pivotal role in many posterior segment diseases. In this article, a review of the histological characteristics of the choroid, which must be considered for the proper interpretation of in vivo imaging, is followed by a comprehensive discussion of fundamental principles of the current state-of-the-art in OCT, including cross-sectional OCT, en face OCT, and OCT angiography using both spectral domain OCT and swept source OCT technologies. A detailed review of the tomographic features of the choroid in the normal eye is followed by relevant findings in prevalent chorioretinal diseases, focusing on major causes of vision loss such as typical early and advanced age-related macular degeneration, polypoidal choroidal vasculopathy, central serous chorioretinopathy, pachychoroid spectrum disorders, diabetic choroidopathy, and myopia. PMID:26478514

  11. The effect of HN-65021 on responses to angiotensin II in human forearm vasculature.

    PubMed Central

    Cockcroft, J R; Chowienczyk, P J; Brett, S E; Mant, T G; Durnin, C; Lynn, F; Stevenson, P; Ritter, J M

    1995-01-01

    We studied the effect of (2-butyl-4-chloro-1[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]methyl]-1H-imadazole-5-carboxylic acid,-1-(ethoxycarbonyloxy) ethyl-ester (HN-65021), on angiotensin II induced vasoconstriction in forearm vasculature of eight healthy men. Placebo and HN-65021 (5, 10 and 100 mg) were administered orally. Forearm blood flow was measured by venous occlusion plethysmography during rising dose brachial artery infusions of angiotensin II (0.3-1000 pmol min-1) 2 h after dosing. HN-65021 inhibited angiotensin II, causing a shift to the right of the dose-response curve. Angiotensin II (100 pmol min-1) decreased mean blood flow in the infused arm by 63.1 +/- 3.2% when infused following placebo and by 49.9 +/- 4.3%, 50.7 +/- 3.5% and 36.4 +/- 2.8% following HN-65021 doses of 5.10 and 100 mg respectively. These results demonstrate that HN-65021 antagonises angiotensin II receptor mediated vasoconstriction in human forearm resistance vessels. PMID:8703667

  12. Analysis of geometrical relations between multiple sclerosis lesions and brain vasculature

    NASA Astrophysics Data System (ADS)

    Kozinska, Dorota E.; Holland, Christopher; Krissian, Karl; Westin, Carl-Fredrik; Guttmann, Charles R. G.

    2004-04-01

    Due to histological evidence of the fundamental role of the cerebral vessels in white matter abnormalities, recently there has been an increased interest in analyzing the relationship between brain white matter lesions in multiple sclerosis (MS) and brain vasculature. We developed a method for visualization and measurement of geometrical relationships between MS lesions and the brain vessels imaged with magnetic resonance (MR) imaging techniques. Using MR images we create surface models of lesions and vessels that constitute a base for quantitative analysis. In this work we analyze correlation between basic lesion geometrical characteristics and two features: 1) distances to vessels, and 2) vessel caliber. For the former, we compute a distance map from the vessel structure, such that each voxel stores its distance vector to the closest vessel. This allows the measurements of Euclidean distances to the closest vessels. For the latter, we compute a radius map in which each voxel stores the radius of its closest vessel. It is used to measure distribution of lesions with respect to the vessel caliber. We compute and analyze relations between the basic geometrical characteristics of lesions and the closest vessels locations and calibers. To demonstrate the feasibility of the developed technique we present results from the study of 3 MS cases.

  13. 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.

  14. 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. PMID:26819602

  15. 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

  16. 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 resines, (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. PMID:26464303

  17. Multiple variations of the coeliac axis, hepatic and renal vasculature as incidental findings illustrated by MDCTA.

    PubMed

    Rafailidis, Vasileios; Papadopoulos, Georgios; Kouskouras, Konstantinos; Chryssogonidis, Ioannis; Velnidou, Anastasia; Kalogera-Fountzila, Anna

    2016-08-01

    Vascular anatomical variations are not uncommon and may affect any organ's arterial or venous vasculature. The coexistence of variations in different organic systems is less commonly found, but of great clinical significance in a series of clinical conditions like organ transplantation and surgical preoperative planning. Multidetector computed tomography angiography (MDCTA) has emerged as a valuable alternative to the conventional angiography for accurate evaluation of vascular anatomy and pathology. Radiologists should be familiar with each organ's vascular variations and always report them to the clinician, even if they represent an incidental finding. This case report presents a 52-year-old female patient undergoing abdominal MDCTA for characterization of a renal lesion. This examination revealed the presence of three hilar arteries on the left kidney, a main renal vein in combination with an additional renal vein in both sides along with a replaced right hepatic artery originating from the superior mesenteric artery. Moreover, both inferior phrenic arteries were found originating from the coeliac axis. 3D volume rendering technique images were used in the evaluation of vascular anatomy as illustrated in this case report. PMID:26627693

  18. 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. PMID:25867067

  19. Cell surface nucleolin antagonist causes endothelial cell apoptosis and normalization of tumor vasculature.

    PubMed

    Fogal, Valentina; Sugahara, Kazuki N; Ruoslahti, Erkki; Christian, Sven

    2009-01-01

    Nucleolin is specifically transported to the surface of proliferating endothelial cells in vitro and in vivo. In contrast to its well defined functions in the nucleus and cytoplasm, the function of cell surface nucleolin is poorly defined. We have previously identified the nucleolin-binding antibody NCL3 that specifically binds to cell surface nucleolin on angiogenic blood vessels in vivo and is internalized into the cell. Here, we show that NCL3 inhibits endothelial tube formation in vitro as well as angiogenesis in the matrigel plaque assay and subcutaneous tumor models in vivo. Intriguingly, the specific targeting of proliferating endothelial cells by NCL3 in subcutaneous tumor models leads to the normalization of the tumor vasculature and as a result to an increase in tumor oxygenation. Treatment of endothelial cells with anti-nucleolin antibody NCL3 leads to a decrease of mRNA levels of the anti-apoptotic molecule Bcl-2 and as a consequence induces endothelial cell apoptosis as evidenced by PARP cleavage. These data reveal a novel mode of action for anti-angiogenic therapy and identify cell surface nucleolin as a novel target for combinatorial chemotherapy. PMID:19225898

  20. 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

  1. 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

  2. Tumor Vasculature Targeting and Imaging in Living Mice with Reduced Graphene Oxide

    PubMed Central

    Shi, Sixiang; Yang, Kai; Hong, Hao; Valdovinos, Hector F.; Nayak, Tapas R.; Zhang, Yin; Theuer, Charles P.; Barnhart, Todd E.; Liu, Zhuang; Cai, Weibo

    2013-01-01

    Graphene-based nanomaterials have attracted tremendous attention in the field of biomedicine due to their intriguing properties. Herein, we report tumor vasculature targeting and imaging in living mice using reduced graphene oxide (RGO), which was conjugated to the anti-CD105 antibody TRC105. The RGO conjugate, 64Cu-NOTA-RGO-TRC105, exhibited excellent stability in vitro and in vivo. Serial positron emission tomography (PET) imaging studies non-invasively assessed the pharmacokinetics and demonstrated specific targeting of 64Cu-NOTA-RGO-TRC105 to 4T1 murine breast tumors in vivo, compared to non-targeted RGO conjugate (64Cu-NOTA-RGO). In vivo (e.g., blocking 4T1 tumor uptake with excess TRC105), in vitro (e.g., flow cytometry), and ex vivo (e.g., histology) experiments confirmed the specificity of 64Cu-NOTA-RGO-TRC105 for tumor vascular CD105. Since RGO exhibits desirable properties for photothermal therapy, the tumor-specific RGO conjugate developed in this work may serve as a promising theranostic agent that integrates imaging and therapeutic components. PMID:23374706

  3. Tumor vasculature targeting and imaging in living mice with reduced graphene oxide.

    PubMed

    Shi, Sixiang; Yang, Kai; Hong, Hao; Valdovinos, Hector F; Nayak, Tapas R; Zhang, Yin; Theuer, Charles P; Barnhart, Todd E; Liu, Zhuang; Cai, Weibo

    2013-04-01

    Graphene-based nanomaterials have attracted tremendous attention in the field of biomedicine due to their intriguing properties. Herein, we report tumor vasculature targeting and imaging in living mice using reduced graphene oxide (RGO), which was conjugated to the anti-CD105 antibody TRC105. The RGO conjugate, (64)Cu-NOTA-RGO-TRC105, exhibited excellent stability in vitro and in vivo. Serial positron emission tomography (PET) imaging studies non-invasively assessed the pharmacokinetics and demonstrated specific targeting of (64)Cu-NOTA-RGO-TRC105 to 4T1 murine breast tumors in vivo, compared to non-targeted RGO conjugate ((64)Cu-NOTA-RGO). In vivo (e.g., blocking 4T1 tumor uptake with excess TRC105), in vitro (e.g., flow cytometry), and ex vivo (e.g., histology) experiments confirmed the specificity of (64)Cu-NOTA-RGO-TRC105 for tumor vascular CD105. Since RGO exhibits desirable properties for photothermal therapy, the tumor-specific RGO conjugate developed in this work may serve as a promising theranostic agent that integrates imaging and therapeutic components. PMID:23374706

  4. Cancer anti-angiogenesis vaccines: Is the tumor vasculature antigenically unique?

    PubMed

    Wagner, Samuel C; Ichim, Thomas E; Ma, Hong; Szymanski, Julia; Perez, Jesus A; Lopez, Javier; Bogin, Vladimir; Patel, Amit N; Marincola, Francisco M; Kesari, Santosh

    2015-01-01

    Angiogenesis is essential for the growth and metastasis of solid tumors. The tumor endothelium exists in a state of chronic activation and proliferation, fueled by the tumor milieu where angiogenic mediators are aberrantly over-expressed. Uncontrolled tumor growth, immune evasion, and therapeutic resistance are all driven by the dysregulated and constitutive angiogenesis occurring in the vasculature. Accordingly, great efforts have been dedicated toward identifying molecular signatures of this pathological angiogenesis in order to devise selective tumor endothelium targeting therapies while minimizing potential autoimmunity against physiologically normal endothelium. Vaccination with angiogenic antigens to generate cellular and/or humoral immunity against the tumor endothelium has proven to be a promising strategy for inhibiting or normalizing tumor angiogenesis and reducing cancer growth. Here we review tumor endothelium vaccines developed to date including active immunization strategies using specific tumor endothelium-associated antigens and whole endothelial cell-based vaccines designed to elicit immune responses against diverse target antigens. Among the novel therapeutic options, we describe a placenta-derived endothelial cell vaccine, ValloVax™, a polyvalent vaccine that is antigenically similar to proliferating tumor endothelium and is supported by pre-clinical studies to be safe and efficacious against several tumor types. PMID:26510973

  5. 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.

  6. 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

  7. 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. PMID:26228815

  8. Functional evidence of α1D-adrenoceptors in the vasculature of young and adult spontaneously hypertensive rats

    PubMed Central

    Villalobos-Molina, Rafael; López-Guerrero, J Javier; Ibarra, Maximiliano

    1999-01-01

    The role of α1D-adrenoceptors in the vasculature of spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY), of different ages was assessed in pithed rats by the use of the selective α1D-adrenoceptor antagonist BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-8-azaspiro [4.5]decane-7,9-dione dihydrochloride). BMY 7378 displaced the pressor effect of phenylephrine in young pre-hypertensive pithed SHR rats, but produced no effect in young WKY rats (dose ratio of 3.4 and 1.6, respectively), while in adult rats BMY 7378 produced a greater shift in the phenylephrine response curve than in younger animals (dose ratio of 3.2 and 6.2 in WKY and SHR, respectively). The presence of α1D-adrenoceptors in the vasculature of pre-hypertensive rats, suggests its role in the pathogenesis/maintenance of increased blood pressure. PMID:10323583

  9. Functional evidence of alpha1D-adrenoceptors in the vasculature of young and adult spontaneously hypertensive rats.

    PubMed

    Villalobos-Molina, R; López-Guerrero, J J; Ibarra, M

    1999-04-01

    The role of alpha1D-adrenoceptors in the vasculature of spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY), of different ages was assessed in pithed rats by the use of the selective alpha1D-adrenoceptor antagonist BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-8-azaspiro [4.5]decane-7,9-dione dihydrochloride). BMY 7378 displaced the pressor effect of phenylephrine in young pre-hypertensive pithed SHR rats, but produced no effect in young WKY rats (dose ratio of 3.4 and 1.6, respectively), while in adult rats BMY 7378 produced a greater shift in the phenylephrine response curve than in younger animals (dose ratio of 3.2 and 6.2 in WKY and SHR, respectively). The presence of alpha1D-adrenoceptors in the vasculature of pre-hypertensive rats, suggests its role in the pathogenesis/maintenance of increased blood pressure. PMID:10323583

  10. A relational-tubular (ReTu) deformable model for vasculature quantification of zebrafish embryo from microangiography image series.

    PubMed

    Feng, Jun; Ip, Horace H S; Cheng, Shuk H; Chan, Po K

    2004-09-01

    Embryonic cardiovascular system plays a vital role in embryonic development of human and animal. In this work, we introduce a novel deformable model, which we called Relational-tubular (ReTu) deformable model for segmenting and quantifying the embryonic vasculature of zebrafish embryo from microangiography image series. Particularly, to incorporate additional constraints on the spatial relationships among vessel branches, we introduce a new energy term called relation energy into the model energy function. This energy item acts as a repulsion force between neighboring vessels during the deformation to encourage them to move towards their respective volume data. Using the ReTu deformable model, the deformation process is an iterative two-stage procedure: vascular axis deformation and vascular surface deformation. The efficiency and robustness of this approach are demonstrated by experiments which show that satisfactory quantifications of the vasculature can be obtained after 3-4 iterations. PMID:15294311

  11. “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.

  12. “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

  13. 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

  14. Adaptive optics for peripheral vision

    NASA Astrophysics Data System (ADS)

    Rosén, R.; Lundström, L.; Unsbo, P.

    2012-07-01

    Understanding peripheral optical errors and their impact on vision is important for various applications, e.g. research on myopia development and optical correction of patients with central visual field loss. In this study, we investigated whether correction of higher order aberrations with adaptive optics (AO) improve resolution beyond what is achieved with best peripheral refractive correction. A laboratory AO system was constructed for correcting peripheral aberrations. The peripheral low contrast grating resolution acuity in the 20° nasal visual field of the right eye was evaluated for 12 subjects using three types of correction: refractive correction of sphere and cylinder, static closed loop AO correction and continuous closed loop AO correction. Running AO in continuous closed loop improved acuity compared to refractive correction for most subjects (maximum benefit 0.15 logMAR). The visual improvement from aberration correction was highly correlated with the subject's initial amount of higher order aberrations (p = 0.001, R 2 = 0.72). There was, however, no acuity improvement from static AO correction. In conclusion, correction of peripheral higher order aberrations can improve low contrast resolution, provided refractive errors are corrected and the system runs in continuous closed loop.

  15. The peripheral chromosome scaffold, a novel structural component of mitotic chromosomes.

    PubMed

    Sheval, Eugene V; Polyakov, Vladimir Y

    2008-06-01

    Using an original high-salt extraction protocol, we observed a novel chromosome substructure, referred to as the peripheral chromosome scaffold. This chromosome domain contained the perichromosomal layer proteins pKi-67, B23/nucleophosmin and fibrillarin, but no DNA fragments (i.e., the loop domain bases were not associated with the peripheral scaffold). Modern models of chromosome organization do not predict the existence of a peripheral chromosome scaffold domain, and thus our observations have conceptual implications for understanding chromosome architecture. PMID:18337132

  16. PERIPHERAL MECHANISMS IN APPETITE REGULATION

    PubMed Central

    Camilleri, Michael

    2014-01-01

    Peripheral mechanisms in appetite regulation include the motor functions of the stomach, such as the rate of emptying and accommodation, which convey symptoms of satiation to the brain. The rich repertoire of peripherally released peptides and hormones provides feedback from the arrival of nutrients in different regions of the gut from where they are released to exert effects on satiation, or regulate metabolism through their incretin effects. Ultimately, these peripheral factors provide input to the highly organized hypothalamic circuitry and vagal complex of nuclei to determine cessation of energy intake during meal ingestion, and the return of appetite and hunger after fasting. Understanding these mechanisms is key to the physiological control of feeding and the derangements that occur in obesity and their restoration with treatment (as demonstrated by the effects of bariatric surgery). PMID:25241326

  17. Peripheral nerve conduits: technology update

    PubMed Central

    Arslantunali, D; Dursun, T; Yucel, D; Hasirci, N; Hasirci, V

    2014-01-01

    Peripheral nerve injury is a worldwide clinical problem which could lead to loss of neuronal communication along sensory and motor nerves between the central nervous system (CNS) and the peripheral organs and impairs the quality of life of a patient. The primary requirement for the treatment of complete lesions is a tension-free, end-to-end repair. When end-to-end repair is not possible, peripheral nerve grafts or nerve conduits are used. The limited availability of autografts, and drawbacks of the allografts and xenografts like immunological reactions, forced the researchers to investigate and develop alternative approaches, mainly nerve conduits. In this review, recent information on the various types of conduit materials (made of biological and synthetic polymers) and designs (tubular, fibrous, and matrix type) are being presented. PMID:25489251

  18. Increased Oxidative and Nitrative Stress Accelerates Aging of the Retinal Vasculature in the Diabetic Retina

    PubMed Central

    Lamoke, Folami; Shaw, Sean; Yuan, Jianghe; Ananth, Sudha; Duncan, Michael; Martin, Pamela; Bartoli, Manuela

    2015-01-01

    Hyperglycemia-induced retinal oxidative and nitrative stress can accelerate vascular cell aging, which may lead to vascular dysfunction as seen in diabetes. There is no information on whether this may contribute to the progression of diabetic retinopathy (DR). In this study, we have assessed the occurrence of senescence-associated markers in retinas of streptozotocin-induced diabetic rats at 8 and 12 weeks of hyperglycemia as compared to normoglycemic aging (12 and 14 months) and adult (4.5 months) rat retinas. We have found that in the diabetic retinas there was an up-regulation of senescence-associated markers SA-β-Gal, p16INK4a and miR34a, which correlated with decreased expression of SIRT1, a target of miR34a. Expression of senescence-associated factors primarily found in retinal microvasculature of diabetic rats exceeded levels measured in adult and aging rat retinas. In aging rats, retinal expression of senescence associated-factors was mainly localized at the level of the retinal pigmented epithelium and only minimally in the retinal microvasculature. The expression of oxidative/nitrative stress markers such as 4-hydroxynonenal and nitrotyrosine was more pronounced in the retinal vasculature of diabetic rats as compared to normoglycemic aging and adult rat retinas. Treatments of STZ-rats with the anti-nitrating drug FeTPPS (10mg/Kg/day) significantly reduced the appearance of senescence markers in the retinal microvasculature. Our results demonstrate that hyperglycemia accelerates retinal microvascular cell aging whereas physiological aging affects primarily cells of the retinal pigmented epithelium. In conclusion, hyperglycemia-induced retinal vessel dysfunction and DR progression involve vascular cell senescence due to increased oxidative/nitrative stress. PMID:26466127

  19. Ethanol withdrawal increases oxidative stress and reduces nitric oxide bioavailability in the vasculature of rats.

    PubMed

    Gonzaga, Natalia A; Mecawi, André S; Antunes-Rodrigues, José; De Martinis, Bruno S; Padovan, Claudia M; Tirapelli, Carlos R

    2015-02-01

    We analyzed the effects of ethanol withdrawal on the vascular and systemic renin-angiotensin system (RAS) and vascular oxidative stress. Male Wistar rats were treated with ethanol 3-9% (v/v) for a period of 21 days. Ethanol withdrawal was induced by abrupt discontinuation of the treatment. Experiments were performed 48 h after ethanol discontinuation. Rats from the ethanol withdrawal group showed decreased exploration of the open arms of the elevated-plus maze (EPM) and increased plasma corticosterone levels. Ethanol withdrawal significantly increased systolic blood pressure and plasma angiotensin II (ANG II) levels without an effect on plasma renin activity (PRA), angiotensin converting enzyme (ACE) activity, or plasma angiotensin I (ANG I) levels. No differences in vascular ANG I, ANG II levels, and ACE activity/expression and AT1 and AT2 receptor expression were detected among the experimental groups. Plasma osmolality, as well as plasma sodium, potassium, and glucose levels were not affected by ethanol withdrawal. Ethanol withdrawal induced systemic and vascular oxidative stress, as evidenced by increased plasma thiobarbituric acid-reacting substances (TBARS) levels and the vascular generation of superoxide anion. Ethanol withdrawal significantly decreased plasma and vascular nitrate/nitrite levels. Major new findings of the present study are that ethanol withdrawal induces vascular oxidative stress and reduces nitric oxide (NO) levels in the vasculature. Additionally, our study provides novel evidence that ethanol withdrawal does not affect the vascular ANG II generating system while stimulating systemic RAS. These responses could predispose individuals to the development of cardiovascular diseases. PMID:25557835

  20. Control of CD8 T-cell Infiltration into Tumors by Vasculature and Microenvironment

    PubMed Central

    Peske, J. David; Woods, Amber B.; Engelhard, Victor H.

    2015-01-01

    CD8 T-cells are a critical brake on the initial development of tumors. In established tumors, the presence of CD8 T-cells is correlated with a positive patient prognosis, although immunosuppressive mechanisms limit their effectiveness and they are rarely curative without manipulation. Cancer immunotherapies aim to shift the balance back to dominant anti-tumor immunity through antibody blockade of immunosuppressive signaling pathways, vaccination, and adoptive transfer of activated or engineered T-cells. These approaches have yielded striking responses in small subsets of patients with solid tumors, most notably those with melanoma. Importantly, the subset of patients who respond to vaccination or immunosuppression blockade therapies are those with CD8 T-cells present in the tumor prior to initiating therapy. While current adoptive cell therapy approaches can be dramatically effective, they require infusion of extremely large numbers of T-cells, but the number that actually infiltrate the tumor is very small. Thus, poor representation of CD8 T-cells in tumors is a fundamental hurdle to successful immunotherapy, over and above the well-established barrier of immunosuppression. In this review, we discuss the factors that determine whether immune cells are present in tumors, with a focus on the representation of cytotoxic CD8 T-cells. We emphasize the critically important role of tumor-associated vasculature as a gateway that enables the active infiltration of both effector and naïve CD8 T-cells that exert anti-tumor activity. We also discuss strategies to enhance the gateway function and extend the effectiveness of immunotherapies to a broader set of cancer patients. PMID:26216636

  1. Control of CD8 T-Cell Infiltration into Tumors by Vasculature and Microenvironment.

    PubMed

    Peske, J David; Woods, Amber B; Engelhard, Victor H

    2015-01-01

    CD8 T-cells are a critical brake on the initial development of tumors. In established tumors, the presence of CD8 T-cells is correlated with a positive patient prognosis, although immunosuppressive mechanisms limit their effectiveness and they are rarely curative without manipulation. Cancer immunotherapies aim to shift the balance back to dominant antitumor immunity through antibody blockade of immunosuppressive signaling pathways, vaccination, and adoptive transfer of activated or engineered T-cells. These approaches have yielded striking responses in small subsets of patients with solid tumors, most notably those with melanoma. Importantly, the subset of patients who respond to vaccination or immunosuppression blockade therapies are those with CD8 T-cells present in the tumor prior to initiating therapy. While current adoptive cell therapy approaches can be dramatically effective, they require infusion of extremely large numbers of T-cells, but the number that actually infiltrates the tumor is very small. Thus, poor representation of CD8 T-cells in tumors is a fundamental hurdle to successful immunotherapy, over and above the well-established barrier of immunosuppression. In this review, we discuss the factors that determine whether immune cells are present in tumors, with a focus on the representation of cytotoxic CD8 T-cells. We emphasize the critically important role of tumor-associated vasculature as a gateway that enables the active infiltration of both effector and naïve CD8 T-cells that exert antitumor activity. We also discuss strategies to enhance the gateway function and extend the effectiveness of immunotherapies to a broader set of cancer patients. PMID:26216636

  2. Expansion of the fetoplacental vasculature in late gestation is strain dependent in mice.

    PubMed

    Rennie, Monique Y; Detmar, Jacqui; Whiteley, Kathie J; Jurisicova, Andrea; Adamson, S Lee; Sled, John G

    2012-03-15

    How the fetoplacental arterial tree grows and expands during late gestational development is largely unknown. In this study, we quantified changes in arterial branching in the fetal exchange region of the mouse placenta during late gestation, when capillarization increases rapidly. We studied two commonly used mouse strains, CD1 and C57Bl/6 (B6), at embryonic days (E)13.5, 15.5, and 17.5. B6 mice differ from CD1 mice by exhibiting a blunted fetal weight gain in late gestation. We found that B6 capillarization and interhemal membrane thinning were reduced and placental hypoxia-inducible factor-1α and VEGF-A expression were higher than CD1 near term. Automated vascular segmentation of microcomputed tomography data sets revealed that the number of arterial vessels ≥50 μm remained constant during late gestation in both strains, despite large increases in downstream capillary volume quantified by stereology (+65% in B6 mice and +200% in CD1 mice). Arterial diameters expanded in both strains from E13.5 to E15.5; however, diameters continued to expand to E17.5 in B6 mice only. The diameter scaling coefficient at branch sites was near optimal (-3.0) and remained constant in CD1 mice, whereas it decreased, becoming abnormal, in B6 mice at term (-3.5 ± 0.2). Based on arterial tree geometry, resistance remained constant throughout late gestation (∼0.45 mmHg·s·μl(-1)) in CD1 mice, whereas it decreased by 50% in late gestation in B6 mice. Quantification of the fetoplacental vasculature revealed significant strain-dependent differences in arterial and capillary expansion in late gestation. In both strains, enlargement of the fetoplacental arterial tree occurred primarily by increased arterial diameters with no change in segment numbers in late gestation. PMID:22268107

  3. Effects of stimulation of nasal and superior laryngeal inputs on the hindlimb vasculature of anaesthetized cats.

    PubMed Central

    Jordan, D; Paton, J F; Wood, L M

    1987-01-01

    1. In chloralose-anaesthetized artificially ventilated cats, either stimulation of the nasal mucosae with water or electrical stimulation of the superior laryngeal nerve (s.l.n.) resulted in apnoea, as measured from the phrenic nerve activity, and a rise in perfusion pressure of a hindlimb perfused at constant flow. In the absence of changes in venous pressure this vascular response would indicate vasoconstriction in the hindlimb. There was, however, no significant change in either heart rate or arterial blood pressure. 2. Simultaneous stimulation of the nasal mucosae and s.l.n. also resulted in apnoea but with a larger hindlimb vasoconstriction than was obtained with stimulation of only one input. This increased vasoconstriction was not significantly different from the one which in theory could be obtained by summing the two individual responses from stimulation of the nasal mucosae or s.l.n. 3. In cats anaesthetized with chloralose-urethane, stimulation of the nasal mucosae or s.l.n. also evoked an apnoea and hindlimb vasoconstriction. However, in these animals this was accompanied by a bradycardia and small fall in arterial blood pressure. 4. The present results show that whilst stimulation of two parts of the upper respiratory tract evokes qualitatively similar responses in the hindlimb vasculature, simultaneous activation of the two stimuli does not appear to result in facilitation of this hindlimb vasoconstrictor response, simply an addition of those obtained on separate stimulation. The bradycardia evoked in response to upper airway stimulation is dependent on the anaesthetic used and in the present experiments could only be obtained in animals anaesthetized with choralose-urethane. PMID:3446794

  4. 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

  5. A mitochondrial redox oxygen sensor in the pulmonary vasculature and ductus arteriosus.

    PubMed

    Dunham-Snary, Kimberly J; Hong, Zhigang G; Xiong, Ping Y; Del Paggio, Joseph C; Herr, Julia E; Johri, Amer M; Archer, Stephen L

    2016-01-01

    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 (SMCs) in pulmonary arteries (PAs), ductus arteriosus (DA), and fetoplacental arteries. Hypoxic pulmonary vasoconstriction (HPV) optimizes 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 dilates the pulmonary vasculature and constricts 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 PASMCs 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 [Ca(2+)]i and calcium sensitivity and eliciting homeostatic responses to hypoxia. In PASMCs, 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 [Ca(2+)]i, and causing vasoconstriction. In DASMCs, 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 [Ca(2+)]i, and rho kinase activation) is similar to the PASMC's hypoxic response. Impaired O2 sensing contributes to

  6. Measurement of circulation time in the retinal vasculature using selective angiography.

    PubMed

    Khoobehi, B; Schuele, K M; Ali, O M; Peyman, G A

    1990-08-01

    Retinal circulation times (RCT) and mean circulation time (MCT) in the retinal vasculature have been used to determine the effect of ocular disease on retinal circulation. Both RCT and MCT are usually determined by measuring dye dilution curves during a traditional fluorescein angiogram. The authors present a variation of the dye dilution technique. The primary difference is that a fluorescent dye (carboxyfluorescein or calcein) was encapsulated in liposomes at a very high concentration. The dye was then released at a specific site in a retinal artery by the application of a laser pulse delivered through the pupil of the eye. The heat pulse produced by the laser lysed the liposomes in the targeted vessel, causing a stream of dye to be released. The time it took the dye front to pass through the artery and return through the vein (RCT) was then measured. To clarify the situation, two times were actually measured, the shortest path the dye traveled from the exposure site to a corresponding site on the vein (short RCT) and the longest path through the periphery to venous filling (long RCT). The measurements were made in both cynomolgus monkeys and squirrel monkeys. The local dye release achieved with this method was found to produce a more distinct dye front than traditional angiography while also eliminating the problem of recirculation. Choroidal background fluorescence, a factor that often obscures the dye front in traditional angiography, was minimal. Furthermore, it was possible to make individual measurements on each of the four arteries and to repeat the measurements several times. PMID:2402418

  7. 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

  8. Inter- and intra-tumoral relationships between vasculature characteristics, GLUT1 and budding in colorectal carcinoma.

    PubMed

    Mezheyeuski, Artur; Nerovnya, Alexander; Bich, Tatjana; Tur, Gennadiy; Ostman, Arne; Portyanko, Anna

    2015-10-01

    Vascular characteristics, hypoxia and tumor budding are features that have been implied in the biology and prognosis of colorectal cancer. Internal relationships and the inter- and intra-tumoral variation of these tumor properties remain to be determined. In the current study we have characterized blood vessel status in different areas of CRC and in the peritumoral fibroblastic stroma. Analyses of these characteristics have been supplemented by characterization of budding and hypoxia. Analyses revealed significantly lower values of vessel perimeter (VP) and vessel lumen area (VL) at the invasive front and surrounding stroma as compared to the tumor center. Also, the number of vessels (VN) in the peritumoral stroma was higher than in the center. Thus, tumor center displays larger and fewer vessels as compared to the tumor periphery. GLUT1 expression was correlated directly with VN (r=0.351, p=0.028) and inversely with VL and VP (r=-0.432, p=0.006 and r=-0.484, p=0.002) at the invasive front. Moreover, GLUT1 expression, VP at the invasive front, and VN in the surrounding peritumoral stroma, were associated with budding score (r=0.574, p<0.000, r=-0.340, p=0,034 and r=-0.389, p=0.025 respectively). Furthermore, GLUT1, budding score, vessel number in peritumoral stroma, and vessel size in the invasive front, were significantly different in tumors with or without lymph node metastasis. This study reports previously unrecognized relationships between localization-specific vascular characteristics, hypoxia and tumor budding. The findings suggest potential functional relationships, which should be further explored, and also highlight the inter-tumoral variations in vasculature, which is highly relevant for ongoing efforts to identify vessel-based biomarkers. PMID:25811313

  9. Developmental Progression of the Coronary Vasculature in Human Embryos and Fetuses.

    PubMed

    Tomanek, Robert J

    2016-01-01

    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, and 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

  10. Peripheral signals modifying food reward.

    PubMed

    Menzies, John R W; Skibicka, Karolina P; Egecioglu, Emil; Leng, Gareth; Dickson, Suzanne L

    2012-01-01

    The pleasure derived from eating may feel like a simple emotion, but the decision to eat, and perhaps more importantly what to eat, involves central pathways linking energy homeostasis and reward and their regulation by metabolic and endocrine factors. Evidence is mounting that modulation of the hedonic aspects of energy balance is under the control of peripheral neuropeptides conventionally associated with homeostatic appetite control. Here, we describe the significance of reward in feeding, the neural substrates underlying the reward pathway and their modification by peptides released into the circulation from peripheral tissues. PMID:22249813

  11. Effects of hyperthermia on the peripheral nervous system: a review.

    PubMed

    Haveman, J; Van Der Zee, J; Wondergem, J; Hoogeveen, J F; Hulshof, M C C M

    2004-06-01

    The present paper overviews the current knowledge about effects of hyperthermia at temperatures used in clinical oncology on the peripheral nervous system. From the experimental studies it may be concluded that the heat sensitivity of the nerve is determined by the sensitivity of the nerve vasculature. These studies show that in order to avoid induction of severe neuropathy, application of heat to the peripheral nerves should not be in excess of doses of 30 min at 44 degrees C or equivalent. Using modern equipment for application of loco-regional hyperthermia the incidence of even mild neurological complications is very low. In hyperthermic isolated limb perfusion (HILP) neurotoxicity is an often-mentioned side effect, this is in spite of the fact that in all studies a relatively mild hyperthermic temperature is used that, based on the experimental studies, should be well tolerated by the nerves and other normal tissues in the limbs. It seems that the neurotoxicity observed after HILP results from thermal enhancement of drug toxicity, very probably combined with effects of a high tourniquet pressure that is used to isolate the blood flow in the leg. Whole body hyperthermia (WBH), using anesthesia and appropriate monitoring to avoid cardiovascular stress is at present considered a safe procedure. Still in the recent past cases of neuropathy after treatment have been described. When chemotherapy, and notably cisplatin, is administered before or during hyperthermia there are several clinical and experimental observations that indicate a limited tolerance of the peripheral nervous tissue in such case. Also previous radiotherapy may limit the tolerance of nerves to hyperthermia, notably when radiation is applied with a large field size. Experimental studies show that combined treatment with radiation and heat leads to enhancement of effects of radiation (enhancement ratio approximately 1.5 at 60 min at 44 degrees C). A clear contraindication for the application of

  12. How to Pick Computer Peripherals.

    ERIC Educational Resources Information Center

    Fisher, Glenn

    1983-01-01

    A guide to computer peripherals--additional hardware that can expand the educational uses of computers--is given. Tips are furnished on selection and possible use of computer printers; modulator/demodulators (modems); graphics tablets; plotters, speech synthesizers, and robots. (PP)

  13. [Peripheral Nerve Injuries in Sports].

    PubMed

    Tettenborn, B; Mehnert, S; Reuter, I

    2016-09-01

    Peripheral nerve injuries due to sports are relatively rare but the exact incidence is not known due to a lack of epidemiological studies. Particular sports activities tend to cause certain peripheral nerve injuries including direct acute compression or stretching, repetitive compression and stretching over time, or another mechanism such as ischemia or laceration. These nerve lesions may be severe and delay or preclude the athlete's return to sports, especially in cases with delayed diagnosis. Repetitive and vigorous use or overuse makes the athlete vulnerable to disorders of the peripheral nerves, and sports equipment may cause compression of the nerves. Depending on etiology, the treatment is primarily conservative and includes physiotherapy, modification of movements and sports equipment, shoe inserts, splinting, antiphlogistic drugs, sometimes local administration of glucocorticoids or, lately, the use of extracorporeal shock waves. Most often, cessation of the offending physical activity is necessary. Surgery is only indicated in the rare cases of direct traumatic nerve injury or when symptoms are refractory to conservative therapy. Prognosis mainly depends on the etiology and the available options of modifying measures.This article is based on the publications "Reuter I, Mehnert S. Engpasssyndrome peripherer Nerven bei Sportlern". Akt Neurol 2012;39:292-308 and Sportverl Sportschad 2013;27:130-146. PMID:27607069

  14. Central and Peripheral Components of Working Memory Storage

    PubMed Central

    Cowan, Nelson; Saults, J. Scott; Blume, Christopher L.

    2014-01-01

    This study re-examines the issue of how much of working memory storage is central, or shared across sensory modalities and verbal and nonverbal codes, and how much is peripheral, or specific to a modality or code. In addition to the exploration of many parameters in 9 new dual-task experiments and re-analysis of some prior evidence, the innovations of the present work compared to previous studies of memory for two stimulus sets include (1) use of a principled set of formulas to estimate the number of items in working memory, and (2) a model to dissociate central components, which are allocated to very different stimulus sets depending on the instructions, from peripheral components, which are used for only one kind of material. We consistently find that the central contribution is smaller than was suggested by Saults and Cowan (2007), and that the peripheral contribution is often much larger when the task does not require the binding of features within an object. Previous capacity estimates are consistent with the sum of central plus peripheral components observed here. We consider the implications of the data as constraints on theories of working memory storage and maintenance. PMID:24867488

  15. Platelet peripheral benzodiazepine receptors are decreased in Parkinson's disease

    SciTech Connect

    Bonuccelli, U.; Nuti, A.; Del Dotto, P.; Piccini, P.; Martini, C.; Giannacccini, G.; Lucacchini, A.; Muratorio, A. )

    1991-01-01

    Peripheral benzodiazepine (BDZ) receptors are located in a variety of tissues, including platelets, in the nuclear and/or mitochondrial membranes. The authors studied the density of peripheral BDZ receptors in platelets of 10 de novo Parkinson's disease (PD) patients, 18 PD patients treated with a levodopa/carbidopa combination, and in 15 healthy subjects matched for sex and age. The binding assay was conducted using ({sup 3}H)PK 11195, a specific ligand for peripheral BDZ receptors. A significant decrease in the density of ({sup 3}H)PK 11195 binding sites has been observed in PD patients with respect to controls but not between de novo and treated PD patients. No correlation has been found between the decrease in density of ({sup 3}H)PK 11195 binding sites in platelets and either the duration or severity of PD. Peripheral BDZ receptors are implicated in the regulation of mitochondrial respiratory function. Thus, their decrease in PD might parallel the abnormalities in mitochondrial function recently found in this neurologic disease.

  16. Probing the Peripheral Site of Human Butyrylcholinesterase

    PubMed Central

    2012-01-01

    Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) catalyze the hydrolysis of the neurotransmitter acetylcholine and, thereby, function as coregulators of cholinergic neurotransmission. For both enzymes, hydrolysis takes place near the bottom of a 20 Å deep active site gorge. A number of amino acid residues within the gorge have been identified as important in facilitating efficient catalysis and inhibitor binding. Of particular interest is the catalytic triad, consisting of serine, histidine, and glutamate residues, that mediates hydrolysis. Another site influencing the catalytic process is located above the catalytic triad toward the periphery of the active site gorge. This peripheral site (P-site) contains a number of aromatic amino acid residues as well as an aspartate residue that is able to interact with cationic substrates and guide them down the gorge to the catalytic triad. In human AChE, certain aryl residues in the vicinity of the anionic aspartate residue (D74), such as W286, have been implicated in ligand binding and have therefore been considered part of the P-site of the enzyme. The present study was undertaken to explore the P-site of human BuChE and determine whether, like AChE, aromatic side chains near the peripheral aspartate (D70) of this enzyme contribute to ligand binding. Results obtained, utilizing inhibitor competition studies and BuChE mutant species, indicate the participation of aryl residues (F329 and Y332) in the E-helix component of the BuChE active site gorge, along with the anionic aspartate residue (D70), in binding ligands to the P-site of the enzyme. PMID:22901043

  17. Effect of angiotensin II on uterine and systemic vasculature in pregnant sheep.

    PubMed Central

    Naden, R P; Rosenfeld, C R

    1981-01-01

    The response of uteroplacental blood flow (UBF) to angiotensin II is controversial. Moreover, the relationship of the uterine and systemic responses to infused angiotensin II is not well understood. Thus, in eight chronically instrumented, near-term pregnant sheep, we have determined the relationships between the dose and duration of constant systemic infusions of angiotensin II ([Val5] ANG II) and changes in UBF, uterine vascular resistance (UVR), mean arterial pressure (MAP), and systemic vascular resistance (SVR). [Val5] ANG II caused dose-dependent increases in UVR and MAP at all doses studied (P less than 0.05). The response in UBF was bidirectional, with increases at doses less than or equal to 1.15 microgram/min and decreases at greater than or equal to 2.29 micrograms/min (P less than 0.05). Increases in UBP occurred when the relative rise (delta) in MAP greater than delta UVR, whereas UBF was unchanged when delta MAP = delta UVR and decreased when delta MAP less than delta UVR. SVR also rose in a dose-dependent fashion (P less than 0.05); delta SVR was greater than delta UVR at doses less than or equal to 2.29 micrograms [Val5] ANG II/min (P less than 0.01). In studies of the effect of duration of [Val5] ANG II infusions, UBF increased at all doses during the 1st min, followed by stabilization at 4--5 min, with eventual decreases at doses greater than or equal to 2.29 micrograms/min and increases at doses less than 2.29 micrograms/min. The relationship between the changes in MAP and UVR to the response of UBF was as noted above. It is evident that (a) [Val5] NAG II is uterine vasoconstrictor, (b) changes in UBF are dependent upon relative changes in perfusion pressure and UVR, which in turn are dependent upon both the dose and duration of a [Val5] ANG II infusion, and (c) the uteroplacental vasculature is relatively refractory to the vasoconstricting effects of low doses of [Val5] ANG II. PMID:7263862

  18. Preclinical In Vivo Evaluation of Npe6-Mediated Photodynamic Therapy on Normal Vasculature

    PubMed Central

    Moy, Wesley J.; Patel, Shreyas J.; Lertsakdadet, Ben S.; Arora, Rajan P.; Nielsen, Katherine M.; Kelly, Kristen M.; Choi, Bernard

    2012-01-01

    Background and Objective Current treatments of port-wine stain birthmarks typically involve use of a pulsed dye laser (PDL) combined with cooling of the skin. Currently, PDL therapy protocols result in varied success, as some patients experience complete blanching, while others do not. Over the past decade, we have studied the use of photodynamic therapy (PDT) as either a replacement or adjuvant treatment option to photocoagulate both small and large vasculature. The objective of the current study was to evaluate a PDT protocol that involves use of an alternate intravascular photosensitizer mono-L-aspartylchlorin-e6 (NPe6) activated by an array of low-cost light emitting diodes. Study Design/Materials and Methods To monitor the microvasculature, a dorsal window chamber model was installed on 22 adult male mice. The light source consisted of a custom-built LED array that emitted 10 W at a center wavelength of 664 nm (FWHM = 20 nm). The light source was positioned at a fixed distance from the window chamber to achieve a fixed irradiance of 127 mW/cm2. A retroorbital injection of NPe6 (5 mg/kg) was performed to deliver the drug into the bloodstream. Laser irradiation was initiated immediately after injection. To monitor blood-flow dynamics in response to PDT, we used laser speckle imaging. We employed a dose–response experimental design to evaluate the efficacy of NPe6-mediated PDT. Results We observed three general hemodynamic responses to PDT: (1) At low radiant exposures, we did not observe any persistent vascular shutdown; (2) at intermediate radiant exposures, we observed an acute decrease in blood flow followed by gradual restoration of blood flow over the 7-day monitoring period; and (3) at high radiant exposures, we observed acute vascular shutdown that persisted during the entire 7-day monitoring period. Dose–response analysis enabled identification of 85 J/cm2 as a characteristic radiant exposure required to achieve persistent vascular shutdown at Day 7

  19. Dietary exposure to ergot alkaloids decreases contractility of bovine mesenteric vasculature.

    PubMed

    Egert, A M; Kim, D H; Schrick, F N; Harmon, D L; Klotz, J L

    2014-04-01

    vasoactive in the bovine midgut, and steers exposed to E+ had diminished contractility to some ergot alkaloids in small intestinal vasculature. The findings of this study suggest that dietary exposure to ergot alkaloids has the potential to alter nutrient absorption from the midgut by decreasing blood flow to and from the midgut due to vasoconstriction. PMID:24492572

  20. In situ localization of F-actin microfilaments in the vasculature of the porcine retina.

    PubMed

    Strauss, B I; Langille, B L; Gotlieb, A I

    1987-10-01

    The organization of F-actin microfilaments in the vascular endothelium of the porcine retina was studied in situ using rhodamine phalloidin labelling and fluorescence microscopy. A comparison was made between arterial and venous endothelial-cell microfilament distribution. The arterial cells in straight segments, bifurcations and branch points were elongated with their long axis in the direction of flow. Venous endothelial cells, on the other hand, were ellipsoid to rhomboid in shape throughout. F-actin was localized at the periphery of both arterial and venous endothelial cells. Prominent central microfilament bundles, similar to in vitro stress fibres, were oriented parallel to the long axis of arterial cells but were rarely present in venous cells. Only occasional venous endothelial cells contained short central actin filaments which were mainly in the venules. Central microfilaments were not identified in pre-capillary, capillary, or post-capillary endothelial cells. Incubation of the retinal organ cultures for 24 hr resulted in loss of the central microfilaments while peripheral staining persisted. Short-term incubation of the retinas in organ culture with low-dose cytochalasin B resulted in disruption of the central microfilaments while the peripheral actin microfilaments remained intact. The central microfilament bundles may reflect an adaptive response to arterial blood flow and may indeed be a sensitive dynamic system reflecting the influence of environmental factors on endothelial cells. PMID:3428383

  1. Role of R-type calcium channels in the response of the perfused arterial and venous mesenteric vasculature of the rat to platelet-activating factor.

    PubMed Central

    Claing, A.; Bkaily, G.; Berthiaume, N.; Sirois, P.; Rola-Pleszczynski, M.; D'Orléans-Juste, P.

    1994-01-01

    1. The vasoactive properties of platelet-activating factor (PAF) were studied in the arterial and venous vasculature of the rat double-perfused mesenteric bed. Although PAF (0.01-0.3 pmol) induced a dose-dependent vasodilatation of the arterial mesenteric vasculature, it triggered only vasoconstrictions on the venous side, with an intact endothelium as bradykinin induced a significant venodilatation. 2. NG-nitro-L-arginine methyl ester (L-NAME, 100 microM), a nitric oxide synthase inhibitor, markedly reduced the vasodilatation induced by PAF in the arterial mesenteric vasculature and potentiated the contractile responses of the venous side to the same agent. 3. The PAF antagonist, WEB-2170, markedly reduced the response to PAF on both sides of the mesenteric vasculature. However, the IC50 of WEB-2170 against PAF was reached at a much higher concentration (1 x 10(-8) M) on the arterial side than on the venous side (5.3 x 10(-11) M). Furthermore, a second antagonist of PAF receptors, SRI-63441, although being less potent on the venous vasculature than WEB-2170, was equipotent in antagonizing the venoconstriction and the arterial dilatation induced by PAF (IC50 of SRI-63441, arterial side: 2.9 x 10(-9) M; venous side: 3.1 x 10(-9) M). 4. The dual L- and R-calcium channel blocker, isradipine (PN 200-110), but not the L-type calcium channel blocker, nifedipine, markedly reduced the PAF-induced vasoactive properties on both sides of the mesenteric vasculature. 5. Our results illustrate the differential vasoactive properties of PAF in the mesenteric vasculature of the rat.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7952882

  2. Vasculature-specific MRI reveals differential anti-angiogenic effects of a biomimetic peptide in an orthotopic breast cancer model.

    PubMed

    Kim, Eugene; Lee, Esak; Plummer, Charlesa; Gil, Stacy; Popel, Aleksander S; Pathak, Arvind P

    2015-04-01

    Translational vasculature-specific MRI biomarkers were used to measure the effects of a novel anti-angiogenic biomimetic peptide in an orthotopic MDA-MB-231 human triple-negative breast cancer model at an early growth stage. In vivo diffusion-weighted and steady-state susceptibility contrast (SSC) MRI was performed pre-treatment and 2 weeks post-treatment in tumor volume-matched treatment and control groups (n = 5/group). Treatment response was measured by changes in tumor volume; baseline transverse relaxation time (T2); apparent diffusion coefficient (ADC); and SSC-MRI metrics of blood volume, vessel size, and vessel density. These vasculature-specific SSC-MRI biomarkers were compared to the more conventional, non-vascular biomarkers (tumor growth, ADC, and T2) in terms of their sensitivity to anti-angiogenic treatment response. After 2 weeks of peptide treatment, tumor growth inhibition was evident but not yet significant, and the changes in ADC or T2 were not significantly different between treated and control groups. In contrast, the vascular MRI biomarkers revealed a significant anti-angiogenic response to the peptide after 2 weeks—blood volume and vessel size decreased, and vessel density increased in treated tumors; the opposite was seen in control tumors. The MRI results were validated with histology—H&E staining showed no difference in tumor viability between groups, while peptide-treated tumors exhibited decreased vascularity. These results indicate that translational SSC-MRI biomarkers are able to detect the differential effects of anti-angiogenic therapy on the tumor vasculature before significant tumor growth inhibition or changes in tumor viability. PMID:25408417

  3. Novel Anti-TM4SF1 Antibody-Drug Conjugates with Activity against Tumor Cells and Tumor Vasculature.

    PubMed

    Visintin, Alberto; Knowlton, Kelly; Tyminski, Edyta; Lin, Chi-Iou; Zheng, Xiang; Marquette, Kimberly; Jain, Sadhana; Tchistiakova, Lioudmila; Li, Dan; O'Donnell, Christopher J; Maderna, Andreas; Cao, Xianjun; Dunn, Robert; Snyder, William B; Abraham, Anson K; Leal, Mauricio; Shetty, Shoba; Barry, Anthony; Zawel, Leigh; Coyle, Anthony J; Dvorak, Harold F; Jaminet, Shou-Ching

    2015-08-01

    Antibody-drug conjugates (ADC) represent a promising therapeutic modality for managing cancer. Here, we report a novel humanized ADC that targets the tetraspanin-like protein TM4SF1. TM4SF1 is highly expressed on the plasma membranes of many human cancer cells and also on the endothelial cells lining tumor blood vessels. TM4SF1 is internalized upon interaction with antibodies. We hypothesized that an ADC against TM4SF1 would inhibit cancer growth directly by killing cancer cells and indirectly by attacking the tumor vasculature. We generated a humanized anti-human TM4SF1 monoclonal antibody, v1.10, and armed it with an auristatin cytotoxic agent LP2 (chemical name mc-3377). v1.10-LP2 selectively killed cultured human tumor cell lines and human endothelial cells that express TM4SF1. Acting as a single agent, v1.10-LP2 induced complete regression of several TM4SF1-expressing tumor xenografts in nude mice, including non-small cell lung cancer and pancreas, prostate, and colon cancers. As v1.10 did not react with mouse TM4SF1, it could not target the mouse tumor vasculature. Therefore, we generated a surrogate anti-mouse TM4SF1 antibody, 2A7A, and conjugated it to LP2. At 3 mpk, 2A7A-LP2 regressed several tumor xenografts without noticeable toxicity. Combination therapy with v1.10-LP2 and 2A7A-LP2 together was more effective than either ADC alone. These data provide proof-of-concept that TM4SF1-targeting ADCs have potential as anticancer agents with dual action against tumor cells and the tumor vasculature. Such agents could offer exceptional therapeutic value and warrant further investigation. Mol Cancer Ther; 14(8); 1868-76. ©2015 AACR. PMID:26089370

  4. Physical activity-induced remodeling of vasculature in skeletal muscle: role in treatment of type 2 diabetes.

    PubMed

    Laughlin, M Harold

    2016-01-01

    This manuscript summarizes and discusses adaptations of skeletal muscle vasculature induced by physical activity and applies this understanding to benefits of exercise in prevention and treatment of type 2 diabetes (T2D). Arteriolar trees of skeletal muscle are heterogeneous. Exercise training increases capillary exchange and blood flow capacities. The distribution of vascular adaptation to different types of exercise training are influenced by muscle fiber type composition and fiber recruitment patterns that produce different modes of exercise. Thus training-induced adaptations in vascular structure and vascular control in skeletal muscle are not homogeneously distributed throughout skeletal muscle or along the arteriolar tree within a muscle. Results summarized indicate that similar principles apply to vascular adaptation in skeletal muscle in T2D. It is concluded that exercise training-induced changes in vascular gene expression differ along the arteriolar tree and by skeletal muscle fiber type composition. Results suggest that it is unlikely that hemodynamic forces are the only exercise-induced signals mediating the regulation of vascular gene expression. In patients with T2D, exercise training is perhaps the most effective treatment of the many related symptoms. Training-induced changes in the vasculature and in insulin signaling in the muscle fibers and vasculature augment glucose and insulin delivery as well as glucose uptake. If these adaptations occur in a sufficient amount of muscle mass, exposure to hyperglycemia and hyperinsulinemia will decrease along with the risk of microvascular complications throughout the body. It is postulated that exercise sessions in programs of sufficient duration, that engage as much skeletal muscle mass as possible, and that recruit as many muscle fibers within each muscle as possible will produce the greatest benefit. The added benefit of combined resistance and aerobic training programs and of high-intensity exercise

  5. Targeting Tumor Vasculature Endothelial Cells and Tumor Cells for Immunotherapy of Human Melanoma in a Mouse Xenograft Model

    NASA Astrophysics Data System (ADS)

    Hu, Zhiwei; Sun, Ying; Garen, Alan

    1999-07-01

    An immunotherapy treatment for cancer that targets both the tumor vasculature and tumor cells has shown promising results in a severe combined immunodeficient mouse xenograft model of human melanoma. The treatment involves systemic delivery of an immunoconjugate molecule composed of a tumor-targeting domain conjugated to the Fc effector domain of human IgG1. The effector domain induces a cytolytic immune response against the targeted cells by natural killer cells and complement. Two types of targeting domains were used. One targeting domain is a human single-chain Fv molecule that binds to a chondroitin sulfate proteoglycan expressed on the surface of most human melanoma cells. Another targeting domain is factor VII (fVII), a zymogen that binds with high specificity and affinity to the transmembrane receptor tissue factor (TF) to initiate the blood coagulation cascade. TF is expressed by endothelial cells lining the tumor vasculature but not the normal vasculature, and also by many types of tumor cells including melanoma. Because the binding of a fVII immunoconjugate to TF might cause disseminated intravascular coagulation, the active site of fVII was mutated to inhibit coagulation without affecting the affinity for TF. The immunoconjugates were encoded as secreted molecules in a replication-defective adenovirus vector, which was injected into the tail vein of severe combined immunodeficient mice. The results demonstrate that a mutated fVII immunoconjugate, administered separately or together with a single-chain Fv immunoconjugate that binds to the tumor cells, can inhibit the growth or cause regression of an established human tumor xenograft. This procedure could be effective in treating a broad spectrum of human solid tumors that express TF on vascular endothelial cells and tumor cells.

  6. Peripheral Giant Cell Granuloma in a Dog.

    PubMed

    Hiscox, Lorraine A; Dumais, Yvan

    2015-01-01

    Peripheral giant cell granuloma is considered rare in the dog with little known about the clinicopathologic features. There are few reports in the veterinary literature concerning this benign, reactive lesion, formerly known as giant cell epulis. In humans, the four most commonly described reactive epulides are focal fibrous hyperplasia (fibrous epulis), pyogenic granuloma, peripheral ossifying fibroma, and peripheral giant cell granuloma. This case report describes the diagnosis and surgical management of a peripheral giant cell granuloma in a dog. PMID:26415387

  7. Theory underlying the peripheral vision horizon device

    NASA Technical Reports Server (NTRS)

    Money, K. E.

    1984-01-01

    Peripheral Vision Horizon Device (PVHD) theory states that the likelihood of pilot disorientation in flight is reduced by providing an artificial horizon that provides orientation information to peripheral vision. In considering the validity of the theory, three areas are explored: the use of an artificial horizon device over some other flight instrument; the use of peripheral vision over foveal vision; and the evidence that peripheral vision is well suited to the processing of orientation information.

  8. Modulation of retinal image vasculature analysis to extend utility and provide secondary value from optical coherence tomography imaging.

    PubMed

    Cameron, James R; Ballerini, Lucia; Langan, Clare; Warren, Claire; Denholm, Nicholas; Smart, Katie; MacGillivray, Thomas J

    2016-04-01

    Retinal image analysis is emerging as a key source of biomarkers of chronic systemic conditions affecting the cardiovascular system and brain. The rapid development and increasing diversity of commercial retinal imaging systems present a challenge to image analysis software providers. In addition, clinicians are looking to extract maximum value from the clinical imaging taking place. We describe how existing and well-established retinal vasculature segmentation and measurement software for fundus camera images has been modulated to analyze scanning laser ophthalmoscope retinal images generated by the dual-modality Heidelberg SPECTRALIS(®) instrument, which also features optical coherence tomography. PMID:27175375

  9. Peripheral Neuropathy – Clinical and Electrophysiological Considerations

    PubMed Central

    Chung, Tae; Prasad, Kalpana; Lloyd, Thomas E.

    2013-01-01

    This article is a primer on the pathophysiology and clinical evaluation of peripheral neuropathy for the radiologist. Magnetic resonance neurography (MRN) has utility in the diagnosis of many focal peripheral nerve lesions. When combined with history, examination, electrophysiology, and laboratory data, future advancements in high-field MRN may play an increasingly important role in the evaluation of patients with peripheral neuropathy. PMID:24210312

  10. Coaching Peripheral Vision Training for Soccer Athletes

    ERIC Educational Resources Information Center

    Marques, Nelson Kautzner, Jr.

    2010-01-01

    Brazilian Soccer began developing its current emphasis on peripheral vision in the late 1950s, by initiative of coach of the Canto do Rio Football Club, in Niteroi, Rio de Janeiro, a pioneer in the development of peripheral vision training in soccer players. Peripheral vision training gained world relevance when a young talent from Canto do Rio,…

  11. Peripheral neuromodulation in chronic migraine.

    PubMed

    Perini, F; De Boni, A

    2012-05-01

    Patients with chronic migraines are often refractory to medical treatment. Therefore, they might need other strategies to modulate their pain, according to their level of disability. Neuromodulation can be achieved with several tools: meditation, biofeedback, physical therapy, drugs and electric neurostimulation (ENS). ENS can be applied to the central nervous system (brain and spinal cord), either invasively (cortical or deep brain) or non-invasively [cranial electrotherapy stimulation, transcranial direct current stimulation and transcranial magnetic stimulation]. Among chronic primary headaches, cluster headaches are most often treated either through deep brain stimulation or occipital nerve stimulation because there is a high level of disability related to this condition. ENS, employed through several modalities such as transcutaneous electrical nerve stimulation, interferential currents and pulsed radiofrequency, has been applied to the peripheral nervous system at several sites. We briefly review the indications for the use of peripheral ENS at the site of the occipital nerves for the treatment of chronic migraine. PMID:22644166

  12. PERIPHERAL BLOOD FILM - A REVIEW

    PubMed Central

    Adewoyin, AS; Nwogoh, B.

    2014-01-01

    The peripheral blood film (PBF) is a laboratory work-up that involves cytology of peripheral blood cells smeared on a slide. As basic as it is, PBF is invaluable in the characterization of various clinical diseases. This article highlights the basic science and art behind the PBF. It expounds its laboratory applications, clinical indications and interpretations in the light of various clinical diseases. Despite advances in haematology automation and application of molecular techniques, the PBF has remained a very important diagnostic test to the haematologist. A good quality smear, thorough examination and proper interpretation in line with patient's clinical state should be ensured by the haemato-pathologist. Clinicians should be abreast with its clinical utility and proper application of the reports in the management of patients. PMID:25960697

  13. Peripheral neuritis due to isoniazid*

    PubMed Central

    Devadatta, S.; Gangadharam, P. R. J.; Andrews, R. H.; Fox, Wallace; Ramakrishnan, C. V.; Selkon, J. B.; Velu, S.

    1960-01-01

    It is well known that in the treatment of tuberculosis with isoniazid the complication of peripheral neuritis may arise. This complication is normally rare when small dosages of the drug are used, but a high incidence of the neuropathy has recently been observed in East Africa in a group of malnourished tuberculous patients receiving isoniazid in comparatively low dosage (4-6 mg/kg body-weight daily). The present paper reports on 20 cases of peripheral neuritis encountered in Madras, India, among 338 poorly nourished tuberculous patients during a trial of four isoniazid regimens, two of low and two of high dosage (3.9-5.5 and 7.8-9.6 mg/kg body-weight daily, respectively). Nineteen of the 20 cases occurred in the two groups of patients receiving the high dosage and these 19 patients were found to have a higher mean serum level of free isoniazid than the patients in the same groups who did not develop the complication. The authors consider that dosages of 7.8-9.6 mg/kg body-weight daily should not be used for the mass therapy of poorly nourished patients unless steps are taken to prevent the development of peripheral neuritis. Pyridoxine has been reported to be an effective preventive, but is too expensive for use on a large scale. This study indicates, however, that administration of the cheaper vitamin B complex might give satisfactory results and warrants further investigation. PMID:13722334

  14. Isolating the effects of surface vasculature in infant neuroimaging using short-distance optical channels: a combination of local and global effects.

    PubMed

    Emberson, Lauren L; Crosswhite, Stephen L; Goodwin, James R; Berger, Andrew J; Aslin, Richard N

    2016-07-01

    Functional near-infrared spectroscopy (fNIRS) records hemodynamic changes in the cortex arising from neurovascular coupling. However, (noninvasive) fNIRS recordings also record surface vascular signals arising from noncortical sources (e.g., in the skull, skin, dura, and other tissues located between the sensors and the brain). A current and important focus in the fNIRS community is determining how to remove these noncortical vascular signals to reduce noise and to prevent researchers from erroneously attributing responses to cortical sources. The current study is the first to test a popular method for removing signals from the surface vasculature (removing short, 1 cm, channel recordings from long, 3 cm, channel recordings) in human infants, a population frequently studied using fNIRS. We find evidence that this method does remove surface vasculature signals and indicates the presence of both local and global surface vasculature signals. However, we do not find that the removal of this information changes the statistical inferences drawn from the data. This latter result not only questions the importance of removing surface vasculature responses for empiricists employing this method, but also calls for future research using other tasks (e.g., ones with a weaker initial result) with this population and possibly additional methods for removing signals arising from the surface vasculature in infants. PMID:27158631

  15. Effects of Motion in the Far Peripheral Visual Field on Cognitive Test Performance and Cognitive Load.

    PubMed

    Bevilacqua, Andy; Paas, Fred; Krigbaum, Genomary

    2016-04-01

    Cognitive load theory posits that limited attention is in actuality a limitation in working memory resources. The load theory of selective attention and cognitive control sees the interplay between attention and awareness as separate modifying functions that act on working memory. Reconciling the theoretical differences in these two theories has important implications for learning. Thirty-nine adult participants performed a cognitively demanding test, with and without movement in the far peripheral field. Although the results for movement effects on cognitive load in this experiment were not statistically significant, men spent less time on the cognitive test in the peripheral movement condition than in the conditions without peripheral movement. No such difference was found for women. The implications of these results and recommendations for future research that extends the present study are presented. PMID:27166327

  16. The structure of the peripheral stalk of Thermus thermophilus H+-ATPase/synthase

    SciTech Connect

    Lee, Lawrence K; Stewart, Alastair G; Donohoe, Mhairi; Bernal, Ricardo A; Stock, Daniela

    2010-03-22

    Proton-translocating ATPases are ubiquitous protein complexes that couple ATP catalysis with proton translocation via a rotary catalytic mechanism. The peripheral stalks are essential components that counteract torque generated from proton translocation during ATP synthesis or from ATP hydrolysis during proton pumping. Despite their essential role, the peripheral stalks are the least conserved component of the complexes, differing substantially between subtypes in composition and stoichiometry. We have determined the crystal structure of the peripheral stalk of the A-type ATPase/synthase from Thermus thermophilus consisting of subunits E and G. The structure contains a heterodimeric right-handed coiled coil, a protein fold never observed before. We have fitted this structure into the 23 {angstrom} resolution EM density of the intact A-ATPase complex, revealing the precise location of the peripheral stalk and new implications for the function and assembly of proton-translocating ATPases.

  17. Diabetic peripheral neuropathy may not be as its name suggests: evidence from magnetic resonance imaging.

    PubMed

    Tesfaye, Solomon; Selvarajah, Dinesh; Gandhi, Rajiv; Greig, Marni; Shillo, Pallai; Fang, Fang; Wilkinson, Iain D

    2016-02-01

    Diabetic peripheral neuropathy (DPN) affects up to 50% of patients with diabetes and is a major cause of morbidity and increased mortality. Its clinical manifestations include distressing painful neuropathic symptoms and insensitivity to trauma that result in foot ulcerations and amputations. Several recent studies have implicated poor glycemic control, duration of diabetes, hyperlipidemia (particularly hypertryglyceridaemia), elevated albumin excretion rates, and obesity as risk factors for the development of DPN. However, similar data are not available for painful DPN. Moreover, although there is now strong evidence for the importance of peripheral nerve microvascular disease in the pathogenesis of DPN, peripheral structural biomarkers of painful DPN are lacking. However, there is now emerging evidence for the involvement of the central nervous system in both painful and painless DPN afforded by magnetic resonance imaging. This review will focus on this emerging evidence for central changes in DPN, hitherto considered a peripheral nerve disease only. PMID:26785159

  18. Peripheral doses from pediatric IMRT

    SciTech Connect

    Klein, Eric E.; Maserang, Beth; Wood, Roy; Mansur, David

    2006-07-15

    Peripheral dose (PD) data exist for conventional fields ({>=}10 cm) and intensity-modulated radiotherapy (IMRT) delivery to standard adult-sized phantoms. Pediatric peripheral dose reports are limited to conventional therapy and are model based. Our goal was to ascertain whether data acquired from full phantom studies and/or pediatric models, with IMRT treatment times, could predict Organ at Risk (OAR) dose for pediatric IMRT. As monitor units (MUs) are greater for IMRT, it is expected IMRT PD will be higher; potentially compounded by decreased patient size (absorption). Baseline slab phantom peripheral dose measurements were conducted for very small field sizes (from 2 to 10 cm). Data were collected at distances ranging from 5 to 72 cm away from the field edges. Collimation was either with the collimating jaws or the multileaf collimator (MLC) oriented either perpendicular or along the peripheral dose measurement plane. For the clinical tests, five patients with intracranial or base of skull lesions were chosen. IMRT and conventional three-dimensional (3D) plans for the same patient/target/dose (180 cGy), were optimized without limitation to the number of fields or wedge use. Six MV, 120-leaf MLC Varian axial beams were used. A phantom mimicking a 3-year-old was configured per Center for Disease Control data. Micro (0.125 cc) and cylindrical (0.6 cc) ionization chambers were appropriated for the thyroid, breast, ovaries, and testes. The PD was recorded by electrometers set to the 10{sup -10} scale. Each system set was uniquely calibrated. For the slab phantom studies, close peripheral points were found to have a higher dose for low energy and larger field size and when MLC was not deployed. For points more distant from the field edge, the PD was higher for high-energy beams. MLC orientation was found to be inconsequential for the small fields tested. The thyroid dose was lower for IMRT delivery than that predicted for conventional (ratio of IMRT/cnventional ranged

  19. Stability and function of adult vasculature is sustained by Akt/Jagged1 signalling axis in endothelium

    PubMed Central

    Kerr, Bethany A.; West, Xiaoxia Z.; Kim, Young-Woong; Zhao, Yongzhong; Tischenko, Miroslava; Cull, Rebecca M.; Phares, Timothy W.; Peng, Xiao-Ding; Bernier-Latmani, Jeremiah; Petrova, Tatiana V.; Adams, Ralf H.; Hay, Nissim; Naga Prasad, Sathyamangla V.; Byzova, Tatiana V.

    2016-01-01

    The signalling pathways operational in quiescent, post-development vasculature remain enigmatic. Here we show that unlike neovascularization, endothelial Akt signalling in established vasculature is crucial not for endothelial cell (EC) survival, but for sustained interactions with pericytes and vascular smooth muscle cells (VSMCs) regulating vascular stability and function. Inducible endothelial-specific Akt1 deletion in adult global Akt2KO mice triggers progressive VSMC apoptosis. In hearts, this causes a loss of arteries and arterioles and, despite a high capillary density, diminished vascular patency and severe cardiac dysfunction. Similarly, endothelial Akt deletion induces retinal VSMC loss and basement membrane deterioration resulting in vascular regression and retinal atrophy. Mechanistically, the Akt/mTOR axis controls endothelial Jagged1 expression and, thereby, Notch signalling regulating VSMC maintenance. Jagged1 peptide treatment of Akt1ΔEC;Akt2KO mice and Jagged1 re-expression in Akt-deficient endothelium restores VSMC coverage. Thus, sustained endothelial Akt1/2 signalling is critical in maintaining vascular stability and homeostasis, thereby preserving tissue and organ function. PMID:26971877

  20. Curcumin elevates sirtuin level but does not postpone in vitro senescence of human cells building the vasculature

    PubMed Central

    Grabowska, Wioleta; Suszek, Małgorzata; Wnuk, Maciej; Lewinska, Anna; Wasiak, Emilia; Sikora, Ewa; Bielak-Zmijewska, Anna

    2016-01-01

    It is believed that curcumin, a component of the turmeric that belongs to hormetins, possesses anti-aging propensity. This property of curcumin can be partially explained by its influence on the level of sirtuins. Previously, we have shown that relatively high (2.5-10 μM) doses of curcumin induce senescence of cancer cells and cells building the vasculature. In the present study we examined whether curcumin at low doses (0.1 and 1 μM) is able to delay cell senescence and upregulate the level of sirtuins in human cells building the vasculature, namely vascular smooth muscle (VSMC) and endothelial (EC) cells. To this end we used cells senescing in a replicative and premature manner. We showed that low doses of curcumin in case of VSMC neither postponed the replicative senescence nor protected from premature senescence induced by doxorubicin. Moreover, curcumin slightly accelerated replicative senescence of EC. Despite some fluctuations, a clear increasing tendency in the level of sirtuins was observed in curcumin-treated young, senescing or already senescent cells. Sirtuin activation could be caused by the activation of AMPK resulting from superoxide elevation and ATP reduction. Our results show that curcumin at low doses can increase the level of sirtuins without delaying senescence of VSMC. PMID:27034011

  1. Fistulous connection between internal mammary graft and pulmonary vasculature after coronary artery bypass grafting: a rare cause of continuous murmur.

    PubMed

    Guray, Umit; Guray, Yesim; Ozbakir, Cemal; Yilmaz, M Birhan; Sasmaz, Hatice; Korkmaz, Sule

    2004-09-01

    A 58-year-old male who had undergone coronary artery bypass grafting (CABG) using left internal mammary artery and a sequential saphenous vein graft 2 years ago presented with new onset angina. His initial physical examination revealed an unexpected continuous murmur over the left sternal border, and two-dimensional echocardiography has failed to identy the cause. Cardiac catheterization then performed and revealed patent left internal mammary artery and saphenous vein grafts. Besides, selective injection of the left internal mammary artery graft also showed a fistula formation between left internal mammary artery graft and pulmonary vasculature of the left upper lobe. He was managed conservatively because of the severely diseased left anterior descending artery distal to internal mammary artery anastomosis and low pulmonary artery pressure. The development of fistulous connection between internal mammary artery and pulmonary vasculature is an extremely rare complication following CABG. Patients with such fistulae usually present with chest pain due to coronary steal syndrome. A new heart sound, especially a continuous murmur, may be detected during physical examination. Surgical correction is indicated in the event of refractory angina, growing fistula causing heart failure or endarteritis. Otherwise, a conservative approach with instruction of the patient for prophylactic precautions of subacute bacterial endocarditis may be recommended for asymptomatic patients. PMID:15301909

  2. Logarithmic intensity and speckle-based motion contrast methods for human retinal vasculature visualization using swept source optical coherence tomography

    PubMed Central

    Motaghiannezam, Reza; Fraser, Scott

    2012-01-01

    We formulate a theory to show that the statistics of OCT signal amplitude and intensity are highly dependent on the sample reflectivity strength, motion, and noise power. Our theoretical and experimental results depict the lack of speckle amplitude and intensity contrasts to differentiate regions of motion from static areas. Two logarithmic intensity-based contrasts, logarithmic intensity variance (LOGIV) and differential logarithmic intensity variance (DLOGIV), are proposed for serving as surrogate markers for motion with enhanced sensitivity. Our findings demonstrate a good agreement between the theoretical and experimental results for logarithmic intensity-based contrasts. Logarithmic intensity-based motion and speckle-based contrast methods are validated and compared for in vivo human retinal vasculature visualization using high-speed swept-source optical coherence tomography (SS-OCT) at 1060 nm. The vasculature was identified as regions of motion by creating LOGIV and DLOGIV tomograms: multiple B-scans were collected of individual slices through the retina and the variance of logarithmic intensities and differences of logarithmic intensities were calculated. Both methods captured the small vessels and the meshwork of capillaries associated with the inner retina in en face images over 4 mm2 in a normal subject. PMID:22435098

  3. Correlation of changes in the mandible and retina/choroid vasculature of a rat model of BRONJ.

    PubMed

    Borke, James L; McAllister, Bennett; Harris, Tiffenie; Neiberg, Maryke; Guevarra-Toth, Chestine; Fulzele, Sadanand; Stoianovici, Charles; Guerra, Carlos

    2015-09-01

    Bisphosphonate-related osteonecrosis of the jaw (BRONJ) causes bones of the mandible and maxilla to become necrotic and protrude into the oral cavity. Compromised blood supply to bone is also a feature of BRONJ. The design of this study was first to use our established technique of molar extraction and IV bisphosphonate injection to produce features of BRONJ in rats that mimic the human disease; second to confirm vascular changes in the mandible and eye using micro-CT of vascular casts, and image analysis of retina/choroid images; and third to show parallel bisphosphonate-induced changes in the structure and markers of the vasculature of the bone and eye. The results of this study show structural changes in the eye and mandible as well as biochemical changes including the up-regulation of VEGF in response to the bisphosphonate-associated ischemia. These changes are not associated with angiogenesis in either the eye or mandible as determined by reduced vascular complexity. These results suggest that observations of direct changes to the vasculature in the retina/choroid structures of the eye in patients taking bisphosphonates could serve as a window to the progression of debilitating changes occurring as a result of bisphosphonate therapy. PMID:26154398

  4. Stability and function of adult vasculature is sustained by Akt/Jagged1 signalling axis in endothelium.

    PubMed

    Kerr, Bethany A; West, Xiaoxia Z; Kim, Young-Woong; Zhao, Yongzhong; Tischenko, Miroslava; Cull, Rebecca M; Phares, Timothy W; Peng, Xiao-Ding; Bernier-Latmani, Jeremiah; Petrova, Tatiana V; Adams, Ralf H; Hay, Nissim; Naga Prasad, Sathyamangla V; Byzova, Tatiana V

    2016-01-01

    The signalling pathways operational in quiescent, post-development vasculature remain enigmatic. Here we show that unlike neovascularization, endothelial Akt signalling in established vasculature is crucial not for endothelial cell (EC) survival, but for sustained interactions with pericytes and vascular smooth muscle cells (VSMCs) regulating vascular stability and function. Inducible endothelial-specific Akt1 deletion in adult global Akt2KO mice triggers progressive VSMC apoptosis. In hearts, this causes a loss of arteries and arterioles and, despite a high capillary density, diminished vascular patency and severe cardiac dysfunction. Similarly, endothelial Akt deletion induces retinal VSMC loss and basement membrane deterioration resulting in vascular regression and retinal atrophy. Mechanistically, the Akt/mTOR axis controls endothelial Jagged1 expression and, thereby, Notch signalling regulating VSMC maintenance. Jagged1 peptide treatment of Akt1ΔEC;Akt2KO mice and Jagged1 re-expression in Akt-deficient endothelium restores VSMC coverage. Thus, sustained endothelial Akt1/2 signalling is critical in maintaining vascular stability and homeostasis, thereby preserving tissue and organ function. PMID:26971877

  5. Assessing transmission of Salmonella to bovine peripheral lymph nodes upon horn fly feeding

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Blood-feeding ectoparasites are an economic burden to cattle production systems. Their role in mechanical dissemination of bacterial pathogens is also of significance. Biting arthropods are implicated in the transdermal transmission of Salmonella to bovine peripheral lymph nodes (PLNs), which may ul...

  6. Marvels, Mysteries, and Misconceptions of Vascular Compensation to Peripheral Artery Occlusion

    PubMed Central

    ZIEGLER, MATTHEW A.; DISTASI, MATTHEW R.; BILLS, RANDALL G.; MILLER, STEVEN J.; ALLOOSH, MOUHAMAD; MURPHY, MICHAEL P.; AKINGBA, A. GEORGE; STUREK, MICHAEL; DALSING, MICHAEL C.; UNTHANK, JOSEPH L.

    2010-01-01

    Peripheral arterial disease is a major health problem and there is a significant need to develop therapies to prevent its progression to claudication and critical limb ischemia. Promising results in rodent models of arterial occlusion have generally failed to predict clinical success and led to questions of their relevance. While sub-optimal models may have contributed to the lack of progress, we suggest that advancement has also been hindered by misconceptions of the human capacity for compensation and the specific vessels which are of primary importance. We present and summarize new and existing data from humans, Ossabaw miniature pigs, and rodents which provide compelling evidence that natural compensation to occlusion of a major artery (i) may completely restore perfusion, (ii) occurs in specific pre-existing small arteries, rather than the distal vasculature, via mechanisms involving flow-mediated dilation and remodeling (iii) is impaired by cardiovascular risk factors which suppress the flow-mediated mechanisms and (iv) can be restored by reversal of endothelial dysfunction. We propose that restoration of the capacity for flow-mediated dilation and remodeling in small arteries represents a largely unexplored potential therapeutic opportunity to enhance compensation for major arterial occlusion and prevent the progression to critical limb ischemia in the peripheral circulation. PMID:20141596

  7. Design and verification of a shape memory polymer peripheral occlusion device.

    PubMed

    Landsman, Todd L; Bush, Ruth L; Glowczwski, Alan; Horn, John; Jessen, Staci L; Ungchusri, Ethan; Diguette, Katelin; Smith, Harrison R; Hasan, Sayyeda M; Nash, Daniel; Clubb, Fred J; Maitland, Duncan J

    2016-10-01

    Shape memory polymer foams have been previously investigated for their safety and efficacy in treating a porcine aneurysm model. Their biocompatibility, rapid thrombus formation, and ability for endovascular catheter-based delivery to a variety of vascular beds makes these foams ideal candidates for use in numerous embolic applications, particularly within the peripheral vasculature. This study sought to investigate the material properties, safety, and efficacy of a shape memory polymer peripheral embolization device in vitro. The material characteristics of the device were analyzed to show tunability of the glass transition temperature (Tg) and the expansion rate of the polymer to ensure adequate time to deliver the device through a catheter prior to excessive foam expansion. Mechanical analysis and flow migration studies were performed to ensure minimal risk of vessel perforation and undesired thromboembolism upon device deployment. The efficacy of the device was verified by performing blood flow studies that established affinity for thrombus formation and blood penetration throughout the foam and by delivery of the device in an ultrasound phantom that demonstrated flow stagnation and diversion of flow to collateral pathways. PMID:27419615

  8. 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. PMID:26920689

  9. A robust method for high-precision quantification of the complex three-dimensional vasculatures acquired by X-ray microtomography.

    PubMed

    Tan, Hai; Wang, Dadong; Li, Rongxin; Sun, Changming; Lagerstrom, Ryan; He, You; Xue, Yanling; Xiao, Tiqiao

    2016-09-01

    The quantification of micro-vasculatures is important for the analysis of angiogenesis on which the detection of tumor growth or hepatic fibrosis depends. Synchrotron-based X-ray computed micro-tomography (SR-µCT) allows rapid acquisition of micro-vasculature images at micrometer-scale spatial resolution. Through skeletonization, the statistical features of the micro-vasculature can be extracted from the skeleton of the micro-vasculatures. Thinning is a widely used algorithm to produce the vascular skeleton in medical research. Existing three-dimensional thinning methods normally emphasize the preservation of topological structure rather than geometrical features in generating the skeleton of a volumetric object. This results in three problems and limits the accuracy of the quantitative results related to the geometrical structure of the vasculature. The problems include the excessively shortened length of elongated objects, eliminated branches of blood vessel tree structure, and numerous noisy spurious branches. The inaccuracy of the skeleton directly introduces errors in the quantitative analysis, especially on the parameters concerning the vascular length and the counts of vessel segments and branching points. In this paper, a robust method using a consolidated end-point constraint for thinning, which generates geometry-preserving skeletons in addition to maintaining the topology of the vasculature, is presented. The improved skeleton can be used to produce more accurate quantitative results. Experimental results from high-resolution SR-µCT images show that the end-point constraint produced by the proposed method can significantly improve the accuracy of the skeleton obtained using the existing ITK three-dimensional thinning filter. The produced skeleton has laid the groundwork for accurate quantification of the angiogenesis. This is critical for the early detection of tumors and assessing anti-angiogenesis treatments. PMID:27577778

  10. Detection of peripheral nerve pathology

    PubMed Central

    Seelig, Michael J.; Baker, Jonathan C.; Mackinnon, Susan E.; Pestronk, Alan

    2013-01-01

    Objective: To compare accuracy of ultrasound and MRI for detecting focal peripheral nerve pathology, excluding idiopathic carpal or cubital tunnel syndromes. Methods: We performed a retrospective review of patients referred for neuromuscular ultrasound to identify patients who had ultrasound and MRI of the same limb for suspected brachial plexopathy or mononeuropathies, excluding carpal/cubital tunnel syndromes. Ultrasound and MRI results were compared to diagnoses determined by surgical or, if not performed, clinical/electrodiagnostic evaluation. Results: We identified 53 patients who had both ultrasound and MRI of whom 46 (87%) had nerve pathology diagnosed by surgical (n = 39) or clinical/electrodiagnostic (n = 14) evaluation. Ultrasound detected the diagnosed nerve pathology (true positive) more often than MRI (43/46 vs 31/46, p < 0.001). Nerve pathology was correctly excluded (true negative) with equal frequency by MRI and ultrasound (both 6/7). In 25% (13/53), ultrasound was accurate (true positive or true negative) when MRI was not. These pathologies were typically (10/13) long (>2 cm) and only occasionally (2/13) outside the MRI field of view. MRI missed multifocal pathology identified with ultrasound in 6 of 7 patients, often (5/7) because pathology was outside the MRI field of view. Conclusions: Imaging frequently detects peripheral nerve pathology and contributes to the differential diagnosis in patients with mononeuropathies and brachial plexopathies. Ultrasound is more sensitive than MRI (93% vs 67%), has equivalent specificity (86%), and better identifies multifocal lesions than MRI. In sonographically accessible regions ultrasound is the preferred initial imaging modality for anatomic evaluation of suspected peripheral nervous system lesions. PMID:23553474

  11. Scleritis and Peripheral Ulcerative Keratitis

    PubMed Central

    Galor, Anat; Thorne, Jennifer E.

    2008-01-01

    Scleritis and peripheral ulcerative keratitis (PUK) can present as isolated conditions or as part of a systemic inflammatory or infectious disorder. Both are serious ocular conditions that can result in vision loss and therefore require early diagnosis and treatment. Nearly two-thirds of patients with non-infectious scleritis require systemic glucocorticoid therapy, and one fourth need a glucocorticoid-sparing agent, as well. Essentially all patients with non-infectious PUK require systemic glucocorticoids. Detailed clinical history, thorough physical examination, and thoughtful laboratory evaluations are all important in the exclusion of underlying disorders and extraocular involvement. PMID:18037120

  12. Peripheral ossifying fibroma: case report.

    PubMed

    Pradeep, A R; Guruprasad, C N; Agarwal, Esha

    2012-01-01

    We present a case of peripheral ossifying fibroma (POF) in a 17-year-old boy. Clinical, radiographic and histologic characteristics are discussed and recommendations regarding differential diagnosis, treatment and follow-up are provided. Lesions histologically similar to POF have been given various names in the existing literature; therefore, the controversial varied nomenclature and possible etiopathogenesis of POF are discussed. A slowly growing soft tissue mass with speckled calcifications in the anterior oral cavity of children or young adults should raise the suspicion of a reactive gingival lesion such as POF. PMID:23252197

  13. Peripheral nerve disease in pregnancy.

    PubMed

    Klein, Autumn

    2013-06-01

    Neuropathies during pregnancy and the postpartum period are common and are usually due to compression around pregnancy and childbirth. The most common peripheral neuropathies are Bell's palsy, carpal tunnel syndrome (CTS), and lower extremity neuropathies. Although most neuropathies are usually reversible, associated disabilities or morbidities can limit functioning and require therapy. Nerve conduction study tests and imaging should only be considered if symptoms are unusual or prolonged. Some neuropathies may be associated with preeclampsia or an inherent underlying neuropathy that increases the risk of nerve injury. All neuropathies in pregnancy should be followed as some may be persistent and require follow-up. PMID:23563878

  14. ARF6 inhibition stabilizes the vasculature and enhances survival during endotoxic shock

    PubMed Central

    Davis, Chadwick T.; Zhu, Weiquan; Gibson, Christopher C.; Bowman-Kirigin, Jay; Sorensen, Lise; Ling, Jing; Sun, Huiming; Navankasattusas, Sutip; Li, Dean Y.

    2014-01-01

    The vascular endothelium responds to infection by destabilizing endothelial cell-cell junctions to allow fluid and cells to pass into peripheral tissues facilitating clearance of infection and tissue repair. During sepsis, endotoxin and other pro-inflammatory molecules induce excessive vascular leak, which can cause organ dysfunction, shock, and death. Current therapies for sepsis are limited to antibiotics and supportive care, which are often insufficient to reduce morbidity and prevent mortality. Previous attempts at blocking inflammatory cytokine responses in humans have proven ineffective at reducing the pathologies associated with sepsis, thus highlighting the need for a new therapeutic strategy. The small GTPase ARF6 is activated by a MYD88-ARNO interaction to induce vascular leak through disruption of endothelial adherens junctions. Here we show that the MYD88-ARNO-ARF6 signaling axis is responsible for lipopolysaccharide (LPS)-induced endothelial permeability and is a destabilizing convergence point utilized by multiple inflammatory cues. We also show that blocking ARF6 with a peptide construct of its N-terminus is sufficient to reduce vascular leak and enhance survival during endotoxic shock without inhibiting host cytokine response. Our data highlight the therapeutic potential of blocking ARF6 and reducing vascular leak for the treatment of inflammatory conditions such as endotoxemia. PMID:24835390

  15. Pathobiology of cancer chemotherapy-induced peripheral neuropathy (CIPN)

    PubMed Central

    Han, Yaqin; Smith, Maree T.

    2013-01-01

    Chemotherapy induced peripheral neuropathy (CIPN) is a type of neuropathic pain that is a major dose-limiting side-effect of potentially curative cancer chemotherapy treatment regimens that develops in a “stocking and glove” distribution. When pain is severe, a change to less effective chemotherapy agents may be required, or patients may choose to discontinue treatment. Medications used to alleviate CIPN often lack efficacy and/or have unacceptable side-effects. Hence the unmet medical need for novel analgesics for relief of this painful condition has driven establishment of rodent models of CIPN. New insights on the pathobiology of CIPN gained using these models are discussed in this review. These include mitochondrial dysfunction and oxidative stress that are implicated as key mechanisms in the development of CIPN. Associated structural changes in peripheral nerves include neuronopathy, axonopathy and/or myelinopathy, especially intra-epidermal nerve fiber (IENF) degeneration. In patients with CIPN, loss of heat sensitivity is a hallmark symptom due to preferential damage to myelinated primary afferent sensory nerve fibers in the presence or absence of demyelination. The pathobiology of CIPN is complex as cancer chemotherapy treatment regimens frequently involve drug combinations. Adding to this complexity, there are also subtle differences in the pathobiological consequences of commonly used cancer chemotherapy drugs, viz platinum compounds, taxanes, vincristine, bortezomib, thalidomide and ixabepilone, on peripheral nerves. PMID:24385965

  16. Alpha4-integrin (CD49d) expression on bovine peripheral blood neutrophils is related to inflammation of the respiratory system.

    PubMed

    Soethout, Ernst C; Rutten, Victor P M G; Houwers, Dirk J; de Groot, Hugo S J; Antonis, Adriaan F G; Niewold, Theo A; Müller, Kerstin E

    2003-05-30

    Neutrophil emigration from the pulmonary vasculature, is mediated by cellular adhesion molecules (CAM) expressed on the outer membranes of endothelial cells and neutrophils. Although beta(2)-integrin-dependent migration is a major mechanism of neutrophil migration, which was demonstrated by extensive invasion of neutrophils in pulmonary tissue of calves suffering from a genetic deficit in expression of beta(2)-integrins, termed bovine leukocyte adhesion deficiency (LAD), the role of alternative CAM is still unclear. We investigated whether an alternate CAM for beta(2)-integrin function, i.e. the alpha(4)-integrin, was expressed on peripheral blood neutrophils of calves. As we detected basal but significant expression, the effect of naturally acquired pulmonary infection on the expression of either integrin was determined, as an indication for its function in the migration process. In our experiments, basal expression of alpha(4)-integrins on peripheral blood neutrophils from clinically healthy calves was detected. On neutrophils of calves, experiencing field outbreaks of enzootic bronchopneumonia, higher expression of the alpha(4)-integrin was detected, which returned to normal after successful treatment of the disease. In addition, its level of expression was linearly related to plasma acute phase protein (haptoglobin) concentrations, which is a sensitive parameter for severity of respiratory inflammation. Increased expression of the alpha(4)-integrin on peripheral blood neutrophils during pulmonary inflammation indicates a role for this CAM in neutrophil migration in the lung. PMID:12753772

  17. In vivo targeting of metastatic breast cancer via tumor vasculature-specific nano-graphene oxide.

    PubMed

    Yang, Dongzhi; Feng, Liangzhu; Dougherty, Casey A; Luker, Kathryn E; Chen, Daiqin; Cauble, Meagan A; Banaszak Holl, Mark M; Luker, Gary D; Ross, Brian D; Liu, Zhuang; Hong, Hao

    2016-10-01

    Angiogenesis, i.e. the formation of neovasculatures, is a critical process during cancer initiation, progression, and metastasis. Targeting of angiogenic markers on the tumor vasculature can result in more efficient delivery of nanomaterials into tumor since no extravasation is required. Herein we demonstrated efficient targeting of breast cancer metastasis in an experimental murine model with nano-graphene oxide (GO), which was conjugated to a monoclonal antibody (mAb) against follicle-stimulating hormone receptor (FSHR). FSHR has been confirmed to be a highly selective tumor vasculature marker, which is abundant in both primary and metastatic tumors. These functionalized GO nano-conjugates had diameters of ∼120 nm based on atomic force microscopy (AFM), TEM, and dynamic laser scattering (DLS) measurement. (64)Cu was incorporated as a radiolabel which enabled the visualization of these GO conjugates by positron emission tomography (PET) imaging. Breast cancer lung metastasis model was established by intravenous injection of click beetle green luciferase-transfected MDA-MB-231 (denoted as cbgLuc-MDA-MB-231) breast cancer cells into female nude mice and the tumor growth was monitored by bioluminescence imaging (BLI). Systematic in vitro and in vivo studies have been performed to investigate the stability, targeting efficacy and specificity, and tissue distribution of GO conjugates. Flow cytometry and fluorescence microscopy examination confirmed the targeting specificity of FSHR-mAb attached GO conjugates against cellular FSHR. More potent and persistent uptake of (64)Cu-NOTA-GO-FSHR-mAb in cbgLuc-MDA-MB-231 nodules inside the lung was witnessed when compared with that of non-targeted GO conjugates ((64)Cu-NOTA-GO). Histology evaluation also confirmed the vasculature accumulation of GO-FSHR-mAb conjugates in tumor at early time points while they were non-specifically captured in liver and spleen. In addition, these GO conjugates can serve as good drug carriers

  18. Targeting mutant p53 protein and the tumor vasculature: an effective combination therapy for advanced breast tumors

    PubMed Central

    Liang, Yayun; Besch-Williford, Cynthia; Benakanakere, Indira; Thorpe, Philip E.

    2010-01-01

    Breast cancer progression depends upon the elaboration of a vasculature sufficient for the nourishment of the developing tumor. Breast tumor cells frequently contain a mutant form of p53 (mtp53), a protein which promotes their survival. The aim of this study was to determine whether combination therapy targeting mtp53 and anionic phospholipids (AP) on tumor blood vessels might be an effective therapeutic strategy for suppressing advanced breast cancer. We examined the therapeutic effects, singly, or in combination, of p53 reactivation and induction of massive apoptosis (PRIMA-1), which reactivates mtp53 and induces tumor cell apoptosis, and 2aG4, a monoclonal antibody that disrupts tumor vasculature by targeting AP on the surface of tumor endothelial cells and causes antibody-dependent destruction of tumor blood vessels, leading to ischemia and tumor cell death. Xenografts from two tumor cell lines containing mtp53, BT-474 and HCC-1428, were grown in nude mice to provide models of advanced breast tumors. After treatment with PRIMA-1 and/or 2aG4, regressing tumors were analyzed for vascular endothelial growth factor (VEGF) expression, blood vessel loss, and apoptotic markers. Individual drug treatment led to partial suppression of breast cancer progression. In contrast, combined treatment with PRIMA-1 and 2aG4 was extremely effective in suppressing tumor growth in both models and completely eradicated approximately 30% of tumors in the BT-474 model. Importantly, no toxic effects were observed in any treatment group. Mechanistic studies determined that PRIMA-1 reactivated mtp53 and also exposed AP on the surface of tumor cells as determined by enhanced 2aG4 binding. Combination treatment led to significant induction of tumor cell apoptosis, loss of VEGF expression, as well as destruction of tumor blood vessels. Furthermore, combination treatment severely disrupted tumor blood vessel perfusion in both tumor models. The observed in vitro PRIMA-1-induced exposure of

  19. Diagnostic approach to peripheral neuropathy

    PubMed Central

    Misra, Usha Kant; Kalita, Jayantee; Nair, Pradeep P.

    2008-01-01

    Peripheral neuropathy refers to disorders of the peripheral nervous system. They have numerous causes and diverse presentations; hence, a systematic and logical approach is needed for cost-effective diagnosis, especially of treatable neuropathies. A detailed history of symptoms, family and occupational history should be obtained. General and systemic examinations provide valuable clues. Neurological examinations investigating sensory, motor and autonomic signs help to define the topography and nature of neuropathy. Large fiber neuropathy manifests with the loss of joint position and vibration sense and sensory ataxia, whereas small fiber neuropathy manifests with the impairment of pain, temperature and autonomic functions. Electrodiagnostic (EDx) tests include sensory, motor nerve conduction, F response, H reflex and needle electromyography (EMG). EDx helps in documenting the extent of sensory motor deficits, categorizing demyelinating (prolonged terminal latency, slowing of nerve conduction velocity, dispersion and conduction block) and axonal (marginal slowing of nerve conduction and small compound muscle or sensory action potential and dennervation on EMG). Uniform demyelinating features are suggestive of hereditary demyelination, whereas difference between nerves and segments of the same nerve favor acquired demyelination. Finally, neuropathy is classified into mononeuropathy commonly due to entrapment or trauma; mononeuropathy multiplex commonly due to leprosy and vasculitis; and polyneuropathy due to systemic, metabolic or toxic etiology. Laboratory investigations are carried out as indicated and specialized tests such as biochemical, immunological, genetic studies, cerebrospinal fluid (CSF) examination and nerve biopsy are carried out in selected patients. Approximately 20% patients with neuropathy remain undiagnosed but the prognosis is not bad in them. PMID:19893645

  20. Role of Central β-Adrenergic Receptors in Regulating Proinflammatory Cytokine Responses to a Peripheral Bacterial Challenge

    PubMed Central

    Johnson, John D.; Cortez, Valerie; Kennedy, Sarah L.; Foley, Teresa E.; Hanson, Hugo; Fleshner, Monika

    2008-01-01

    Elevation of proinflammatory cytokines in the brain have potent effects on altering physiological, behavioral, and cognitive processes. The mechanism(s) by which brain cytokines are induced during a peripheral immune challenge remains unclear since microorganisms/cytokines do not cross the blood-brain barrier (BBB). Recent studies indicate that central β-adrenergic receptors (β-ADRs) may mediate brain interleukin-1beta (IL-1) production. This has direct implications for the production of brain cytokines during a peripheral immune response since peripheral pathogens and cytokines rapidly stimulate brainstem catecholamine neurons via peripheral nerves and circumventricular pathways. Studies here examine the role of central β-ADRs in regulating brain cytokine production following peripheral Escherichia coli (E.coli) challenge. Rats were centrally administered propranolol (β-ADR antagonist) or vehicle followed by peripheral E.coli or saline and sacrificed 6h later for measurement of cytokines. Pretreatment with propranolol completely blocked the induction of brain IL-1 following E.coli. Surprisingly, central propranolol also attenuated E.coli-induced peripheral cytokines. To examine whether the attenuated peripheral cytokine response following central propranolol administration was due leakage of propranolol into the general circulation and blockade of peripheral β-blockade, nadolol (β-ADR antagonist that does not cross the BBB) was administered peripherally prior to E.coli. Nadolol administration did not block central cytokine production following E.coli, but instead enhanced both peripheral and central proinflammatory cytokine production. Furthermore, central administration of isoproterenol (β-ADR agonist) results in a time-dependent increase in brain IL-1 production. These data demonstrate central β-ADRs may play a critical role to induce brain IL-1, while peripheral β-ADRs inhibit cytokine response to bacterial challenge. PMID:18468841

  1. Peripheral Neuropathy Associated withHypereosinophilic Syndrome

    PubMed Central

    Lee, Kyung Ho; Kim, Jung Eun

    2008-01-01

    The idiopathic hypereosinophilic syndrome (HES) represents a leukoproliferative disorder, characterized by unexplained prolonged eosinophilia (>6 months) and evidence of specific organ damage. So far, the peripheral neuropathy associated with skin manifestations of HES has not been reported in the dermatologic literature although the incidence of peripheral neuropathy after HES ranges from 6~52%. Herein, we report the peripheral neuropathy associated with HES, documented by clinical, histopathological, and electrodiagnostic criteria. PMID:27303181

  2. Monocyte chemoattractant protein-1 in patients with peripheral arterial disease.

    PubMed Central

    Petrkova, Jana; Szotkowska, Jaroslava; Hermanova, Zuzana; Lukl, Jan; Petrek, Martin

    2004-01-01

    BACKGROUND: Chemokine-driven migration of inflammatory cells has been implicated in the pathogenesis of atherosclerotic conditions including peripheral arterial disease (PAD). Monocyte chemoattractant protein-1 (MCP-1) is elevated in patients with coronary artery disease and in hypertensive patients. This study therefore investigated MCP-1 in patients with PAD. METHODS: Serum MCP-1 was determined by enzyme-linked immunosorbent assay in 36 healthy, control subjects and in 19 patients with PAD. Statistical analysis utilised the Mann-Whitney test and Spearman correlation (p < 0.05). RESULTS: MCP-1 (pg/ml) was increased in patients compared with in controls (mean+/-standard error of the mean: PAD group, 748+/-60; control group, 459+/-27; p=0.0001). MCP-1 levels tended to decrease with progressing disease. From atherosclerosis risk factors, diabetes inclined to increase MCP-1 levels; hypertension had no effect. Serum MCP-1 correlated with cholesterol, triglycerides, low-density lipoprotein but not high-density lipoprotein. Conclusion: Elevation of MCP-1 in the circulation of PAD patients shown in the present pilot study implicates this CC chemokine ligand 2 in inflammatory processes contributing to PAD clinical symptomatology. Further investigations are necessary to evaluate whether MCP-1 can be used as a potential marker of peripheral arterial disease follow-up and/or prognosis. PMID:15203564

  3. Solitary peripheral osteomas of the jaws

    PubMed Central

    de França, Talita Ribeiro Tenório; Gueiros, Luiz Alcino Monteiro; de Castro, Jurema Freire Lisboa; Catunda, Ivson; Leão, Jair Carneiro

    2012-01-01

    Osteoma is a benign osteogenic tumor composed of cancellous or compact bone, classified as peripheral, central, or extraskeletal. Peripheral osteomas are uncommon. Excluding the maxillary sinuses, the maxilla is a rare site for osteomas. The purpose of this report was to describe clinicopathological and radiological features of two peripheral osteomas occurring in the jaws, one located in the mandible and another in the edentulous maxillary alveolar ridge. The tumors were asymptomatic and were fully excised without any complications or recurrence. The lesions were submitted to histopathological analysis and diagnosed as peripheral osteoma, compact type. PMID:22783479

  4. Quantifying the Effects of Radiation on Tumour Vasculature with High-Frequency Three-Dimensional Power Doppler Ultrasound

    NASA Astrophysics Data System (ADS)

    Hupple, Clinton

    Recent evidence suggests that radiation may have a significant effect on tumour vasculature in addition to damaging tumour cell DNA. It is well established that endothelial cells are among the first cells to respond after administration of ionizing radiation in both normal and tumour tissues. It has also been suggested that microvascular dysfunction may regulate tumour response to radiotherapy at high doses. However, due to limitations in imaging the microcirculation this response is not well characterized. Advances in high-frequency ultrasound and computation methods now make it possible to acquire and analyze 3-D ultrasound data of tumour blood flow in tumour microcirculation. This thesis outlines the work done to test the hypothesis that single dose 8 Gy radiotherapy produces changes in tumour blood vessels which can be quantified using high-frequency power Doppler ultrasound. In addition, the issue of reproducibility of power Doppler measurements and the relationship between histopathology and power Doppler measurements have been examined.

  5. Unilateral anterior persistent fetal vasculature in a child with blepharophimosis-ptosis-epicanthus inversus syndrome: A surgical challenge

    PubMed Central

    Kemmanu, Vasudha; Rathod, Pragnya; Anaspure, Hemant; Yadav, Naresh K

    2016-01-01

    Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant genetic disease. It is clinically characterized by four major features; blepharophimosis, ptosis, epicanthus inversus, and telecanthus. We report a case of a 1-year-old female with BPES with unilateral anterior persistent fetal vasculature (PFV). On examination, she was found to have all the clinical features of BPES, along with calcified and partially absorbed cataract with elongated ciliary processes in her left eye. B-scan of left eye showed attached retina with no evidence of posterior PFV. Systemic examination was normal. She underwent cataract surgery with primary posterior capsulotomy with intraocular lens implantation under general anesthesia. Literature search did not reveal any previous reports of unilateral anterior PFV and BPES. The clinical features, other associations, and the difficulties in the surgical management of this condition are discussed. PMID:27488160

  6. Vesicular trafficking mechanisms in endothelial cells as modulators of the tumor vasculature and targets of antiangiogenic therapies.

    PubMed

    Maes, Hannelore; Olmeda, David; Soengas, María S; Agostinis, Patrizia

    2016-01-01

    A common feature of solid tumors is their ability to incite the formation of new blood and lymph vessels trough the processes of angiogenesis and lymphangiogenesis, respectively, to support tumor growth and favor metastatic dissemination. As a result of the lack of feedback regulatory control mechanisms or due to the exacerbated presence of pro-angiogenic signals within the tumor microenvironment, the tumor endothelium receives continuous signals to sprout and develop, generating vessels that are structurally and functionally abnormal. An emerging mechanism playing a central role in shaping the tumor vasculature is the endothelial-vesicular network that regulates trafficking/export and degradation of key signaling proteins and membrane receptors, including the vascular endothelial growth-factor receptor-2/3 and members of the Notch pathway. Here we will discuss recent evidence highlighting how vesicular trafficking mechanisms in endothelial cells contribute to pathological angiogenesis/lymphangiogenesis and can provide novel and exploitable targets in antiangiogenic therapies. PMID:26443003

  7. Biodegradable scaffold with built-in vasculature for organ-on-a-chip engineering and direct surgical anastomosis

    NASA Astrophysics Data System (ADS)

    Zhang, Boyang; Montgomery, Miles; Chamberlain, M. Dean; Ogawa, Shinichiro; Korolj, Anastasia; Pahnke, Aric; Wells, Laura A.; Massé, Stéphane; Kim, Jihye; Reis, Lewis; Momen, Abdul; Nunes, Sara S.; Wheeler, Aaron R.; Nanthakumar, Kumaraswamy; Keller, Gordon; Sefton, Michael V.; Radisic, Milica

    2016-06-01

    We report the fabrication of a scaffold (hereafter referred to as AngioChip) that supports the assembly of parenchymal cells on a mechanically tunable matrix surrounding a perfusable, branched, three-dimensional microchannel network coated with endothelial cells. The design of AngioChip decouples the material choices for the engineered vessel network and for cell seeding in the parenchyma, enabling extensive remodelling while maintaining an open-vessel lumen. The incorporation of nanopores and micro-holes in the vessel walls enhances permeability, and permits intercellular crosstalk and extravasation of monocytes and endothelial cells on biomolecular stimulation. We also show that vascularized hepatic tissues and cardiac tissues engineered by using AngioChips process clinically relevant drugs delivered through the vasculature, and that millimetre-thick cardiac tissues can be engineered in a scalable manner. Moreover, we demonstrate that AngioChip cardiac tissues implanted with direct surgical anastomosis to the femoral vessels of rat hindlimbs establish immediate blood perfusion.

  8. Stem cell-derived vasculature: A potent and multidimensional technology for basic research, disease modeling, and tissue engineering.

    PubMed

    Lowenthal, Justin; Gerecht, Sharon

    2016-05-01

    Proper blood vessel networks are necessary for constructing and re-constructing tissues, promoting wound healing, and delivering metabolic necessities throughout the body. Conversely, an understanding of vascular dysfunction has provided insight into the pathogenesis and progression of diseases both common and rare. Recent advances in stem cell-based regenerative medicine - including advances in stem cell technologies and related progress in bioscaffold design and complex tissue engineering - have allowed rapid advances in the field of vascular biology, leading in turn to more advanced modeling of vascular pathophysiology and improved engineering of vascularized tissue constructs. In this review we examine recent advances in the field of stem cell-derived vasculature, providing an overview of stem cell technologies as a source for vascular cell types and then focusing on their use in three primary areas: studies of vascular development and angiogenesis, improved disease modeling, and the engineering of vascularized constructs for tissue-level modeling and cell-based therapies. PMID:26427871

  9. An overview of the influence of therapeutic ultrasound exposures on the vasculature: high intensity ultrasound and microbubble-mediated bioeffects.

    PubMed

    Goertz, David E

    2015-03-01

    It is well established that the interaction of ultrasound with soft tissues can induce a wide range of bioeffects. One of the most important and complex of these interactions in the context of therapeutic ultrasound is with the vasculature. Potential vascular effects range from enhancing microvascular permeability to inducing vascular damage and vessel occlusion. While aspects of these effects are broadly understood, the development of improved approaches to exploit these effects and gain a more detailed mechanistic understanding is ongoing and largely anchored in preclinical research. Here a general overview of this established yet rapidly evolving topic is provided, with a particular emphasis on effects arising from high-intensity focused ultrasound and microbubble-mediated exposures. PMID:25716770

  10. Photoacoustic- and Magnetic Resonance-Guided Photothermal Therapy and Tumor Vasculature Visualization Using Theranostic Magnetic Gold Nanoshells.

    PubMed

    Zhou, Min; Singhana, Burapol; Liu, Yang; Huang, Qian; Mitcham, Trevor; Wallace, Michael J; Stafford, R Jason; Bouchard, Richard R; Melancon, Marites P

    2015-08-01

    Nanoparticle based image-guided therapy is an emerging technology for cancer in recent years. Here, we report simultaneous photoacoustic (PA)- and magnetic resonance (MR)-guided photothermal ablation (PTA) therapy using multifunctional superparamagnetic iron oxide-containing gold nanoshells (SPIO@AuNS). Based on the intrinsic high near-infrared optical absorbance and strong magnetic property of SPIO@AuNS, we carried out in vivo dual-modality PA-MR imaging of mouse tumors. PA- and MR-guided imaging can monitor therapeutic effect after photothermal therapy mediated by our multifunctional nanomaterial. In addition, using our pulsed laser PA technique, we also observe a clearer structure of the tumor vasculature after intravenously administration SPIO@AuNS. The novel dual PA-MRI image-guided PTA therapy provides a promising new platform for cancer diagnosis and treatment simultaneously. PMID:26295144

  11. The action of a dopamine (DA1) receptor agonist, fenoldopam in human vasculature in vivo and in vitro.

    PubMed Central

    Hughes, A; Thom, S; Martin, G; Redman, D; Hasan, S; Sever, P

    1986-01-01

    This study was designed to investigate dopaminergic mechanisms in human vasculature using the selective vascular dopamine receptor agonist fenoldopam in vivo and in vitro. In vivo, forearm blood flow was measured plethysmographically and in vitro isolated rings of human blood vessels from a variety of sites were used for tissue bath studies. Intra-arterial fenoldopam markedly increased forearm blood flow, this effect was antagonised by (R) sulpiride, a vascular dopamine (DA1) antagonist, but not by metoclopramide, a neuronal (DA2) antagonist, or by guanethidine, an adrenergic neurone blocking agent. In vitro, fenoldopam relaxed preconstricted human renal, mesenteric and lumbar arteries, but not saphenous vein in a concentration dependent manner. (RS) sulpiride and SCH 23390 competitively antagonised this effect. These studies demonstrate the presence of a vasodilatory vascular dopamine receptor in man both in vivo and in vitro. PMID:2878679

  12. In Vivo Quantitative Microcomputed Tomographic Analysis of Vasculature and Organs in a Normal and Diseased Mouse Model

    PubMed Central

    Das, Nanditha Mohan; Hatsell, Sarah; Nannuru, Kalyan; Huang, Lily; Wen, Xialing; Wang, Lili; Wang, Li-Hsien; Idone, Vincent; Meganck, Jeffrey A.; Murphy, Andrew; Economides, Aris; Xie, LiQin

    2016-01-01

    Non-bone in vivo micro-CT imaging has many potential applications for preclinical evaluation. Specifically, the in vivo quantification of changes in the vascular network and organ morphology in small animals, associated with the emergence and progression of diseases like bone fracture, inflammation and cancer, would be critical to the development and evaluation of new therapies for the same. However, there are few published papers describing the in vivo vascular imaging in small animals, due to technical challenges, such as low image quality and low vessel contrast in surrounding tissues. These studies have primarily focused on lung, cardiovascular and brain imaging. In vivo vascular imaging of mouse hind limbs has not been reported. We have developed an in vivo CT imaging technique to visualize and quantify vasculature and organ structure in disease models, with the goal of improved quality images. With 1–2 minutes scanning by a high speed in vivo micro-CT scanner (Quantum CT), and injection of a highly efficient contrast agent (Exitron nano 12000), vasculature and organ structure were semi-automatically segmented and quantified via image analysis software (Analyze). Vessels of the head and hind limbs, and organs like the heart, liver, kidneys and spleen were visualized and segmented from density maps. In a mouse model of bone metastasis, neoangiogenesis was observed, and associated changes to vessel morphology were computed, along with associated enlargement of the spleen. The in vivo CT image quality, voxel size down to 20 μm, is sufficient to visualize and quantify mouse vascular morphology. With this technique, in vivo vascular monitoring becomes feasible for the preclinical evaluation of small animal disease models. PMID:26910759

  13. In Vivo Quantitative Microcomputed Tomographic Analysis of Vasculature and Organs in a Normal and Diseased Mouse Model.

    PubMed

    Das, Nanditha Mohan; Hatsell, Sarah; Nannuru, Kalyan; Huang, Lily; Wen, Xialing; Wang, Lili; Wang, Li-Hsien; Idone, Vincent; Meganck, Jeffrey A; Murphy, Andrew; Economides, Aris; Xie, LiQin

    2016-01-01

    Non-bone in vivo micro-CT imaging has many potential applications for preclinical evaluation. Specifically, the in vivo quantification of changes in the vascular network and organ morphology in small animals, associated with the emergence and progression of diseases like bone fracture, inflammation and cancer, would be critical to the development and evaluation of new therapies for the same. However, there are few published papers describing the in vivo vascular imaging in small animals, due to technical challenges, such as low image quality and low vessel contrast in surrounding tissues. These studies have primarily focused on lung, cardiovascular and brain imaging. In vivo vascular imaging of mouse hind limbs has not been reported. We have developed an in vivo CT imaging technique to visualize and quantify vasculature and organ structure in disease models, with the goal of improved quality images. With 1-2 minutes scanning by a high speed in vivo micro-CT scanner (Quantum CT), and injection of a highly efficient contrast agent (Exitron nano 12000), vasculature and organ structure were semi-automatically segmented and quantified via image analysis software (Analyze). Vessels of the head and hind limbs, and organs like the heart, liver, kidneys and spleen were visualized and segmented from density maps. In a mouse model of bone metastasis, neoangiogenesis was observed, and associated changes to vessel morphology were computed, along with associated enlargement of the spleen. The in vivo CT image quality, voxel size down to 20 μm, is sufficient to visualize and quantify mouse vascular morphology. With this technique, in vivo vascular monitoring becomes feasible for the preclinical evaluation of small animal disease models. PMID:26910759

  14. Functional evidence for oxygen-sensitive voltage-gated potassium channels in human placental vasculature.

    PubMed

    Kiernan, M F; Barrie, A; Szkolar, J; Mills, T A; Wareing, M

    2010-06-01

    Hypoxic fetoplacental vasoconstriction (HFPV), involving voltage-gated potassium (K(V)) channels, has been suggested in human placenta; the identity of these channels remains unclear. Using wire myography, chorionic plate blood vessels were exposed to isoform-specific K(V) channel blockers. Dose-response curves (thromboxane mimetic U46619; 0.1-2000 nM) pre- and post-addition of K(V) channel modulator were analysed. Arterial U46619-induced contraction increased with margatoxin and stromatoxin-1, whilst only correolide increased U46619-induced contraction in veins (P < 0.05 two-way ANOVA). Basal tone was unaffected in arteries or veins. These data implicate K(V)1.2 and/or K(V)2.1 and K(V)1.5 in the control of agonist-induced contraction of human placental arteries and veins respectively. PMID:20451247

  15. Advanced glycation end products (AGEs) co-localize with AGE receptors in the retinal vasculature of diabetic and of AGE-infused rats.

    PubMed Central

    Stitt, A. W.; Li, Y. M.; Gardiner, T. A.; Bucala, R.; Archer, D. B.; Vlassara, H.

    1997-01-01

    Advanced glycation end products (AGEs), formed from the nonenzymatic glycation of proteins and lipids with reducing sugars, have been implicated in many diabetic complications; however, their role in diabetic retinopathy remains largely unknown. Recent studies suggest that the cellular actions of AGEs may be mediated by AGE-specific receptors (AGE-R). We have examined the immunolocalization of AGEs and AGE-R components R1 and R2 in the retinal vasculature at 2, 4, and 8 months after STZ-induced diabetes as well as in nondiabetic rats infused with AGE bovine serum albumin for 2 weeks. Using polyclonal or monoclonal anti-AGE antibodies and polyclonal antibodies to recombinant AGE-R1 and AGE-R2, immunoreactivity (IR) was examined in the complete retinal vascular tree after isolation by trypsin digestion. After 2, 4, and 8 months of diabetes, there was a gradual increase in AGE IR in basement membrane. At 8 months, pericytes, smooth muscle cells, and endothelial cells of the retinal vessels showed dense intracellular AGE IR. AGE epitopes stained most intensely within pericytes and smooth muscle cells but less in basement membrane of AGE-infused rats compared with the diabetic group. Retinas from normal or bovine-serum-albumin-infused rats were largely negative for AGE IR. AGE-R1 and -R2 co-localized strongly with AGEs of vascular endothelial cells, pericytes, and smooth muscle cells of either normal, diabetic, or AGE-infused rat retinas, and this distribution did not vary with each condition. The data indicate that AGEs accumulate as a function of diabetes duration first within the basement membrane and then intracellularly, co-localizing with cellular AGE-Rs. Significant AGE deposits appear within the pericytes after long-term diabetes or acute challenge with AGE infusion conditions associated with pericyte damage. Co-localization of AGEs and AGE-Rs in retinal cells points to possible interactions of pathogenic significance. Images Figure 1 Figure 2 Figure 3 PMID

  16. Updates in diabetic peripheral neuropathy

    PubMed Central

    Juster-Switlyk, Kelsey; Smith, A. Gordon

    2016-01-01

    Diabetes has become one of the largest global health-care problems of the 21 st century. According to the Centers for Disease Control and Prevention, the population prevalence of diabetes in the US is approaching 10% and is increasing by 5% each year. Diabetic neuropathy is the most common complication associated with diabetes mellitus. Diabetes causes a broad spectrum of neuropathic complications, including acute and chronic forms affecting each level of the peripheral nerve, from the root to the distal axon. This review will focus on the most common form, distal symmetric diabetic polyneuropathy. There has been an evolution in our understanding of the pathophysiology and the management of diabetic polyneuropathy over the past decade. We highlight these new perspectives and provide updates from the past decade of research. PMID:27158461

  17. Peripheral arterial injuries: a reassessment.

    PubMed Central

    Burnett, H F; Parnell, C L; Williams, G D; Campbell, G S

    1976-01-01

    Ninety-four patients with peripheral arterial injuries were subjected to acute repair, negative exploration, or late repair of the complications of the arterial injury (false aneurysm, A-V fistula, and/or limb ischemia). The causes of failure after acute injury include extensive local soft tissue and bony damage, severe concomitant head, chest or abdominal wounding, stubborn reliance on negative arteriograms in patients with probable arterial injury, failure to repair simultaneous venous injuries, or harvesting of a vein graft from a severely damaged extremity. There is a positive correlation between non-operative expectant treatment and the incidence of late vascular complications requiring late arterial repair. Delayed complications of arterial injuries occurred most frequently in wounds below the elbow and knee. PMID:973757

  18. How Necessary is the Vasculature in the Life of Neural Stem and Progenitor Cells? Evidence from Evolution, Development and the Adult Nervous System

    PubMed Central

    Koutsakis, Christos; Kazanis, Ilias

    2016-01-01

    Augmenting evidence suggests that such is the functional dependance of neural stem cells (NSCs) on the vasculature that they normally reside in “perivascular niches”. Two examples are the “neurovascular” and the “oligovascular” niches of the adult brain, which comprise specialized microenvironments where NSCs or oligodendrocyte progenitor cells survive and remain mitotically active in close proximity to blood vessels (BVs). The often observed co-ordination of angiogenesis and neurogenesis led to these processes being described as “coupled”. Here, we adopt an evo-devo approach to argue that some stages in the life of a NSC, such as specification and commitment, are independent of the vasculature, while stages such as proliferation and migration are largely dependent on BVs. We also explore available evidence on the possible involvement of the vasculature in other phenomena such as the diversification of NSCs during evolution and we provide original data on the senescence of NSCs in the subependymal zone stem cell niche. Finally, we will comment on the other side of the story; that is, on how much the vasculature is dependent on NSCs and their progeny. PMID:26909025

  19. Peripheral Leptin Regulates Bone Formation

    PubMed Central

    Turner, Russell T.; Kalra, Satya P.; Wong, Carmen P.; Philbrick, Kenneth A.; Lindenmaier, Laurence B.; Boghossian, Stephane; Iwaniec, Urszula T.

    2012-01-01

    Substantial evidence does not support the prevailing view that leptin, acting through a hypothalamic relay, decreases bone accrual by inhibiting bone formation. To clarify the mechanisms underlying regulation of bone architecture by leptin, we evaluated bone growth and turnover in wild type (WT) mice, leptin receptor-deficient db/db mice, leptin-deficient ob/ob mice and ob/ob mice treated with leptin. We also performed hypothalamic leptin gene therapy to determine the effect of elevated hypothalamic leptin levels on osteoblasts. Finally, to determine the effects of loss of peripheral leptin signaling on bone formation and energy metabolism, we used bone marrow (BM) from WT or db/db donor mice to reconstitute the hematopoietic and mesenchymal stem cell compartments in lethally irradiated WT recipient mice. Decreases in bone growth, osteoblast-lined bone perimeter and bone formation rate were observed in ob/ob mice and greatly increased in ob/ob mice following subcutaneous administration of leptin. Similarly, hypothalamic leptin gene therapy increased osteoblast-lined bone perimeter in ob/ob mice. In spite of normal osteoclast-lined bone perimeter, db/db mice exhibited a mild but generalized osteopetrotic-like (calcified cartilage encased by bone) skeletal phenotype and greatly reduced serum markers of bone turnover. Tracking studies and histology revealed quantitative replacement of BM cells following BM transplantation. WT mice engrafted with db/db BM did not differ in energy homeostasis from untreated WT mice or WT mice engrafted with WT BM. Bone formation in WT mice engrafted with WT BM did not differ from WT mice, whereas bone formation in WT mice engrafted with db/db cells did not differ from the low rates observed in untreated db/db mice. In summary, our results indicate that leptin, acting primarily through peripheral pathways, increases osteoblast number and activity. PMID:22887758

  20. Peripheral Developing Odontoma or Peripheral Ameloblastic Fibroodontoma: A Rare Challenging Case

    PubMed Central

    Atarbashi Moghadam, Saede

    2016-01-01

    Peripheral odontogenic lesions are considered to be rare within the classification of odontogenic tumors. They share the same microscopic characteristics of their central counterparts. Here, we report an ulcerated mass of the maxillary gingiva that on histopathological examination was diagnosed as peripheral developing odontoma or peripheral ameloblastic fibroodontoma. The diagnosis of this tumor is challenging and may lead to unnecessary treatment. PMID:26981293

  1. Peripheral Developing Odontoma or Peripheral Ameloblastic Fibroodontoma: A Rare Challenging Case.

    PubMed

    Atarbashi Moghadam, Saede; Mokhtari, Sepideh

    2016-01-01

    Peripheral odontogenic lesions are considered to be rare within the classification of odontogenic tumors. They share the same microscopic characteristics of their central counterparts. Here, we report an ulcerated mass of the maxillary gingiva that on histopathological examination was diagnosed as peripheral developing odontoma or peripheral ameloblastic fibroodontoma. The diagnosis of this tumor is challenging and may lead to unnecessary treatment. PMID:26981293

  2. Drug-eluting stents in the management of peripheral arterial disease

    PubMed Central

    Bosiers, Marc; Cagiannos, Catherine; Deloose, Koen; Verbist, Jürgen; Peeters, Patrick

    2008-01-01

    Since major meta-analyses of randomized controlled trials in interventional cardiology showed the potential of drug-eluting stents in decreasing restenosis and reintervention rates after coronary artery stenting, one of the next steps in the treatment of arterial occlusive disease is the transfer of the active coating technology towards peripheral arterial interventions. In this manuscript, we aim to provide a literature overview on available peripheral (lower limb, renal, and supra-aortic) drug-eluting stent applications, debate the cost implications, and give recommendations for future treatment strategies. PMID:18827906

  3. The coexistence of peripheral nerve sheath tumors and vitiligo: more than coincidence?

    PubMed

    Elsherif, Mohamed A; Spinner, Robert J; Miest, Rachel Y

    2016-01-01

    Neurocristopathies arise from abnormal migration, differentiation, or proliferation of neural crest derivatives, leading to diverse clinical and pathological features. They are classified into dysgenetic or neoplastic, and can affect single or multiple sites (simple versus complex). Examples include congenital melanocytic nevi, neuroblastoma, Hirshsprung's disease, Waardenburg's syndrome, neurofibromatosis (NF) 1 and multiple endocrine neoplasia (MEN) 2A and 2B. We report two cases of peripheral nerve sheath tumors associated with vitiligo and discuss the possible implicated embryologic, genetic and molecular mechanisms. To our knowledge, we also report the first case of de novo malignant peripheral nerve sheath tumor (MPNST) associated with vitiligo. PMID:26607956

  4. Raman microspectroscopy for visualization of peripheral nerves

    NASA Astrophysics Data System (ADS)

    Minamikawa, Takeo; Harada, Yoshinori; Koizumi, Noriaki; Takamatsu, Tetsuro

    2013-02-01

    The peripheral nervous system plays an important role in motility, sensory, and autonomic functions of the human body. Preservation of peripheral nerves in surgery is essential for improving quality of life of patients. To preserve peripheral nerves, detection of ne peripheral nerves that cannot be identi ed by human eye or under white light imaging is necessary. In this study, we sought to provide a proof-of-principle demonstration of a label-free detection technique of peripheral nerve tissues against adjacent tissues that employs spontaneous Raman microspectroscopy. A line-illumination confocal Raman microscope was used for the experiment. A laser operating at the wavelength of 532 nm was used as an excitation laser light. We obtained Raman spectra of peripheral nerve, brous connective tissue, skeletal muscle, blood vessel, and adipose tissue of Wistar rats, and extracted speci c spectral features of peripheral nerves and adjacent tissues. By applying multivariate image analysis, peripheral nerves were clearly detected against adjacent tissues without any preprocessing neither xation nor staining. These results suggest the potential of the Raman spectroscopic observation for noninvasive and label-free nerve detection, and we expect this method could be a key technique for nerve-sparing surgery.

  5. Beauty and cuteness in peripheral vision

    PubMed Central

    Kuraguchi, Kana; Ashida, Hiroshi

    2015-01-01

    Guo et al. (2011) showed that attractiveness was detectable in peripheral vision. Since there are different types of attractiveness (Rhodes, 2006), we investigated how beauty and cuteness are detected in peripheral vision with a brief presentation. Participants (n = 45) observed two Japanese female faces for 100 ms, then were asked to respond which face was more beautiful (or cuter). The results indicated that both beauty and cuteness were detectable in peripheral vision, but not in the same manner. Discrimination rates for judging beauty were invariant in peripheral and central vision, while discrimination rates for judging cuteness declined in peripheral vision as compared with central vision. This was not explained by lower resolution in peripheral vision. In addition, for male participants, it was more difficult to judge cuteness than beauty in peripheral vision, thus suggesting that gender differences can have a certain effect when judging cuteness. Therefore, central vision might be suitable for judging cuteness while judging beauty might not be affected by either central or peripheral vision. This might be related with the functional difference between beauty and cuteness. PMID:25999883

  6. Color vision in the peripheral retina.

    PubMed

    Johnson, M A

    1986-02-01

    Until recently, color vision in the peripheral field has been thought to be substantially less developed than color vision in the central field. Although the exact dimensions vary from study to study, most estimates of peripheral chromatic perception place the limit of trichromatic vision at no more than 30 degrees from fixation; the visual field is thought to be completely color blind at about 50 degrees of eccentricity. Within the last 10 years, an increased understanding of the changing spatial scale in the peripheral field has led researchers to reevaluate what is believed about peripheral function. We now know that virtually every measure of peripheral color perception can be improved by using a suitably large stimulus in the peripheral field. This paper examines current and past perspectives on peripheral color function, and describes two studies which demonstrate that peripheral and central chromatic processing are the same to the first order if the changes in spatial scale and photopic sensitivity with eccentricity are considered. PMID:3953765

  7. Peripheral Arterial Disease (P.A.D.)

    MedlinePlus

    ... turn Javascript on. Peripheral Artery Disease (P.A.D.) What is P.A.D.? Arteries Clogged With Plaque Peripheral arterial disease (P. ... button on your keyboard.) Why Is P.A.D. Dangerous? Click for more information Blocked blood flow ...

  8. Symmetrical peripheral gangrene caused by septic shock

    PubMed Central

    Shimbo, Keisuke; Yokota, Kazunori; Miyamoto, Junpei; Okuhara, Yukako; Ochi, Mitsuo

    2015-01-01

    We report three cases of symmetrical peripheral gangrene (SPG) caused by septic shock. Most of sepsis survivors with SPG require amputation of the affected extremities. To preserve the length of the thumb and fingers, we performed surgical amputation and used flaps to cover the amputated peripheral extremities.

  9. Angiomodulin, a marker of cancer vasculature, is upregulated by vascular endothelial growth factor and increases vascular permeability as a ligand of integrin αvβ3

    PubMed Central

    Komiya, Eriko; Sato, Hiroki; Watanabe, Naoko; Ise, Marii; Higashi, Shouichi; Miyagi, Yohei; Miyazaki, Kaoru

    2014-01-01

    Angiomodulin (AGM) is a member of insulin-like growth factor binding protein (IGFBP) superfamily and often called IGFBP-rP1 or IGFBP-7. AGM was originally identified as a tumor-derived cell adhesion factor, which was highly accumulated in blood vessels of human cancer tissues. AGM is also overexpressed in cancer-associated fibroblasts (CAFs) and activates fibroblasts. However, some studies have shown tumor-suppressing activity of AGM. To understand the roles of AGM in cancer progression, we here investigated the expression of AGM in benign and invasive breast cancers and its functions in cancer vasculature. Immunohistochemical analysis showed that AGM was highly expressed in cancer vasculature even in ductal carcinoma in situ (DCIS) as compared to normal vasculature, while its expression in CAFs was more prominent in invasive carcinomas than DCIS. In vitro analyses showed that AGM was strongly induced by vascular endothelial cell growth factor (VEGF) in vascular endothelial cells. Although AGM stimulated neither the growth nor migration of endothelial cells, it supported efficient adhesion of endothelial cells. Integrin αvβ3 was identified as a novel major receptor for AGM in vascular endothelial cells. AGM retracted endothelial cells by inducing actin stress fibers and loosened their VE-cadherin-mediated intercellular junction. Consequently, AGM increased vascular permeability both in vitro and in vivo. Furthermore, AGM and integrin αvβ3 were highly expressed and colocalized in cancer vasculature. These results suggest that AGM cooperates with VEGF to induce the aberrant functions of cancer vasculature as a ligand of integrin αvβ3. PMID:24737780

  10. Coronary vasculature patterning requires a novel endothelial ErbB2 holoreceptor

    PubMed Central

    Aghajanian, Haig; Cho, Young Kuk; Manderfield, Lauren J.; Herling, Madison R.; Gupta, Mudit; Ho, Vivienne C.; Li, Li; Degenhardt, Karl; Aharonov, Alla; Tzahor, Eldad; Epstein, Jonathan A.

    2016-01-01

    Organogenesis and regeneration require coordination of cellular proliferation, regulated in part by secreted growth factors and cognate receptors, with tissue nutrient supply provided by expansion and patterning of blood vessels. Here we reveal unexpected combinatorial integration of a growth factor co-receptor with a heterodimeric partner and ligand known to regulate angiogenesis and vascular patterning. We show that ErbB2, which can mediate epidermal growth factor (EGF) and neuregulin signalling in multiple tissues, is unexpectedly expressed by endothelial cells where it partners with neuropilin 1 (Nrp1) to form a functional receptor for the vascular guidance molecule semaphorin 3d (Sema3d). Loss of Sema3d leads to improper patterning of the coronary veins, a phenotype recapitulated by endothelial loss of ErbB2. These findings have implications for possible cardiovascular side-effects of anti-ErbB2 therapies commonly used for cancer, and provide an example of integration at the molecular level of pathways involved in tissue growth and vascular patterning. PMID:27356767

  11. VEGFB/VEGFR1-Induced Expansion of Adipose Vasculature Counteracts Obesity and Related Metabolic Complications.

    PubMed

    Robciuc, Marius R; Kivelä, Riikka; Williams, Ian M; de Boer, Jan Freark; van Dijk, Theo H; Elamaa, Harri; Tigistu-Sahle, Feven; Molotkov, Dmitry; Leppänen, Veli-Matti; Käkelä, Reijo; Eklund, Lauri; Wasserman, David H; Groen, Albert K; Alitalo, Kari

    2016-04-12

    Impaired angiogenesis has been implicated in adipose tissue dysfunction and the development of obesity and associated metabolic disorders. Here, we report the unexpected finding that vascular endothelial growth factor B (VEGFB) gene transduction into mice inhibits obesity-associated inflammation and improves metabolic health without changes in body weight or ectopic lipid deposition. Mechanistically, the binding of VEGFB to VEGF receptor 1 (VEGFR1, also known as Flt1) activated the VEGF/VEGFR2 pathway and increased capillary density, tissue perfusion, and insulin supply, signaling, and function in adipose tissue. Furthermore, endothelial Flt1 gene deletion enhanced the effect of VEGFB, activating the thermogenic program in subcutaneous adipose tissue, which increased the basal metabolic rate, thus preventing diet-induced obesity and related metabolic complications. In obese and insulin-resistant mice, Vegfb gene transfer, together with endothelial Flt1 gene deletion, induced weight loss and mitigated the metabolic complications, demonstrating the therapeutic potential of the VEGFB/VEGFR1 pathway. PMID:27076080

  12. In silico analyses of pericycle cell populations reinforce their relation with associated vasculature in Arabidopsis

    PubMed Central

    Parizot, Boris; Roberts, Ianto; Raes, Jeroen; Beeckman, Tom; De Smet, Ive

    2012-01-01

    In Arabidopsis, lateral root initiation occurs in a subset of pericycle cells at the xylem pole that will divide asymmetrically to give rise to a new lateral root organ. While lateral roots never develop at the phloem pole, it is unclear how the interaction with xylem and phloem poles determines the distinct pericycle identities with different competences. Nevertheless, pericycle cells at these poles are marked by differences in size, by ultrastructural features and by specific proteins and gene expression. Here, we provide transcriptional evidence that pericycle cells are intimately associated with their vascular tissue instead of being a separate concentric layer. This has implications for the identification of cell- and tissue-specific promoters that are necessary to drive and/or alter gene expression locally, avoiding pleiotropic effects. We were able to identify a small set of genes that display specific expression in the phloem or xylem pole pericycle cells, and we were able to identify motifs that are likely to drive expression in either one of those tissues. PMID:22527390

  13. Continuous peripheral nerve blocks in children.

    PubMed

    Dadure, C; Capdevila, X

    2005-06-01

    In recent years, regional anaesthesia in children has generated increasing interest. Continuous peripheral nerve blocks have an important role in the anaesthetic arsenal, allowing effective, safe and prolonged postoperative pain management. Indications for continuous peripheral nerve blocks depend on benefits/risks analysis of each technique for each patient. The indications include surgery associated with intense postoperative pain, surgery requiring painful physical therapy, and complex regional pain syndrome. Continuous peripheral nerve blocks are usually performed under general anaesthesia or sedation, and require appropriate equipment in order to decrease the risk of nerve injury. New techniques, such as transcutaneous stimulation or ultrasound guidance, appear to facilitate nerve and plexus identification in paediatric patients. Nevertheless, continuous peripheral nerve block may mask compartment syndrome in certain surgical procedure or trauma. Finally, ropivacaine appears to be the best local anaesthetic for continuous peripheral nerve blocks in children, requiring low flow rate with low concentration of the local anaesthetic. PMID:15966500

  14. Peripheral Ulcerative Keratitis with Pyoderma Gangrenosum

    PubMed Central

    Imbernón-Moya, Adrián; Vargas-Laguna, Elena; Aguilar, Antonio; Gallego, Miguel Ángel; Vergara, Claudia; Nistal, María Fernanda

    2015-01-01

    Pyoderma gangrenosum is an unusual necrotizing noninfective and ulcerative skin disease whose cause is unknown. Ophthalmic involvement in pyoderma gangrenosum is an unusual event. Only a few cases have been reported, from which we can highlight scleral, corneal, and orbital cases. Peripheral ulcerative keratitis is a process which destroys the peripheral cornea. Its cause is still unknown although it is often associated with autoimmune conditions. Pyoderma gangrenosum should be included in the differential diagnosis of peripheral ulcerative keratitis. Early recognition of these manifestations can vary the prognosis by applying the appropriate treatment. We introduce a 70-year-old woman who suffered pyoderma gangrenosum associated with peripheral ulcerative keratitis in her left eye. The patient's skin lesions and peripheral keratitis responded successfully to systemic steroids and cyclosporine A. PMID:26527531

  15. POSITIVE EMOTIONS ENHANCE RECALL OF PERIPHERAL DETAILS

    PubMed Central

    Talarico, Jennifer M.; Berntsen, Dorthe; Rubin, David C.

    2011-01-01

    Emotional arousal and negative affect enhance recall of central aspects of an event. However, the role of discrete emotions in selective memory processing is understudied. Undergraduates were asked to recall and rate autobiographical memories of eight emotional events. Details of each memory were rated as central or peripheral to the event. Significance of the event, vividness, reliving and other aspects of remembering were also rated for each event. Positive affect enhanced recall of peripheral details. Furthermore, the impairment of peripheral recall was greatest in memories of anger, not of fear. Reliving the experience at retrieval was negatively correlated with recall of peripheral details for some emotions (e.g., anger) but not others (e.g., fear), irrespective of similarities in affect and intensity. Within individuals, recall of peripheral details was correlated with less belief in the memory’s accuracy and more likelihood to recall the memory from one’s own eyes (i.e., a field perspective). PMID:21359127

  16. Change in peripheral refraction and curvature of field of the human eye with accommodation

    NASA Astrophysics Data System (ADS)

    Ho, Arthur; Zimmermann, Frederik; Whatham, Andrew; Martinez, Aldo; Delgado, Stephanie; Lazon de la Jara, Percy; Sankaridurg, Padmaja

    2009-02-01

    Recent research showed that the peripheral refractive state is a sufficient stimulus for myopia progression. This finding led to the suggestion that devices that control peripheral refraction may be efficacious in controlling myopia progression. This study aims to understand whether the optical effect of such devices may be affected by near focus. In particular, we seek to understand the influence of accommodation on peripheral refraction and curvature of field of the eye. Refraction was measured in twenty young subjects using an autorefractor at 0° (i.e. along visual axis), and 20°, 30° and 40° field angles both nasal and temporal to the visual axis. All measurements were conducted at 2.5 m, 40 cm and 30 cm viewing distances. Refractive errors were corrected using a soft contact lens during all measurements. As field angle increased, refraction became less hyperopic. Peripheral refraction also became less hyperopic at nearer viewing distances (i.e. with increasing accommodation). Astigmatism (J180) increased with field angle as well as with accommodation. Adopting a third-order aberration theory approach, the position of the Petzval surface relative to the retinal surface was estimated by considering the relative peripheral refractive error (RPRE) and J180 terms of peripheral refraction. Results for the estimated dioptric position of the Petzval surface relative to the retina showed substantial asymmetry. While temporal field tended to agree with theoretical predictions, nasal response departed dramatically from the model eye predictions. With increasing accommodation, peripheral refraction becomes less hyperopic while the Petzval surface showed asymmetry in its change in position. The change in the optical components (i.e. cornea and/or lens as opposed to retinal shape or position) is implicated as at least one of the contributors of this shift in peripheral refraction during accommodation.

  17. Interaction of Isoflavones and Endophyte-Infected Tall Fescue Seed Extract on Vasoactivity of Bovine Mesenteric Vasculature

    PubMed Central

    Jia, Yang; Harmon, David L.; Flythe, Michael D.; Klotz, James L.

    2015-01-01

    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 isoflavones formononetin (F), biochanin A (B), or an ergovaline-containing tall fescue seed extract (EXT) and their combinations affect ergotamine (ERT)-induced contractility. Multiple segments of mesenteric artery and vein supporting the ileal flange of the small intestine were collected from Angus heifers at slaughter (n = 5, bodyweight = 639 ± 39 kg). Duplicates of each vessel type were incubated in tissue culture flasks at 37°C with a 50-mL volume of Krebs–Henseleit buffer containing: only buffer (control); or 1 × 10−6 M EXT; F; or B; and combinations of 1 × 10−6 M EXT + F; 1 × 10−6 M EXT + B; 1 × 10−6 M F + B; or 1 × 10−6 M EXT + F + B. After incubation for 2 h, sections were mounted in a multimyograph chamber. The ERT dose responses were normalized to 0.12 M KCl. Pretreatment with F, B, and F + B without EXT resulted in similar contractile responses to ERT in mesenteric artery and all incubations containing EXT resulted in a complete loss of vasoactivity to ERT. In mesenteric artery pretreated with EXT, treatments that contained B had higher contractile responses (P < 0.05) at ERT concentrations of 1 × 10−7 and 5 × 10−7 M. Also, treatments containing B tended (P < 0.1) to have greater responses than treatments without B at ERT concentrations of 1 × 10−6, 5 × 10−6, and 5 × 10−5 M. In mesenteric vein pretreated with EXT, treatments containing F had greater contractile responses to ERT at 1 × 10−5, 5 × 10−5, and 1 × 10−4 M (P < 0.05). These data indicated that F and B at 1 × 10−6 M and their

  18. Interaction of Isoflavones and Endophyte-Infected Tall Fescue Seed Extract on Vasoactivity of Bovine Mesenteric Vasculature.

    PubMed

    Jia, Yang; Harmon, David L; Flythe, Michael D; Klotz, James L

    2015-01-01

    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 isoflavones formononetin (F), biochanin A (B), or an ergovaline-containing tall fescue seed extract (EXT) and their combinations affect ergotamine (ERT)-induced contractility. Multiple segments of mesenteric artery and vein supporting the ileal flange of the small intestine were collected from Angus heifers at slaughter (n = 5, bodyweight = 639 ± 39 kg). Duplicates of each vessel type were incubated in tissue culture flasks at 37°C with a 50-mL volume of Krebs-Henseleit buffer containing: only buffer (control); or 1 × 10(-6) M EXT; F; or B; and combinations of 1 × 10(-6) M EXT + F; 1 × 10(-6) M EXT + B; 1 × 10(-6) M F + B; or 1 × 10(-6) M EXT + F + B. After incubation for 2 h, sections were mounted in a multimyograph chamber. The ERT dose responses were normalized to 0.12 M KCl. Pretreatment with F, B, and F + B without EXT resulted in similar contractile responses to ERT in mesenteric artery and all incubations containing EXT resulted in a complete loss of vasoactivity to ERT. In mesenteric artery pretreated with EXT, treatments that contained B had higher contractile responses (P < 0.05) at ERT concentrations of 1 × 10(-7) and 5 × 10(-7) M. Also, treatments containing B tended (P < 0.1) to have greater responses than treatments without B at ERT concentrations of 1 × 10(-6), 5 × 10(-6), and 5 × 10(-5) M. In mesenteric vein pretreated with EXT, treatments containing F had greater contractile responses to ERT at 1 × 10(-5), 5 × 10(-5), and 1 × 10(-4) M (P < 0.05). These data indicated that F and B at 1 × 10(-6) M and their combination

  19. Cardiovascular responses to peripheral chemoreflex activation and comparison of different methods to evaluate baroreflex gain in conscious mice using telemetry.

    PubMed

    Braga, Valdir A; Burmeister, Melissa A; Sharma, Ram V; Davisson, Robin L

    2008-10-01

    Peripheral chemoreceptors located in the carotid bodies are the primary sensors of systemic hypoxia. Although the pattern of responses elicited by peripheral chemoreceptor activation is well established in rats, lambs, and rabbits, the cardiovascular responses to peripheral chemoreflex activation in conscious mice have not been delineated. Here we report that stimulation of peripheral chemoreceptors by potassium cyanide (KCN) in conscious mice elicits a unique biphasic response in blood pressure that is characterized by an initial and robust rise followed by a decrease in blood pressure, which is accompanied by a marked reduction in heart rate. The depressor and bradycardic responses to KCN were abolished by muscarinic receptor blockade with atropine, and the pressor response was abolished by alpha-adrenergic receptor blockade with prazosin, suggesting that vagal and sympathetic drive to the heart and sympathetic drive to the vasculature mediate these cardiovascular responses. These studies characterized the chemoreflex in conscious mice and established the reliability of using them for studying hypoxia-related diseases such as obstructive sleep apnea. In another series of experiments, two methods for analyzing baroreflex sensitivity were compared: the classical pharmacological approach using phenylephrine and sodium nitroprusside (i.e., the Oxford technique) or the sequence method for analyzing spontaneous baroreflex activity. Our findings indicate that both methods are reliable, and the sequence method certainly has its benefits as a predictive tool in the context of long-term noninvasive studies using telemetry. However, for absolute determination of baroreflex function, analysis of spontaneous baroreflex activity should be complemented by the classical pharmacological method. PMID:18667715

  20. Peripheral olfactory signaling in insects

    PubMed Central

    Suh, Eunho; Bohbot, Jonathan; Zwiebel, Laurence J.

    2014-01-01

    Olfactory signaling is a crucial component in the life history of insects. The development of precise and parallel mechanisms to analyze the tremendous amount of chemical information from the environment and other sources has been essential to their evolutionary success. Considerable progress has been made in the study of insect olfaction fueled by bioinformatics- based utilization of genomics along with rapid advances in functional analyses. Here we review recent progress in our rapidly emerging understanding of insect peripheral sensory reception and signal transduction. These studies reveal that the nearly unlimited chemical space insects encounter is covered by distinct chemosensory receptor repertoires that are generally derived by species-specific, rapid gene gain and loss, reflecting the evolutionary consequences of adaptation to meet their specific biological needs. While diverse molecular mechanisms have been put forth, often in the context of controversial models, the characterization of the ubiquitous, highly conserved and insect-specific Orco odorant receptor co-receptor has opened the door to the design and development of novel insect control methods to target agricultural pests, disease vectors and even nuisance insects. PMID:25584200

  1. Malignant Peripheral Nerve Sheath Tumors.

    PubMed

    Durbin, Adam D; Ki, Dong Hyuk; He, Shuning; Look, A Thomas

    2016-01-01

    Malignant peripheral nerve sheath tumors (MPNST) are tumors derived from Schwann cells or Schwann cell precursors. Although rare overall, the incidence of MPNST has increased with improved clinical management of patients with the neurofibromatosis type 1 (NF1) tumor predisposition syndrome. Unfortunately, current treatment modalities for MPNST are limited, with no targeted therapies available and poor efficacy of conventional radiation and chemotherapeutic regimens. Many murine and zebrafish models of MPNST have been developed, which have helped to elucidate the genes and pathways that are dysregulated in MPNST tumorigenesis, including the p53, and the RB1, PI3K-Akt-mTOR, RAS-ERK and Wnt signaling pathways. Preclinical results have suggested that new therapies, including mTOR and ERK inhibitors, may synergize with conventional chemotherapy in human tumors. The discovery of new genome editing technologies, like CRISPR-cas9, and their successful application to the zebrafish model will enable rapid progress in the faithful modeling of MPNST molecular pathogenesis. The zebrafish model is especially suited for high throughput screening of new targeted therapeutics as well as drugs approved for other purposes, which may help to bring enhanced treatment modalities into human clinical trials for this devastating disease. PMID:27165368

  2. Chemotherapy-induced peripheral neuropathy.

    PubMed

    Fehrenbacher, Jill C

    2015-01-01

    Chemotherapy-induced peripheral neuropathy (CIPN) is common in patients receiving anticancer treatment and can affect survivability and long-term quality of life of the patient following treatment. The symptoms of CIPN primarily include abnormal sensory discrimination of touch, vibration, thermal information, and pain. There is currently a paucity of pharmacological agents to prevent or treat CIPN. The lack of efficacious therapeutics is due, at least in part, to an incomplete understanding of the mechanisms by which chemotherapies alter the sensitivity of sensory neurons. Although the clinical presentation of CIPN can be similar with the various classes of chemotherapeutic agents, there are subtle differences, suggesting that each class of drugs might induce neuropathy via different mechanisms. Multiple mechanisms have been proposed to underlie the development and maintenance of neuropathy; however, most pharmacological agents generated from preclinical experiments have failed to alleviate the symptoms of CIPN in the clinic. Further research is necessary to identify the specific mechanisms by which each class of chemotherapeutics induces neuropathy. PMID:25744683

  3. Pretreatment imaging of peripheral vascular malformations

    PubMed Central

    Johnson, Joshua B; Cogswell, Petrice M; McKusick, Michael A; Binkovitz, Larry A; Riederer, Stephen J; Young, Phillip M

    2015-01-01

    Peripheral vascular malformations (VMs) are complex and diverse vascular lesions which require individualized pretreatment planning. Pretreatment imaging using various modalities, especially magnetic resonance imaging and time-resolved magnetic resonance angiography, is a valuable tool for classifying peripheral VMs to allow proper diagnosis, demonstrate complete extent, identify the nidus, and distinguish between low-flow and high-flow dynamics that determines the treatment approach. We discuss pretreatment imaging findings in four patients with peripheral VMs and how diagnostic imaging helped guide management. PMID:25625123

  4. Double-mirror peripheral vitrectomy lens.

    PubMed

    Ohji, M; Tano, Y

    1995-11-01

    Many surgeons use prism lenses to see the periphery of the fundus during vitrectomy; however, chromatic aberrations in higher-power prismatic lenses cause blurring of the peripheral image. For better visualization of the periphery of the fundus, we developed a new contact lens, the double-mirror peripheral vitrectomy lens. The new lens is a quartz cylinder with two mirrors, and it provides a crisp, clear, upright image of much more of the peripheral fundus than is visible through conventional prism lenses. The new lens also provides a wider area of view than conventional prism lenses. PMID:7487611

  5. Peripheral osteoma of maxilla: A case report

    PubMed Central

    Batra, Namish; Batra, Renu; Singh, Gaurav; Gaur, Amit

    2014-01-01

    Osteoma is a benign osteogenic lesion with a very slow growth, characterized by proliferation of either compact or cancellous bone. Most cases of peripheral osteomas are asymptomatic and produce swelling and asymmetry. Its pathogenesis is unclear but commonly accepted theories propose embryologic, traumatic, or infectious causes. The osteoma may appear in the form of a limited peripheral lesion involving the alveoli or cheek or as a tumoral growth developing inward toward the sinus. Recurrences of osteomas have not been reported in the literature. We report a rare case of maxillary peripheral osteoma with impacted right canine in a 32-year-old female patient. PMID:25937746

  6. Systems and methods to control multiple peripherals with a single-peripheral application code

    SciTech Connect

    Ransom, Ray M.

    2013-06-11

    Methods and apparatus are provided for enhancing the BIOS of a hardware peripheral device to manage multiple peripheral devices simultaneously without modifying the application software of the peripheral device. The apparatus comprises a logic control unit and a memory in communication with the logic control unit. The memory is partitioned into a plurality of ranges, each range comprising one or more blocks of memory, one range being associated with each instance of the peripheral application and one range being reserved for storage of a data pointer related to each peripheral application of the plurality. The logic control unit is configured to operate multiple instances of the control application by duplicating one instance of the peripheral application for each peripheral device of the plurality and partitioning a memory device into partitions comprising one or more blocks of memory, one partition being associated with each instance of the peripheral application. The method then reserves a range of memory addresses for storage of a data pointer related to each peripheral device of the plurality, and initializes each of the plurality of peripheral devices.

  7. Peripheral Inflammation is Associated with Altered Substantia Nigra Activity and Psychomotor Slowing in Humans

    PubMed Central

    Brydon, Lena; Harrison, Neil A.; Walker, Cicely; Steptoe, Andrew; Critchley, Hugo D.

    2008-01-01

    Background Systemic infections commonly cause sickness symptoms including psychomotor retardation. Inflammatory cytokines released during the innate immune response are implicated in the communication of peripheral inflammatory signals to the brain. Methods We used functional magnetic resonance brain imaging (fMRI) to investigate neural effects of peripheral inflammation following typhoid vaccination in 16 healthy men, using a double-blind, randomized, crossover-controlled design. Results Vaccination had no global effect on neurovascular coupling but markedly perturbed neural reactivity within substantia nigra during low-level visual stimulation. During a cognitive task, individuals in whom typhoid vaccination engendered higher levels of circulating interleukin-6 had significantly slower reaction time responses. Prolonged reaction times and larger interleukin-6 responses were associated with evoked neural activity within substantia nigra. Conclusions Our findings provide mechanistic insights into the interaction between inflammation and neurocognitive performance, specifically implicating circulating cytokines and midbrain dopaminergic nuclei in mediating the psychomotor consequences of systemic infection. PMID:18242584

  8. [When prions use the systems of communication between the immune system and the peripheral nervous system].

    PubMed

    Dorban, Gauthier; Antoine, Nadine; Defaweux, Valérie

    2010-01-01

    Prion disease pathogenesis has been largely studied since the inter-species transmissibility of the infectious protein (PrPSc), the oral uptake as natural route of infection and the exceptional implication in a problem of public health were highlighted. Two sequential preclinical stages are observed before the development of irreversible and fatal lesions in the central nervous system: the lymphoinvasion and the neuroinvasion. The first is characterized by the accumulation of PrPSc within lymphoid tissues and the second by PrPSc scattering the peripheral nervous system towards the central nervous system. The mechanisms involved in the communication between the immune and the peripheral nervous system are still debated. Recent studies even suggest that neuroinvasion can occur through the hematogenous route, independently of the peripheral nervous system. This review analyses (i) the role of immune cells, implicated in prion pathogenesis: dendritic cells as PrPSc vehicle, follicular dendritic cells as PrPSc accumulator and nerve fibres as PrPSc driver and (ii) the respective relations they maintain with peripheral nerve fibres to migrate to the brain. PMID:20619163

  9. Acupuncture for peripheral joint osteoarthritis

    PubMed Central

    Manheimer, Eric; Cheng, Ke; Linde, Klaus; Lao, Lixing; Yoo, Junghee; Wieland, Susan; van der Windt, Daniëlle AWM; Berman, Brian M; Bouter, Lex M

    2011-01-01

    Background Peripheral joint osteoarthritis is a major cause of pain and functional limitation. Few treatments are safe and effective. Objectives To assess the effects of acupuncture for treating peripheral joint osteoarthritis. Search strategy We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2008, Issue 1), MEDLINE, and EMBASE (both through December 2007), and scanned reference lists of articles. Selection criteria Randomized controlled trials (RCTs) comparing needle acupuncture with a sham, another active treatment, or a waiting list control group in people with osteoarthritis of the knee, hip, or hand. Data collection and analysis Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. We calculated standardized mean differences using the differences in improvements between groups. Main results Sixteen trials involving 3498 people were included. Twelve of the RCTs included only people with OA of the knee, 3 only OA of the hip, and 1 a mix of people with OA of the hip and/or knee. In comparison with a sham control, acupuncture showed statistically significant, short-term improvements in osteoarthritis pain (standardized mean difference -0.28, 95% confidence interval -0.45 to -0.11; 0.9 point greater improvement than sham on 20 point scale; absolute percent change 4.59%; relative percent change 10.32%; 9 trials; 1835 participants) and function (-0.28, -0.46 to -0.09; 2.7 point greater improvement on 68 point scale; absolute percent change 3.97%; relative percent change 8.63%); however, these pooled short-term benefits did not meet our predefined thresholds for clinical relevance (i.e. 1.3 points for pain; 3.57 points for function) and there was substantial statistical heterogeneity. Additionally, restriction to sham-controlled trials using shams judged most likely to adequately blind participants to treatment assignment (which were also the same shams judged most

  10. Stem cell-derived vasculature: A potent and multidimensional technology for basic research, disease modeling, and tissue engineering

    PubMed Central

    Lowenthal, Justin; Gerecht, Sharon

    2016-01-01

    Proper blood vessel networks are necessary for constructing and re-constructing tissues, promoting wound healing, and delivering metabolic necessities throughout the body. Conversely, an understanding of vascular dysfunction has provided insight into the pathogenesis and progression of diseases both common and rare. Recent advances in stem cell-based regenerative medicine – including advances in stem cell technologies and related progress in bioscaffold design and complex tissue engineering – have allowed rapid advances in the field of vascular biology, leading in turn to more advanced modeling of vascular pathophysiology and improved engineering of vascularized tissue constructs. In this review we examine recent advances in the field of stem cell-derived vasculature, providing an overview of stem cell technologies as a source for vascular cell types and then focusing on their use in three primary areas: studies of vascular development and angiogenesis, improved disease modeling, and the engineering of vascularized constructs for tissue-level modeling and cell-based therapies. PMID:26427871

  11. Gold Nanoparticle–Mediated Targeted Delivery of Recombinant Human Endostatin Normalizes Tumour Vasculature and Improves Cancer Therapy

    PubMed Central

    Li, Wei; Zhao, Xiaoxu; Du, Bin; Li, Xin; Liu, Shuhao; Yang, Xiao-Yan; Ding, Hui; Yang, Wende; Pan, Fan; Wu, Xiaobo; Qin, Li; Pan, Yunlong

    2016-01-01

    Tumour vasculature is generally disordered because of the production of excessive angiogenic factors by tumour cells, which results in tumour progression and reduces the effectiveness of radiotherapy or chemotherapy. Transient anti-angiogenic therapies that regulate tumour vascular morphology and function and improve the efficiency of antitumour therapy are under investigation. Recombinant human endostatin (Endostar/rhES) is a vascular angiogenesis–disrupting agent that has been used to treat non-small cell lung cancer (NSCLC) in the clinical setting. In this study, we used gold nanoparticles (AuNPs) as a drug-delivery system (DDS) for targeted tumour delivery of rhES for short therapy, which resulted in transient tumour vascular normalization, reduced permeability and hypoxia, strengthened blood vessel integrity, and increased blood-flow perfusion. Moreover, combination therapy with 5-FU over this timeframe was substantially more effective than 5-FU monotherapy. In conclusion, our research demonstrates the potential use of AuNPs as a drug-delivery platform for transporting rhES into a tumour to induce transient tumour vascular normalization and enhance the antitumour efficacy of cytotoxic drugs. PMID:27470938

  12. Biodegradable scaffold with built-in vasculature for organ-on-a-chip engineering and direct surgical anastomosis

    PubMed Central

    Zhang, Boyang; Montgomery, Miles; Chamberlain, M. Dean; Ogawa, Shinichiro; Korolj, Anastasia; Pahnke, Aric; Wells, Laura A.; Massé, Stéphane; Kim, Jihye; Reis, Lewis; Momen, Abdulah; Nunes, Sara S.; Wheeler, Aaron; Nanthakumar, Kumaraswamy; Keller, Gordon; Sefton, Michael V.; Radisic, Milica

    2016-01-01

    We report the fabrication of a scaffold (hereafter referred to as AngioChip) that supports the assembly of parenchymal cells on a mechanically tunable matrix surrounding a perfusable, branched, three-dimensional microchannel network coated with endothelial cells. The design of AngioChip decouples the material choices for the engineered vessel network and for cell seeding in the parenchyma, enabling extensive remodelling while maintaining an open-vessel lumen. The incorporation of nanopores and micro-holes in the vessel walls enhances permeability, and permits intercellular crosstalk and extravasation of monocytes and endothelial cells on biomolecular stimulation. We also show that vascularized hepatic tissues and cardiac tissues engineered by using AngioChips process clinically relevant drugs delivered through the vasculature, and that millimeter-thick cardiac tissues can be engineered in a scalable manner. Moreover, we demonstrate that AngioChip cardiac tissues implanted via direct surgical anastomosis to the femoral vessels of rat hindlimbs establish immediate blood perfusion. PMID:26950595

  13. Three-Dimensional Imaging of the Developing Vasculature within Stem Cell-Seeded Scaffolds Cultured in ovo

    PubMed Central

    Woloszyk, Anna; Liccardo, Davide; Mitsiadis, Thimios A.

    2016-01-01

    Successful tissue engineering requires functional vascularization of the three-dimensional constructs with the aim to serve as implants for tissue replacement and regeneration. The survival of the implant is only possible if the supply of oxygen and nutrients by developing capillaries from the host is established. The chorioallantoic membrane (CAM) assay is a valuable tool to study the ingrowth and distribution of vessels into scaffolds composed by appropriate biomaterials and stem cell populations that are used in cell-based regenerative approaches. The developing vasculature of chicken embryos within cell-seeded scaffolds can be visualized with microcomputed tomography after intravenous injection of MicroFil®, which is a radiopaque contrast agent. Here, we provide a step-by-step protocol for the seeding of stem cells into silk fibroin scaffolds, the CAM culture conditions, the procedure of MicroFil® perfusion, and finally the microcomputed tomography scanning. Three-dimensional imaging of the vascularized tissue engineered constructs provides an important analytical tool for studying the potential of cell seeded scaffolds to attract vessels and form vascular networks, as well as for analyzing the number, density, length, branching, and diameter of vessels. This in ovo method can greatly help to screen implants that will be used for tissue regeneration purposes before their in vivo testing, thereby reducing the amount of animals needed for pre-clinical studies. PMID:27148081

  14. Destruction of tumor vasculature and abated tumor growth upon VEGF blockade is driven by proapoptotic protein Bim in endothelial cells.

    PubMed

    Naik, Edwina; O'Reilly, Lorraine A; Asselin-Labat, Marie-Liesse; Merino, Delphine; Lin, Ann; Cook, Michele; Coultas, Leigh; Bouillet, Philippe; Adams, Jerry M; Strasser, Andreas

    2011-07-01

    For malignant growth, solid cancers must stimulate the formation of new blood vessels by producing vascular endothelial growth factor (VEGF-A), which is required for the survival of tumor-associated vessels. Novel anticancer agents that block VEGF-A signaling trigger endothelial cell (EC) apoptosis and vascular regression preferentially within tumors, but how the ECs die is not understood. In this study, we demonstrate that VEGF-A deprivation, provoked either by drug-induced tumor shrinkage or direct VEGF-A blockade, up-regulates the proapoptotic BH3 (Bcl-2 homology 3)-only Bcl-2 family member Bim in ECs. Importantly, the tumor growth inhibitory activity of a VEGF-A antagonist required Bim-induced apoptosis of ECs. These findings thus reveal the mechanism by which VEGF-A blockade induces EC apoptosis and impairs tumor growth. They also indicate that drugs mimicking BH3-only proteins may be exploited to kill tumor cells not only directly but also indirectly by ablating the tumor vasculature. PMID:21646395

  15. Biodegradable scaffold with built-in vasculature for organ-on-a-chip engineering and direct surgical anastomosis.

    PubMed

    Zhang, Boyang; Montgomery, Miles; Chamberlain, M Dean; Ogawa, Shinichiro; Korolj, Anastasia; Pahnke, Aric; Wells, Laura A; Massé, Stéphane; Kim, Jihye; Reis, Lewis; Momen, Abdul; Nunes, Sara S; Wheeler, Aaron R; Nanthakumar, Kumaraswamy; Keller, Gordon; Sefton, Michael V; Radisic, Milica

    2016-06-01

    We report the fabrication of a scaffold (hereafter referred to as AngioChip) that supports the assembly of parenchymal cells on a mechanically tunable matrix surrounding a perfusable, branched, three-dimensional microchannel network coated with endothelial cells. The design of AngioChip decouples the material choices for the engineered vessel network and for cell seeding in the parenchyma, enabling extensive remodelling while maintaining an open-vessel lumen. The incorporation of nanopores and micro-holes in the vessel walls enhances permeability, and permits intercellular crosstalk and extravasation of monocytes and endothelial cells on biomolecular stimulation. We also show that vascularized hepatic tissues and cardiac tissues engineered by using AngioChips process clinically relevant drugs delivered through the vasculature, and that millimetre-thick cardiac tissues can be engineered in a scalable manner. Moreover, we demonstrate that AngioChip cardiac tissues implanted with direct surgical anastomosis to the femoral vessels of rat hindlimbs establish immediate blood perfusion. PMID:26950595

  16. How to teach an old dog new tricks: autophagy-independent action of chloroquine on the tumor vasculature.

    PubMed

    Maes, Hannelore; Kuchnio, Anna; Carmeliet, Peter; Agostinis, Patrizia

    2014-01-01

    Chloroquine (CQ) is exploited in clinical trials as an autophagy blocker to potentiate anticancer therapy, but it is unknown if it solely acts by inhibiting cancer cell-autonomous autophagy. Our recent study shows that besides blocking cancer cell growth, CQ also affects endothelial cells (ECs) and promotes tumor vessel normalization. This vessel normalizing effect of CQ reduces tumor hypoxia, cancer cell intravasation, and metastasis, while improving the delivery and response to chemotherapy. By compromising autophagy in melanoma cells or using mice with a conditional knockout of ATG5 in ECs, we found that the favorable effects of CQ on the tumor vasculature do not rely on autophagy. CQ-induced vessel normalization relies mainly on altered endolysosomal trafficking and sustained NOTCH1 signaling in ECs. Remarkably these CQ-mediated effects are abrogated when tumors are grown in mice harboring EC-specific deletion of NOTCH1. The autophagy-independent vessel normalization by CQ leading to improved delivery and tumor response to chemotherapy further advocates its clinical use in combination with anticancer treatments. PMID:25484095

  17. VEGFR-1 targeted DNAzyme via transcatheter arterial delivery influences tumor vasculature assessed through dynamic contrast-enhanced magnetic resonance imaging.

    PubMed

    Zhang, Liqing; Zhao, Wei; Liang, Chen; Yi, Xiaoping; Pei, Yigang; Lin, Yiting; He, Jiang; Li, Wenzheng

    2016-09-01

    DNAzymes are synthetic single-stranded DNA oligonucleotides that bind and cleave target mRNA in a sequence-specific manner. Although the therapeutic potential has been demonstrated in both preclinical and clinical settings, the efficient delivery and in vivo assessment of the DNAzyme efficacy remain the vital unsolved issue. In the present study, we examined the feasibility of using transcatheter arterial chemoembolization (TACE) strategy to deliver a DNAzyme targeting VEGFR-1 and monitoring its effect on tumor angiogenesis in vivo via dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). In a rabbit liver cancer model (VX2), we showed that the DNAzyme was efficiently delivered into the tumor by TACE. DCE-MRI revealed that the VEGFR-1-targeted DNAzyme affected the tumor vasculature through inhibiting VEGFR-1 expression in vivo, which was reflected by a reduction of Ktrans and Kep, the parameters of tumor microvascular permeability. Our findings offer an efficient strategy of delivery and assessment of the VEGFR-1 DNAzyme, and further demonstrate the feasibility of DNAzyme for cancer therapy. PMID:27431919

  18. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature.

    PubMed

    Miao, Zhenhua; Luker, Kathryn E; Summers, Bretton C; Berahovich, Rob; Bhojani, Mahaveer S; Rehemtulla, Alnawaz; Kleer, Celina G; Essner, Jeffrey J; Nasevicius, Aidas; Luker, Gary D; Howard, Maureen C; Schall, Thomas J

    2007-10-01

    Chemokines and chemokine receptors have been posited to have important roles in several common malignancies, including breast and lung cancer. Here, we demonstrate that CXCR7 (RDC1, CCX-CKR2), recently deorphanized as a chemokine receptor that binds chemokines CXCL11 and CXCL12, can regulate these two common malignancies. Using a combination of overexpression and RNA interference, we establish that CXCR7 promotes growth of tumors formed from breast and lung cancer cells and enhances experimental lung metastases in immunodeficient as well as immunocompetent mouse models of cancer. These effects did not depend on expression of the related receptor CXCR4. Furthermore, immunohistochemistry of primary human tumor tissue demonstrates extensive CXCR7 expression in human breast and lung cancers, where it is highly expressed on a majority of tumor-associated blood vessels and malignant cells but not expressed on normal vasculature. In addition, a critical role for CXCR7 in vascular formation and angiogenesis during development is demonstrated by using morpholino-mediated knockdown of CXCR7 in zebrafish. Taken together, these data suggest that CXCR7 has key functions in promoting tumor development and progression. PMID:17898181

  19. Wide-field imaging of retinal vasculature using optical coherence tomography-based microangiography provided by motion tracking

    NASA Astrophysics Data System (ADS)

    Zhang, Qinqin; Huang, Yanping; Zhang, Thomas; Kubach, Sophie; An, Lin; Laron, Michal; Sharma, Utkarsh; Wang, Ruikang K.

    2015-06-01

    Optical coherence tomography (OCT)-based optical microangiography (OMAG) is a high-resolution, noninvasive imaging technique capable of providing three-dimensional in vivo blood flow visualization within microcirculatory tissue beds in the eye. Although the technique has demonstrated early clinical utility by imaging diseased eyes, its limited field of view (FOV) and the sensitivity to eye motion remain the two biggest challenges for the widespread clinical use of the technology. Here, we report the results of retinal OMAG imaging obtained from a Zeiss Cirrus 5000 spectral domain OCT system with motion tracking capability achieved by a line scan ophthalmoscope (LSO). The tracking LSO is able to guide the OCT scanning, which minimizes the effect of eye motion in the final results. We show that the tracking can effectively correct the motion artifacts and remove the discontinuities and distortions of vascular appearance due to microsaccade, leading to almost motion-free OMAG angiograms with good repeatability and reliability. Due to the robustness of the tracking LSO, we also show the montage scan protocol to provide unprecedented wide field retinal OMAG angiograms. We experimentally demonstrate a 12×16 mm2 retinal OMAG angiogram acquired from a volunteer, which is the widest FOV retinal vasculature imaging up to now in the community.

  20. Combination of T-cell therapy and trigger of inflammation induces remodeling of the vasculature and tumor eradication.

    PubMed

    Ganss, Ruth; Ryschich, Eduard; Klar, Ernst; Arnold, Bernd; Hämmerling, Günter J

    2002-03-01

    In a transgenic mouse model of multistep carcinogenesis, highly angiogenic insulinomas contain an irregular vascular network and develop an intrinsic resistance to leukocyte infiltration and effector function. Even persistently high levels of activated tumor-specific T lymphocytes fail to eradicate the tumors. In contrast, we show that irradiation before adoptive transfer results in complete macroscopic tumor regression. Thus, effective tumor therapy requires a proinflammatory microenvironment that permits T cells to extravasate and to destroy the tumor. Early after initiation of the irradiation/adoptive transfer therapy, the capillary network reacquires an almost normal appearance, a likely consequence of strong induction of the chemokines monokine induced by IFN-gamma (Mig) and IFN-inducible protein 10 (IP10). This remodeling of the vasculature in a proinflammatory environment may directly affect lymphocyte extravasation and effector function. Therefore, irradiation/adoptive transfer therapy combines antigen-driven tumor cell eradication with anti-angiogenic effects on tumor endothelium, a powerful synergy that has not been previously appreciated. PMID:11888921

  1. RGD-conjugated two-photon absorbing near-IR emitting fluorescent probes for tumor vasculature imaging.

    PubMed

    Yue, Xiling; Morales, Alma R; Githaiga, Grace W; Woodward, Adam W; Tang, Simon; Sawada, Junko; Komatsu, Masanobu; Liu, Xuan; Belfield, Kevin D

    2015-11-21

    Observation of the activation and inhibition of angiogenesis processes is important in the progression of cancer. Application of targeting peptides, such as a small peptide that contains adjacent L-arginine (R), glycine (G) and L-aspartic acid (D) residues can afford high selectivity and deep penetration in vessel imaging. To facilitate deep tissue vasculature imaging, probes that can be excited via two-photon absorption (2PA) in the near-infrared (NIR) and subsequently emit in the NIR are essential. In this study, the enhancement of tissue image quality with RGD conjugates was investigated with new NIR-emitting pyranyl fluorophore derivatives in two-photon fluorescence microscopy. Linear and nonlinear photophysical properties of the new probes were comprehensively characterized; significantly the probes exhibited good 2PA over a broad spectral range from 700-1100 nm. Cell and tissue images were then acquired and examined, revealing deep penetration and high contrast with the new pyranyl RGD-conjugates up to 350 μm in tumor tissue. PMID:26351137

  2. Long-acting progestin-only contraceptives impair endometrial vasculature by inhibiting uterine vascular smooth muscle cell survival

    PubMed Central

    Kayisli, Umit A.; Basar, Murat; Guzeloglu-Kayisli, Ozlem; Semerci, Nihan; Atkinson, Helen C.; Shapiro, John; Summerfield, Taryn; Huang, S. Joseph; Prelle, Katja; Schatz, Frederick; Lockwood, Charles J.

    2015-01-01

    Molecular mechanisms responsible for abnormal endometrial vasculature in women receiving long-acting progestin-only contraceptives (LAPCs) are unknown. We hypothesize that LAPCs impair vascular smooth muscle cell (VSMC) and pericyte proliferation and migration producing thin-walled hyperdilated fragile microvessels prone to bleeding. Proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (αSMA) double-immunostaining assessed VSMC differentiation and proliferation in endometria from women before and after DepoProvera (Depo) treatment and from oophorectomized guinea pigs (OVX-GPs) treated with vehicle, estradiol (E2), medroxyprogesterone acetate (MPA), or E2+MPA. Whole-genome profiling, proliferation, and migration assays were performed on cultured VSMCs treated with MPA or etonogestrel (ETO). Endometrial vessels of Depo-administered women displayed reduced αSMA immunoreactivity and fewer PCNA (+) nuclei among αSMA (+) cells (P < 0.008). Microarray analysis of VSMCs identified several MPA- and ETO-altered transcripts regulated by STAT1 signaling (P < 2.22 × 10−6), including chemokine (C-C motif) ligand 2 (CCL2). Both MPA and ETO reduce VSMC proliferation and migration (P < 0.001). Recombinant CCL2 reversed this progestin-mediated inhibition, whereas a STAT1 inhibitor abolished the CCL2 effect. Similarly, the endometria of MPA treated OVX-GPs displayed decreased αSMA staining and fewer PCNA (+) nuclei in VSMC (P < 0.005). In conclusion, LAPCs promote abnormal endometrial vessel formation by inhibiting VSMC proliferation and migration. PMID:25847994

  3. Evidence for an age-dependent functional expression of alpha 1D-adrenoceptors in the rat vasculature.

    PubMed

    Ibarra, M; Terrón, J A; López-Guerrero, J J; Villalobos-Molina, R

    1997-03-19

    The role of the alpha 1-adrenoceptor subtypes, and their possible change with maturation, in alpha 1-adrenoceptor-induced pressor responses in the rat has not been established. Thus, the effects of the alpha 1D-, alpha 1A/1D- and alpha 1B/1D-adrenoceptor antagonists, BMY 7378 (8-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl) 8-azaspiro (4.5) decane-7,9-dione 2HCl), 5-methyl-urapidil and chloroethylclonidine, respectively, on the pressor responses induced by phenylephrine in 1- and 5-month-old pithed rats were investigated. The pressor responses induced by phenylephrine were competitively antagonized by both BMY 7378 and chloroethylclonidine in 5-month-old, but not in young immature animals; in marked contrast, 5-methylurapidil antagonized with similar potency the phenylephrine-induced pressor responses in animals of both ages. The present pharmacological data suggest that functional expression of alpha 1D-adrenoceptors in the rat resistance vessels increases with age; alpha 1A-, but not alpha 1B- or alpha 1D-adrenoceptors, seem to predominate in immature animals. These findings represent the first evidence that age-related changes in functional alpha 1-adrenoceptor subtypes occur in the systemic vasculature in vivo. PMID:9098690

  4. New vessel formation in the context of cardiomyocyte regeneration – the role and importance of an adequate perfusing vasculature

    PubMed Central

    Michelis, Katherine C.; Boehm, Manfred; Kovacic, Jason C.

    2014-01-01

    The history of revascularization for cardiac ischemia dates back to the early 1960's when the first coronary artery bypass graft procedures were performed in humans. With this 50 year history of providing a new vasculature to ischemic and hibernating myocardium, a profound depth of experience has been amassed in clinical cardiovascular medicine as to what does, and does not work in the context of cardiac revascularization, alleviating ischemia and adequacy of myocardial perfusion. These issues are of central relevance to contemporary cell-based cardiac regenerative approaches. While the cardiovascular cell therapy field is surging forward on many exciting fronts, several well accepted clinical axioms related to the cardiac arterial supply appear to be almost overlooked by some of our current basic conceptual and experimental cell therapy paradigms. We present here information drawn from five decades of the clinical revascularization experience, review relevant new data on vascular formation via cell therapy, and put forward the case that for optimal cell-based cardiac regeneration due attention must be paid to providing an adequate vascular supply. PMID:24841067

  5. Photodynamic Therapy Induced Enhancement of Tumor Vasculature Permeability Using an Upconversion Nanoconstruct for Improved Intratumoral Nanoparticle Delivery in Deep Tissues

    PubMed Central

    Gao, Weidong; Wang, Zhaohui; Lv, Liwei; Yin, Deyan; Chen, Dan; Han, Zhihao; Ma, Yi; Zhang, Min; Yang, Man; Gu, Yueqing

    2016-01-01

    Photodynamic therapy (PDT) has recently emerged as an approach to enhance intratumoral accumulation of nanoparticles. However, conventional PDT is greatly limited by the inability of the excitation light to sufficiently penetrate tissue, rendering PDT ineffective in the relatively deep tumors. To address this limitation, we developed a novel PDT platform and reported for the first time the effect of deep-tissue PDT on nanoparticle uptake in tumors. This platform employed c(RGDyK)-conjugated upconversion nanoparticles (UCNPs), which facilitate active targeting of the nanoconstruct to tumor vasculature and achieve the deep-tissue photosensitizer activation by NIR light irradiation. Results indicated that our PDT system efficiently enhanced intratumoral uptake of different nanoparticles in a deep-seated tumor model. The optimal light dose for deep-tissue PDT (34 mW/cm2) was determined and the most robust permeability enhancement was achieved by administering the nanoparticles within 15 minutes following PDT treatment. Further, a two-step treatment strategy was developed and validated featuring the capability of improving the therapeutic efficacy of Doxil while simultaneously reducing its cardiotoxicity. This two-step treatment resulted in a tumor inhibition rate of 79% compared with 56% after Doxil treatment alone. These findings provide evidence in support of the clinical application of deep-tissue PDT for enhanced nano-drug delivery. PMID:27279907

  6. Ectopic expression a tomato KNOX Gene Tkn4 affects the formation and the differentiation of meristems and vasculature.

    PubMed

    Yan, Fang; Hu, Guojian; Ren, Zhenxin; Deng, Wei; Li, Zhengguo

    2015-12-01

    The KNOTTED-LIKE HOMEODOMAIN genes are involved in maintenance of the shoot apical meristem which produces the whole above-ground body of vascular plants. In this report, a tomato homolog gene, named as Tkn4 (a nucleus targeted transcription factor) was identified and characterized. By performing RT-PCR, the transcript level of Tkn4 was separately found in stem, root, stamen, stigma, fruit and sepal but hardly visible in the leaf. Besides, Tkn4 was induced by a series of plant hormones. Overexpression of Tkn4 gene in tomato resulted in dwarf phenotype and strongly repressed the formation of shoot apical meristem, lateral meristem and cambiums in transgenic lines. The transgenic lines had wrinkled leaves and anatomic analysis showed that there was no obvious palisade tissues in the leaves and the layer of cells changed in vascular tissue (xylem and phloem). To explore the regulation network of Tkn4, RNA-sequencing was performed in overexpression lines and wild type plants, by which many genes related to the synthesis and the signal transduction of cytokinin, auxin, gibberellin, ethylene, abscisic acid, and tracheary element differentiation or extracellular matrix synthesis were significantly regulated. Taken together, our results demonstrate that Tkn4 plays important roles in regulating the biosynthesis and signal transduction of diverse plant hormones, and the formation and differentiation of meristems and vasculature in tomato. PMID:26456092

  7. Specificity of peripheral nerve regeneration: interactions at the axon level.

    PubMed

    Allodi, Ilary; Udina, Esther; Navarro, Xavier

    2012-07-01

    Peripheral nerves injuries result in paralysis, anesthesia and lack of autonomic control of the affected body areas. After injury, axons distal to the lesion are disconnected from the neuronal body and degenerate, leading to denervation of the peripheral organs. Wallerian degeneration creates a microenvironment distal to the injury site that supports axonal regrowth, while the neuron body changes in phenotype to promote axonal regeneration. The significance of axonal regeneration is to replace the degenerated distal nerve segment, and achieve reinnervation of target organs and restitution of their functions. However, axonal regeneration does not always allows for adequate functional recovery, so that after a peripheral nerve injury, patients do not recover normal motor control and fine sensibility. The lack of specificity of nerve regeneration, in terms of motor and sensory axons regrowth, pathfinding and target reinnervation, is one the main shortcomings for recovery. Key factors for successful axonal regeneration include the intrinsic changes that neurons suffer to switch their transmitter state to a pro-regenerative state and the environment that the axons find distal to the lesion site. The molecular mechanisms implicated in axonal regeneration and pathfinding after injury are complex, and take into account the cross-talk between axons and glial cells, neurotrophic factors, extracellular matrix molecules and their receptors. The aim of this review is to look at those interactions, trying to understand if some of these molecular factors are specific for motor and sensory neuron growth, and provide the basic knowledge for potential strategies to enhance and guide axonal regeneration and reinnervation of adequate target organs. PMID:22609046

  8. Angioplasty and stent placement -- peripheral arteries

    MedlinePlus

    ... P. Peripheral arterial diseases. In: Mann DL, Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald's ... noncoronary obstructive vascular disease.In: Mann DL, Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald's ...

  9. [Sleep quality in aged patients with peripheral vascular diseases].

    PubMed

    Corrêa, Karina; Ceolim, Maria Filomena

    2008-03-01

    Peripheral vascular diseases (PVD) are prevalent among the elderly, and, due to their chronic character, result in poor quality of life and poor sleep quality. This study aimed at evaluating sleep quality of elderly people diagnosed with PVD who undergo clinical ambulatory treatment in a university hospital in Campinas, in the State of São Paulo. Subjects (n=50, aged 74 +/- 8 years old) answered the Pittsburgh Sleep Quality Index (PSQI) and provided basic demographic data and PVD history (35 subjects had arterial blockage in lower limbs). Results showed that 34 subjects presented bad sleep quality; sleep length was 5.8 (+/- 2.3) hours, and, according to 23 subjects, night sleep was frequently disturbed by pain (thrice a week or more). Eighteen subjects took analgesics; four took sleep medicines. Findings may have important implications for nurses working with PVD patients, stressing the need to take into account consequences of PVD on sleep disturbances when planning their interventions. PMID:18450142

  10. Inorganic arsenite alters macrophage generation from human peripheral blood monocytes

    SciTech Connect

    Sakurai, Teruaki . E-mail: sakurai@ls.toyaku.ac.jp; Ohta, Takami; Fujiwara, Kitao

    2005-03-01

    Inorganic arsenite has caused severe inflammatory chronic poisoning in humans through the consumption of contaminated well water. In this study, we examined the effects of arsenite at nanomolar concentrations on the in vitro differentiation of human macrophages from peripheral blood monocytes. While arsenite was found to induce cell death in a culture system containing macrophage colony stimulating factor (M-CSF), macrophages induced by granulocyte-macrophage CSF (GM-CSF) survived the treatment, but were morphologically, phenotypically, and functionally altered. In particular, arsenite-induced cells expressed higher levels of a major histocompatibility complex (MHC) class II antigen, HLA-DR, and CD14. They were more effective at inducing allogeneic or autologous T cell responses and responded more strongly to bacterial lipopolysaccharide (LPS) by inflammatory cytokine release as compared to cells induced by GM-CSF alone. On the other hand, arsenite-induced cells expressed lower levels of CD11b and CD54 and phagocytosed latex beads or zymosan particles less efficiently. We also demonstrated that the optimum amount of cellular reactive oxygen species (ROS) induced by nM arsenite might play an important role in this abnormal monocyte differentiation. This work may have implications in chronic arsenic poisoning because the total peripheral blood arsenic concentrations of these patients are at nM levels.

  11. Peripheral biomarkers of stroke: Focus on circulatory microRNAs.

    PubMed

    Vijayan, Murali; Reddy, P Hemachandra

    2016-10-01

    Stroke is the second leading cause of death in the world. Stroke occurs when blood flow stops, and that stoppage results in reduced oxygen supply to neurons in the brain. The occurrence of stroke increases with age, but anyone at any age can suffer from stroke. Recent research has implicated multiple cellular changes in stroke patients, including oxidative stress and mitochondrial dysfunction, inflammatory responses, and changes in mRNA and proteins. Recent research has also revealed that stroke is associated with modifiable and non-modifiable risk factors. Stroke can be controlled by modifiable risk factors, including diet, cardiovascular, hypertension, smoking, diabetes, obesity, metabolic syndrome, depression and traumatic brain injury. Stroke is the major risk factor for vascular dementia (VaD) and Alzheimer's disease (AD). The purpose of this article is to review the latest developments in research efforts directed at identifying 1) latest developments in identifying biomarkers in peripheral and central nervous system tissues, 2) changes in microRNAs (miRNAs) in patients with stroke, 3) miRNA profile and function in animal brain, and 4) protein biomarkers in ischemic stroke. This article also reviews research investigating circulatory miRNAs as peripheral biomarkers of stroke. PMID:27503360

  12. Peripheral hemangioblastoma: clinicopathologic characterization in a series of 22 cases.

    PubMed

    Doyle, Leona A; Fletcher, Christopher D M

    2014-01-01

    in 65% (13/20); they also expressed GLUT1 (7/10, mostly weak), SMA (4/5), epithelial membrane antigen (2/8, focal), PAX8 (1/10), and desmin (1/4). Brachyury was consistently negative (0/19), as were keratin, HMB-45, melan-A, and GFAP. CD31 and CD34 highlighted tumor vasculature. Follow-up information was available for 17 patients (range, 5 to 117 mo; median 36 mo). Three patients had locally persistent disease after incomplete resection. True local recurrence or distant metastasis has not been identified in any patient so far. One patient died of metastatic renal cell carcinoma. Peripheral hemangioblastoma is rare, often associated with VHL syndrome, and may mimic some malignant tumors. The immunohistochemical profile can aid diagnosis. Unresectable cases may be locally aggressive, but complete excision appears to be curative. Recognition of this tumor may identify patients in whom testing for VHL syndrome is warranted. PMID:24145646

  13. Perioperative lower extremity peripheral nerve traction injuries.

    PubMed

    Plastaras, Christopher T; Chhatre, Akhil; Kotcharian, Ashot S

    2014-01-01

    Peripheral nerve traction injuries may occur after surgical care and can involve any of the lower extremity large peripheral nerves. In this review, the authors discuss injuries after knee or hip surgical intervention. The diagnosis, including electrodiagnostic studies, is time sensitive and also relies on a detailed history and physical examination. Successful prevention and treatment involve familiarity with risk and predisposing factors as well as prophylactic measures. PMID:24267207

  14. Optical coherence tomography and hyperspectral imaging of vascular recovery in a model of peripheral arterial disease

    NASA Astrophysics Data System (ADS)

    Poole, Kristin M.; Sit, Wesley W.; Tucker-Schwartz, Jason M.; Duvall, Craig L.; Skala, Melissa C.

    2013-03-01

    Peripheral arterial disease (PAD) leads to an increased risk of myocardial infarction and stroke, increased mortality, and reduced quality of life. The mouse hind limb ischemia (HLI) model is the most commonly used system for studying the mechanisms of collateral vessel formation and for testing new PAD therapies, but there is a lack of techniques for acquiring physiologically-relevant, quantitative data intravitally in this model. In this work, non-invasive, quantitative optical imaging techniques were applied to the mouse HLI model over a time course. Optical coherence tomography (OCT) imaged changes in blood flow (Doppler OCT) and microvessel morphology (speckle variance OCT) through the skin of haired mice with high resolution. Hyperspectral imaging was also used to quantify blood oxygenation. In ischemic limbs, blood oxygenation in the footpad was substantially reduced after induction of ischemia followed by complete recovery by three weeks, consistent with standard measures. Three dimensional images of the vasculature distal to vessel occlusion acquired with speckle variance OCT revealed changes in OCT flow signal and vessel morphology. Taken together, OCT and hyperspectral imaging enable intravital acquisition of both functional and morphological data which fill critical gaps in understanding structure-function relationships that contribute to recovery in the mouse HLI model. Therefore, these optical imaging methods hold promise as tools for studying the mechanisms of vascular recovery and evaluating novel therapeutic treatments in preclinical studies.

  15. Macrophage-Induced Blood Vessels Guide Schwann Cell-Mediated Regeneration of Peripheral Nerves

    PubMed Central

    Cattin, Anne-Laure; Burden, Jemima J.; Van Emmenis, Lucie; Mackenzie, Francesca E.; Hoving, Julian J.A.; Garcia Calavia, Noelia; Guo, Yanping; McLaughlin, Maeve; Rosenberg, Laura H.; Quereda, Victor; Jamecna, Denisa; Napoli, Ilaria; Parrinello, Simona; Enver, Tariq; Ruhrberg, Christiana; Lloyd, Alison C.

    2015-01-01

    Summary The peripheral nervous system has remarkable regenerative capacities in that it can repair a fully cut nerve. This requires Schwann cells to migrate collectively to guide regrowing axons across a ‘bridge’ of new tissue, which forms to reconnect a severed nerve. Here we show that blood vessels direct the migrating cords of Schwann cells. This multicellular process is initiated by hypoxia, selectively sensed by macrophages within the bridge, which via VEGF-A secretion induce a polarized vasculature that relieves the hypoxia. Schwann cells then use the blood vessels as “tracks” to cross the bridge taking regrowing axons with them. Importantly, disrupting the organization of the newly formed blood vessels in vivo, either by inhibiting the angiogenic signal or by re-orienting them, compromises Schwann cell directionality resulting in defective nerve repair. This study provides important insights into how the choreography of multiple cell-types is required for the regeneration of an adult tissue. PMID:26279190

  16. Differential phase-contrast, swept-source optical coherence tomography at 1060 nm for in vivo human retinal and choroidal vasculature visualization

    NASA Astrophysics Data System (ADS)

    Motaghiannezam, S. M. Reza; Koos, David; Fraser, Scott E.

    2012-02-01

    Human retinal and choroidal vasculature was visualized by a differential phase-contrast (DPC) method using high-speed, swept-source optical coherence tomography (SS-OCT) at 1060 nm. The vasculature was recognized as regions of motion by creating differential phase-variance (DPV) tomograms: multiple B-scans of individual slices through the retina were collected and the variance of the phase differences was calculated. DPV captured the small vessels and the meshwork of capillaries associated with the inner retina in en-face images over 4 mm2. The swept-source laser at 1060 nm offered the needed phase sensitivity to perform DPV and generated en-face images that capture motion in the inner choroidal layer exceeding the capabilities of previous spectrometer-based instruments. In comparison with the power Doppler phase-shift method, DPV provided better visualization of the foveal avascular zone in en-face images.

  17. Diffuse traumatic brain injury induces prolonged immune dysregulation and potentiates hyperalgesia following a peripheral immune challenge

    PubMed Central

    Rowe, Rachel K; Ellis, Gavin I; Harrison, Jordan L; Bachstetter, Adam D; Corder, Gregory F; Van Eldik, Linda J; Taylor, Bradley K; Marti, Francesc

    2016-01-01

    Background Nociceptive and neuropathic pain occurs as part of the disease process after traumatic brain injury (TBI) in humans. Central and peripheral inflammation, a major secondary injury process initiated by the traumatic brain injury event, has been implicated in the potentiation of peripheral nociceptive pain. We hypothesized that the inflammatory response to diffuse traumatic brain injury potentiates persistent pain through prolonged immune dysregulation. Results To test this, adult, male C57BL/6 mice were subjected to midline fluid percussion brain injury or to sham procedure. One cohort of mice was analyzed for inflammation-related cytokine levels in cortical biopsies and serum along an acute time course. In a second cohort, peripheral inflammation was induced seven days after surgery/injury with an intraplantar injection of carrageenan. This was followed by measurement of mechanical hyperalgesia, glial fibrillary acidic protein and Iba1 immunohistochemical analysis of neuroinflammation in the brain, and flow cytometric analysis of T-cell differentiation in mucosal lymph. Traumatic brain injury increased interleukin-6 and chemokine ligand 1 levels in the cortex and serum that peaked within 1–9 h and then resolved. Intraplantar carrageenan produced mechanical hyperalgesia that was potentiated by traumatic brain injury. Further, mucosal T cells from brain-injured mice showed a distinct deficiency in the ability to differentiate into inflammation-suppressing regulatory T cells (Tregs). Conclusions We conclude that traumatic brain injury increased the inflammatory pain associated with cutaneous inflammation by contributing to systemic immune dysregulation. Regulatory T cells are immune suppressors and failure of T cells to differentiate into regulatory T cells leads to unregulated cytokine production which may contribute to the potentiation of peripheral pain through the excitation of peripheral sensory neurons. In addition, regulatory T cells are

  18. Peripheral Neuropathy in Rats Exposed to Dichloroacetate

    PubMed Central

    Calcutt, Nigel A.; Lopez, Veronica L.; Bautista, Arjel D.; Mizisin, Leah M.; Torres, Brenda R.; Shroads, Albert L.; Mizisin, Andrew P.; Stacpoole, Peter W.

    2009-01-01

    The use of dichloroacetate (DCA) for treating patients with mitochondrial diseases is limited by the induction of peripheral neuropathy. The mechanisms of DCA-induced neuropathy are not known. Oral DCA treatment (50–500 mg/kg/day for up to 16 weeks) induced tactile allodynia in both juvenile and adult rats; concurrent thermal hypoalgesia developed at higher doses. Both juvenile and adult rats treated with DCA developed nerve conduction slowing that was more pronounced in adult rats. No overt axonal or glial cell abnormalities were identified in peripheral nerves or spinal cord of any DCA-treated rats but morphometric analysis identified a reduction of mean axonal caliber of peripheral nerve myelinated fibers. DCA treatment also caused accumulation of oxidative stress markers in the nerves. These data indicate that behavioral, functional and structural indices of peripheral neuropathy may be induced in both juvenile and adult rats treated with DCA at doses similar to those in clinical use. DCA-induced peripheral neuropathy primarily afflicts axons and involves both metabolic and structural disorders. The DCA-treated rat may provide insight into the pathogenesis of peripheral neuropathy and facilitate development of adjuvant therapeutics to prevent this disorder that currently restricts the clinical use of DCA. PMID:19680144

  19. Identification of a Peptide from In vivo Bacteriophage Display with Homology to EGFL6: A Candidate Tumor Vasculature Ligand in Breast Cancer

    PubMed Central

    Larimer, Benjamin M; Deutscher, Susan L

    2015-01-01

    Background A crucial step in tumorigenesis is the recruitment of novel vasculature to the site of neoplasia. Currently, a number of high throughput techniques are employed to identify genes, mRNA and proteins that are aberrantly expressed in tumor vasculature. One drawback of such techniques is the lack of functional in vivo data that they provide. Bacteriophage (phage) display has been demonstrated in vivo to select peptides that home to tumors and tumor vasculature. The peptides can be compared to sequences of putative cancer-related proteins, in order to identify novel proteins essential for tumorigenesis. Objectives It was hypothesized that an in vivo selection for phage which targeted human breast cancer xenografts could identify peptides with homology to cancer-related proteins for in vivo imaging of breast cancer. Methods Following four rounds of in vivo selection in human MDA-MB-435 breast cancer xenografted mice, peptide 3-G03 was discovered with significant homology to a putative secreted protein termed EGFL6. Egfl6 mRNA is upregulated in several transcriptomic analyses of human cancer biopsies, and the protein may play a role in tumor vascularization. Results Egfl6 mRNA expression was demonstrated in MDA-MB-435 cells and EGFL6 protein was secreted from these cells. Based on homology of 3-G03 to EGFL6, an EGFL6 peptide was synthesized and shown to target MDA-MB-435 cells. EGFL6 peptide was radiolabeled with 111In and analyzed for biodistribution and tumor imaging capabilities. Single photon emission computed tomography imaging revealed uptake of the peptide in a manner consistent with other tumor vasculature targeting agents. PMID:26045973

  20. Naturally high plasma glucose levels in mourning doves (Zenaida macroura) do not lead to high levels of reactive oxygen species in the vasculature.

    PubMed

    Smith, Christina L; Toomey, Matthew; Walker, Benjimen R; Braun, Eldon J; Wolf, Blair O; McGraw, Kevin; Sweazea, Karen L

    2011-06-01

    Plasma glucose (P(Glu)) concentrations in birds are 1.5-2 times higher than those of mammals of similar body mass. In mammals, sustained elevations of P(Glu) lead to oxidative stress and free radical-mediated scavenging of endogenous vasodilators (e.g., nitric oxide), contributing to elevated blood pressure. Despite the relatively high P(Glu) levels in birds, they appear resistant to the development of oxidative stress in tissues such as the heart, brain and kidneys. To our knowledge no information exists on oxidative stress susceptibility in the resistance vasculature of birds. Therefore, we compared endogenous antioxidant mechanisms in the resistance vasculature of mourning doves (MODO; Zenaida macroura) and rats (Rattus norvegicus). Reactive oxygen species (ROS) were assessed with the fluorescent indicator 7'-dichlorodihydrofluorescein diacetate, acetyl ester in mesenteric arteries from rats and wild-caught MODO. Despite having significantly higher P(Glu) than rats, there were no significant differences in ROS levels between mesenteric arteries from rats or doves. Although superoxide dismutase and catalase activities were lower in the plasma, total antioxidant capacity, uric acid, vitamin E (α-tocopherol), and carotenoids (lutein and zeaxanthin) were significantly higher in MODO than in rats. Thus, compared to rats, MODO have multiple circulating antioxidants that may prevent the development of oxidative stress in the vasculature. PMID:21600747

  1. Peripheral vascular responses to fluorocarbon administration.

    PubMed

    Faithfull, N S; King, C E; Cain, S M

    1987-03-01

    To detect the local effect of hyperoxia on skeletal muscle vasculature, 2.5-ml boluses of oxygenated or deoxygenated fluorocarbon emulsion (F-O2 or F-N2) were washed through the hindlimb of anesthetized dogs at prevailing arterial pressure. Instantaneous hematocrit changes at the outflow were registered and stored in digital form with the red cells serving as the nondiffusible tracer in the resulting washout curves. A gamma density function was fitted and the gamma index (1/square root of alpha) was derived as a measure of skewness or perfusion heterogeneity. After recovery from the initial hypotensive reaction to fluorocarbon emulsion, washout curves for F-O2 and F-N2 were registered and blood samples were taken during 40 min of normoxia followed by 40 min of hypoxic hypoxia. The initial reaction to fluorocarbon significantly increased the gamma index so that the experiments began with a high index of perfusion heterogeneity in the limb vasculature. No significant difference was seen between F-O2 and F-N2 in normoxia but F-O2 maintained greater heterogeneity during hypoxia. The increased heterogeneity observed after the fluorocarbon reaction correlated highly with the severity of the hypotensive reaction which was also found to correlate inversely with the ability of the limb musculature to increase the O2 extraction ratio with onset of hypoxia. This blunting of microcirculatory reactivity to hyperoxia and hypoxia was attributed, in part, to the initial transient fluorocarbon reaction, possibly mediated by complement activation. PMID:3587075

  2. IF7-Conjugated Nanoparticles Target Annexin 1 of Tumor Vasculature against P-gp Mediated Multidrug Resistance.

    PubMed

    Yu, De-Hong; Liu, Ya-Rong; Luan, Xin; Liu, Hai-Jun; Gao, Yun-Ge; Wu, Hao; Fang, Chao; Chen, Hong-Zhuan

    2015-08-19

    Multidrug resistance is the main cause of clinical chemotherapeutic failure. Antiangiogenic cancer therapy with nanomedicine that allows the targeted delivery of antiangiogenic agents to tumor endothelial cells may contribute to innovative strategies for treating multidrug-resistant cancers. In this study, we developed a new nanodrug delivery system (nano-DDS), with improved antiangiogenic efficacy against multidrug resistant human breast cancer MCF-7/ADR cells. Here, the IF7 ligand was a peptide designed to bind the annexin 1 (Anxa 1), a highly specific marker of the tumor vasculature surface, with high affinity and specificity. IF7-conjugated Anxa 1-targeting nanoparticles containing paclitaxel (IF7-PTX-NP) allowed controlled drug release and displayed favorable prolonged circulation in vivo. IF7-PTX-NP was significantly internalized by human umbilical vein endothelial cells (HUVEC) through the IF7-Anxa 1 interaction, and this facilitated uptake enhanced the expected antiangiogenic activity of inhibiting HUVEC proliferation, migration, and tube formation in a Matrigel plug relative to those of Taxol and PTX-NP. As IF7-PTX-NP targeted the tumor vessels, more nanoparticles accumulated in MCF-7/ADR tumors, and more importantly, induced significant apoptosis of the tumor vascular endothelial cells and necrosis of the tumor tissues. Low dose paclitaxel (1 mg/kg) formulated in IF7-PTX-NP showed significant anticancer efficacy, delaying the growth of MCF-7/ADR tumors. The same efficacy was only obtained with an 8-fold dose of paclitaxel (8 mg/kg) as Taxol plus XR9576, a potent P-gp inhibitor. The anticancer efficacy of IF7-PTX-NP was strongly associated with the improved antiangiogenic effect, evident as a dramatic reduction in the tumor microvessel density and pronounced increase in apoptotic tumor cells, with no obvious toxicity to the mice. This nano-DDS, which targets the tumor neovasculature, offers a promising strategy for the treatment of multidrug

  3. Multi-timescale Modeling of Activity-Dependent Metabolic Coupling in the Neuron-Glia-Vasculature Ensemble

    PubMed Central

    Jolivet, Renaud; Coggan, Jay S.; Allaman, Igor; Magistretti, Pierre J.

    2015-01-01

    Glucose is the main energy substrate in the adult brain under normal conditions. Accumulating evidence, however, indicates that lactate produced in astrocytes (a type of glial cell) can also fuel neuronal activity. The quantitative aspects of this so-called astrocyte-neuron lactate shuttle (ANLS) are still debated. To address this question, we developed a detailed biophysical model of the brain’s metabolic interactions. Our model integrates three modeling approaches, the Buxton-Wang model of vascular dynamics, the Hodgkin-Huxley formulation of neuronal membrane excitability and a biophysical model of metabolic pathways. This approach provides a template for large-scale simulations of the neuron-glia-vasculature (NGV) ensemble, and for the first time integrates the respective timescales at which energy metabolism and neuronal excitability occur. The model is constrained by relative neuronal and astrocytic oxygen and glucose utilization, by the concentration of metabolites at rest and by the temporal dynamics of NADH upon activation. These constraints produced four observations. First, a transfer of lactate from astrocytes to neurons emerged in response to activity. Second, constrained by activity-dependent NADH transients, neuronal oxidative metabolism increased first upon activation with a subsequent delayed astrocytic glycolysis increase. Third, the model correctly predicted the dynamics of extracellular lactate and oxygen as observed in vivo in rats. Fourth, the model correctly predicted the temporal dynamics of tissue lactate, of tissue glucose and oxygen consumption, and of the BOLD signal as reported in human studies. These findings not only support the ANLS hypothesis but also provide a quantitative mathematical description of the metabolic activation in neurons and glial cells, as well as of the macroscopic measurements obtained during brain imaging. PMID:25719367

  4. Oxygen saturation measurements of the retinal vasculature in treated asymmetrical primary open-angle glaucoma using hyperspectral imaging

    PubMed Central

    Mordant, D J; Al-Abboud, I; Muyo, G; Gorman, A; Harvey, A R; McNaught, A I

    2014-01-01

    Purpose To determine whether there are differences in retinal vascular oxygen saturation measurements, estimated using a hyperspectral fundus camera, between normal eyes and treated eyes of subjects with asymmetrical primary open-angle glaucoma (POAG). Methods A noninvasive hyperspectral fundus camera was used to acquire spectral images of the retina at wavelengths between 556 and 650 nm in 2-nm increments. In total, 14 normal eyes and both eyes of 11 treated POAG subjects were imaged and analyzed using algorithms that use the spectral variation of the optical densities of blood vessels to estimate the oxygen saturation of blood within the retinal vasculature. In the treated POAG group, each of the eyes were categorized, based on the mean deviation of the Humphrey visual-field analyzer result, as either more-advanced or less-advanced, glaucomatous eyes. Unpaired t-tests (two-tailed) with Welch's correction were used to compare the mean oxygen saturation between the normal subjects and the treated POAG subgroups. Results In less-advanced and more-advanced-treated POAG eyes, mean retinal venular oxygen saturations (48.2±21.6% and 42.6±18.8%, respectively) were significantly higher than in normal eyes (27.9±9.9% P=0.03 and 0.01, respectively). Arteriolar oxygen saturation was not significantly different between normal eyes and treated POAG eyes. Conclusions The increased oxygen saturation of the retinal venules in advanced-treated POAG eyes may indicate reduced metabolic consumption of oxygen in the inner retinal tissues. PMID:25060843

  5. Imaging and Analytical Methods as Applied to the Evaluation of Vasculature and Hypoxia in Human Brain Tumors

    PubMed Central

    Evans, Sydney M.; Jenkins, Kevin W.; Jenkins, W. Timothy; Dilling, Thomas; Judy, Kevin D.; Schrlau, Amy; Judkins, Alexander; Hahn, Stephen M.; Koch, Cameron J.

    2008-01-01

    Tissue hypoxia results from the interaction of cellular respiration, vascular oxygen carrying capacity, and vessel distribution. We studied the relationship between tumor vasculature and regions of low pO2 using quantitative analysis of binding of the 2-nitroimidazole EF5 given to patients intravenously (21 mg/kg) approximately 24 h preceding surgery. We describe new computer algorithms for determining EF5 binding as a function of radial distance from individual blood vessels and converting this value to tissue pO2. Tissues from six human brain tumors were assessed. In a hemangiopericytoma, a WHO Grade 2 and WHO Grade 3 glial brain tumor, all tissue pO2 values calculated by EF5 binding were >20 mmHg (described as “physiologically oxygenated”). In these three tumors, EF5 binding gradients (measured as a function of distance from each observed vessel) were low, with small positive and negative values averaging close to zero. Much lower tissue oxygen levels were found, including near some vessels, in glioblastomas. Gradients of EF5 binding away from vessels were larger in glioblastomas than in the low-grade tumors, but positive and negative values again averaged to near zero. Based on these preliminary data, we hypothesize a new paradigm for tumor blood flow in human brain tumors whereby in-flowing and out-flowing blood patterns may have contrasting effects on average tissue EF5 (and by inference, oxygen) gradients. Our studies also imply that neither distance to the nearest blood vessel nor distance from each observed blood vessel provide reliable estimates of tissue pO2. PMID:19138031

  6. Sequestration of neutrophils in the hepatic vasculature during endotoxemia is independent of beta 2 integrins and intercellular adhesion molecule-1.

    PubMed

    Jaeschke, H; Farhood, A; Fisher, M A; Smith, C W

    1996-11-01

    Antibodies against cellular adhesion molecules protect against neutrophil-induced hepatic injury during ischemia-reperfusion and endotoxemia. To test if beta 2 integrins on neutrophils and intercellular adhesion molecule-1 (ICAM-1) on endothelial cells are involved in neutrophil sequestration in the hepatic vasculature, neutrophil accumulation in the liver was characterized during the early phase of endotoxemia. Intravenous injection of Salmonella enteritidis endotoxin induced a dose-dependent activation of complement, tumor necrosis factor-alpha (TNF-alpha) formation, and an increase of hepatic neutrophils with maximal numbers at 5 mg/kg (90 min: 339 +/- 14 cells/50 high power fields; controls: 18 +/- 2). Administration of 15 micrograms/kg TNF-alpha and intravascular complement activation with cobra venom factor (75 micrograms/kg) had additive effects on hepatic neutrophil accumulation compared with each mediator alone. Monoclonal antibodies (2 mg/kg) to ICAM-1 and the alpha-chain (CD11a, CD11b) or the beta-chain (CD18) of beta 2 integrins had no significant effect on hepatic neutrophil count after endotoxin. In contrast, these antibodies inhibited peritoneal neutrophil infiltration in response to glycogen administration by 28% (CD11b), 60% (CD11a, ICAM-1), and 92% (CD18). Our data suggest that TNF-alpha and complement factors contribute to hepatic neutrophil sequestration during the early phase of endotoxemia. Despite the fact that these inflammatory mediators can up-regulate integrins and ICAM-1, these adhesion molecules are not necessary for neutrophil accumulation in hepatic sinusoids. The protective effect of these antibodies against neutrophil-induced liver injury appears to be due to inhibition of transendothelial migration and adherence to parenchymal cells. PMID:8946651

  7. Multi-timescale modeling of activity-dependent metabolic coupling in the neuron-glia-vasculature ensemble.

    PubMed

    Jolivet, Renaud; Coggan, Jay S; Allaman, Igor; Magistretti, Pierre J

    2015-02-01

    Glucose is the main energy substrate in the adult brain under normal conditions. Accumulating evidence, however, indicates that lactate produced in astrocytes (a type of glial cell) can also fuel neuronal activity. The quantitative aspects of this so-called astrocyte-neuron lactate shuttle (ANLS) are still debated. To address this question, we developed a detailed biophysical model of the brain's metabolic interactions. Our model integrates three modeling approaches, the Buxton-Wang model of vascular dynamics, the Hodgkin-Huxley formulation of neuronal membrane excitability and a biophysical model of metabolic pathways. This approach provides a template for large-scale simulations of the neuron-glia-vasculature (NGV) ensemble, and for the first time integrates the respective timescales at which energy metabolism and neuronal excitability occur. The model is constrained by relative neuronal and astrocytic oxygen and glucose utilization, by the concentration of metabolites at rest and by the temporal dynamics of NADH upon activation. These constraints produced four observations. First, a transfer of lactate from astrocytes to neurons emerged in response to activity. Second, constrained by activity-dependent NADH transients, neuronal oxidative metabolism increased first upon activation with a subsequent delayed astrocytic glycolysis increase. Third, the model correctly predicted the dynamics of extracellular lactate and oxygen as observed in vivo in rats. Fourth, the model correctly predicted the temporal dynamics of tissue lactate, of tissue glucose and oxygen consumption, and of the BOLD signal as reported in human studies. These findings not only support the ANLS hypothesis but also provide a quantitative mathematical description of the metabolic activation in neurons and glial cells, as well as of the macroscopic measurements obtained during brain imaging. PMID:25719367

  8. Launching a Novel Preclinical Infrastructure: Comparative Oncology Trials Consortium Directed Therapeutic Targeting of TNFα to Cancer Vasculature

    PubMed Central

    Mazcko, Christina; Hanna, Engy; Kachala, Stefan; LeBlanc, Amy; Newman, Shelley; Vail, David; Henry, Carolyn; Thamm, Douglas; Sorenmo, Karin; Hajitou, Amin; Pasqualini, Renata; Arap, Wadih

    2009-01-01

    Background Under the direction and sponsorship of the National Cancer Institute, we report on the first pre-clinical trial of the Comparative Oncology Trials Consortium (COTC). The COTC is a novel infrastructure to integrate cancers that naturally develop in pet dogs into the development path of new human drugs. Trials are designed to address questions challenging in conventional preclinical models and early phase human trials. Large animal spontaneous cancer models can be a valuable addition to successful studies of cancer biology and novel therapeutic drug, imaging and device development. Methodology/Principal Findings Through this established infrastructure, the first trial of the COTC (COTC001) evaluated a targeted AAV-phage vector delivering tumor necrosis factor (RGD-A-TNF) to αV integrins on tumor endothelium. Trial progress and data was reviewed contemporaneously using a web-enabled electronic reporting system developed for the consortium. Dose-escalation in cohorts of 3 dogs (n = 24) determined an optimal safe dose (5×1012 transducing units intravenous) of RGD-A-TNF. This demonstrated selective targeting of tumor-associated vasculature and sparing of normal tissues assessed via serial biopsy of both tumor and normal tissue. Repetitive dosing in a cohort of 14 dogs, at the defined optimal dose, was well tolerated and led to objective tumor regression in two dogs (14%), stable disease in six (43%), and disease progression in six (43%) via Response Evaluation Criteria in Solid Tumors (RECIST). Conclusions/Significance The first study of the COTC has demonstrated the utility and efficiency of the established infrastructure to inform the development of new cancer drugs within large animal naturally occurring cancer models. The preclinical evaluation of RGD-A-TNF within this network provided valuable and necessary data to complete the design of first-in-man studies. PMID:19330034

  9. Phase Error Correction in Time-Averaged 3D Phase Contrast Magnetic Resonance Imaging of the Cerebral Vasculature

    PubMed Central

    MacDonald, M. Ethan; Forkert, Nils D.; Pike, G. Bruce; Frayne, Richard

    2016-01-01

    Purpose Volume flow rate (VFR) measurements based on phase contrast (PC)-magnetic resonance (MR) imaging datasets have spatially varying bias due to eddy current induced phase errors. The purpose of this study was to assess the impact of phase errors in time averaged PC-MR imaging of the cerebral vasculature and explore the effects of three common correction schemes (local bias correction (LBC), local polynomial correction (LPC), and whole brain polynomial correction (WBPC)). Methods Measurements of the eddy current induced phase error from a static phantom were first obtained. In thirty healthy human subjects, the methods were then assessed in background tissue to determine if local phase offsets could be removed. Finally, the techniques were used to correct VFR measurements in cerebral vessels and compared statistically. Results In the phantom, phase error was measured to be <2.1 ml/s per pixel and the bias was reduced with the correction schemes. In background tissue, the bias was significantly reduced, by 65.6% (LBC), 58.4% (LPC) and 47.7% (WBPC) (p < 0.001 across all schemes). Correction did not lead to significantly different VFR measurements in the vessels (p = 0.997). In the vessel measurements, the three correction schemes led to flow measurement differences of -0.04 ± 0.05 ml/s, 0.09 ± 0.16 ml/s, and -0.02 ± 0.06 ml/s. Although there was an improvement in background measurements with correction, there was no statistical difference between the three correction schemes (p = 0.242 in background and p = 0.738 in vessels). Conclusions While eddy current induced phase errors can vary between hardware and sequence configurations, our results showed that the impact is small in a typical brain PC-MR protocol and does not have a significant effect on VFR measurements in cerebral vessels. PMID:26910600

  10. Anti-endoglin monoclonal antibodies are effective for suppressing metastasis and the primary tumors by targeting tumor vasculature.

    PubMed

    Uneda, Shima; Toi, Hirofumi; Tsujie, Tomoko; Tsujie, Masanori; Harada, Naoko; Tsai, Hilda; Seon, Ben K

    2009-09-15

    Anti-metastatic activity of an antitumor agent is exceedingly important because metastasis is the primary cause of death for most solid cancer patients. In this report, we show that 3 anti-endoglin (ENG) monoclonal antibodies (mAbs) SN6a, SN6j and SN6k which define individually distinct epitopes of ENG of tumor vasculature are capable of suppressing tumor metastases in the multiple metastasis models. The metastasis models were generated by i.v., s.c. (into flank) or mammary gland fat pad injection of 4T1 murine mammary carcinoma cells and splenic injection of two types of colon26 murine colorectal carcinoma cells. Individual mAbs were injected i.v. via the tail vein of mice. SN6a and SN6j effectively suppressed the formation of metastatic colonies of 4T1 in the lung in all of the three 4T1 metastatic models. In addition, these mAbs were effective for suppressing the primary tumors of 4T1 in the skin and mammary fat pad. These mAbs effectively suppressed microvessel density and angiogenesis in tumors as measured by the Matrigel plug assay in mice. No significant side effects of the administered mAbs were detected. Furthermore, SN6a and SN6j extended survival of the tumor-bearing mice. SN6j, SN6k and their immunoconjugates with deglycosylated ricin A-chain were all effective for suppressing hepatic metastasis of colon26. The findings in the present study are clinically relevant in view of the ongoing clinical trial of a humanized (chimerized) form of SN6j. PMID:19533687

  11. In Vivo Targeting and Positron Emission Tomography Imaging of Tumor Vasculature with 66Ga-Labeled Nano-Graphene

    PubMed Central

    Hong, Hao; Zhang, Yin; Engle, Jonathan W.; Nayak, Tapas R.; Theuer, Charles P.; Nickles, Robert J.; Barnhart, Todd E.; Cai, Weibo

    2012-01-01

    The goal of this study was to employ nano-graphene for tumor targeting in an animal tumor model, and quantitatively evaluate the pharmacokinetics and tumor targeting efficacy through positron emission tomography (PET) imaging using 66Ga as the radiolabel. Nano-graphene oxide (GO) sheets with covalently linked, amino group-terminated six-arm branched polyethylene glycol (PEG; 10 kDa) chains were conjugated to NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid, for 66Ga-labeling) and TRC105 (an antibody that binds to CD105). Flow cytometry analyses, size measurements, and serum stability studies were performed to characterize the GO conjugates before in vivo investigations in 4T1 murine breast tumor-bearing mice, which were further validated by histology. TRC105-conjugated GO was specific for CD105 in cell culture. 66Ga-NOTA-GO-TRC105 and 66Ga-NOTA-GO exhibited excellent stability in complete mouse serum. In 4T1 tumor-bearing mice, these GO conjugates were primarily cleared through the hepatobiliary pathway. 66Ga-NOTA-GO-TRC105 accumulated quickly in the 4T1 tumors and tumor uptake remained stable over time (3.8 ± 0.4, 4.5 ± 0.4, 5.8 ± 0.3, and 4.5 ± 0.4 %ID/g at 0.5, 3, 7, and 24 h post-injection respectively; n = 4). Blocking studies with unconjugated TRC105 confirmed CD105 specificity of 66Ga-NOTA-GO-TRC105, which was corroborated by biodistribution and histology studies. Furthermore, histological examination revealed that targeting of NOTA-GO-TRC105 is tumor vasculature CD105 specific with little extravasation. Successful demonstration of in vivo tumor targeting with GO, along with the versatile chemistry of graphene-based nanomaterials, makes them suitable nanoplatforms for future biomedical research such as cancer theranostics. PMID:22386918

  12. In vivo photoacoustic imaging of nude mice vasculature using a photoacoustic imaging system based on a commercial ultrasound scanner

    NASA Astrophysics Data System (ADS)

    Jankovic, Ladislav; Shahzad, Khalid; Wang, Yao; Burcher, Michael; Scholle, Frank-Detlef; Hauff, Peter; Mofina, Sabine; Skobe, Mihaela

    2008-02-01

    In-vivo photoacoustic/ultrasound (PA/US) imaging of nude mice was investigated using a photoacoustic imaging system based on a commercial ultrasound scanner HDI-5000. Raw per-channel data was captured and beamformed to generate each individual photoacoustic image with a single laser shot. An ultra-broadband CL15-7 linear array with a center frequency of 8 MHz, combined with a Schott Glass fiber bundle, was used as a compact high resolution imaging probe, with lateral and axial PA resolutions of about 300µm and 200µm, respectively. The imaging system worked in a dual PA-US mode, with the ultrasound outlining the tissue structure and the photoacoustic image showing the blood vessels. PA signals were generated by exposing mice to ultra-short optical pulses from a Nd:YAG-pumped OPO laser operating in a wavelength range of 700-950nm. The corresponding ultrasound images were generated in the regular B-mode with standard delay-and-sum beamforming algorithm. The system resolution was sufficiently high to identify and clearly distinguish the dorsal artery and the two lateral veins in the mouse tail. Both the saphena artery and the ischiatic vein on the cross-section of the mouse leg were clearly outlined in the PA images and correctly overlaid on the ultrasound image of the tissue structure. Similarly, cross-section PA images of the mouse abdomen revealed mesenteric vasculatures located below the abdominal wall. Finally, a successful PA imaging of the mouse thoracic cavity unveiled the ascending and descending aorta. These initial results demonstrate a great potential for a dual photoacoustic/ultrasound imaging modality implemented on a commercial ultrasound imaging scanner.

  13. Peripheral Biomarkers Revisited: Integrative Profiling of Peripheral Samples for Psychiatric Research

    PubMed Central

    Hayashi-Takagi, Akiko; Vawter, Marquis P.; Iwamoto, Kazuya

    2016-01-01

    Peripheral samples, such as blood and skin, have been used for decades in psychiatric research as surrogates for central nervous system samples. Although the validity of the data obtained from peripheral samples has been questioned and other state-of-the-art techniques, such as human brain imaging, genomics, and induced pluripotent stem cells, seem to reduce the value of peripheral cells, accumulating evidence has suggested that revisiting peripheral samples is worthwhile. Here, we re-evaluate the utility of peripheral samples and argue that establishing an understanding of the common signaling and biological processes in the brain and peripheral samples is required for the validity of such models. First, we present an overview of the available types of peripheral cells and describe their advantages and disadvantages. We then briefly summarize the main achievements of omics studies, including epigenome, transcriptome, proteome, and metabolome analyses, as well as the main findings of functional cellular assays, the results of which imply that alterations in neurotransmission, metabolism, the cell cycle, and the immune system may be partially responsible for the pathophysiology of major psychiatric disorders such as schizophrenia. Finally, we discuss the future utility of peripheral samples for the development of biomarkers and tailor-made therapies, such as multimodal assays that are used as a battery of disease and trait pathways and that might be potent and complimentary tools for use in psychiatric research. PMID:24286759

  14. Surgical Technique for Repair of Peripheral Pulmonary Artery Stenosis and Other Complex Peripheral Reconstructions.

    PubMed

    Mainwaring, Richard D; Ibrahimiye, Ali N; Hanley, Frank L

    2016-08-01

    Surgical reconstruction of peripheral pulmonary artery stenosis is a technically challenging procedure due to the need to access all lobar and segmental branches. This paper describes our surgical approach that entails division of the main pulmonary and separation of the branch pulmonary arteries. This surgical approach can also be utilized for other complex peripheral pulmonary artery reconstructions. PMID:27449462

  15. Tissue engineered constructs for peripheral nerve surgery

    PubMed Central

    Johnson, P. J.; Wood, M. D.; Moore, A. M.; Mackinnon, S. E.

    2013-01-01

    Summary Background Tissue engineering has been defined as “an interdisciplinary field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function or a whole organ”. Traumatic peripheral nerve injury resulting in significant tissue loss at the zone of injury necessitates the need for a bridge or scaffold for regenerating axons from the proximal stump to reach the distal stump. Methods A review of the literature was used to provide information on the components necessary for the development of a tissue engineered peripheral nerve substitute. Then, a comprehensive review of the literature is presented composed of the studies devoted to this goal. Results Extensive research has been directed toward the development of a tissue engineered peripheral nerve substitute to act as a bridge for regenerating axons from the proximal nerve stump seeking the distal nerve. Ideally this nerve substitute would consist of a scaffold component that mimics the extracellular matrix of the peripheral nerve and a cellular component that serves to stimulate and support regenerating peripheral nerve axons. Conclusions The field of tissue engineering should consider its challenge to not only meet the autograft “gold standard” but also to understand what drives and inhibits nerve regeneration in order to surpass the results of an autograft. PMID:24385980

  16. Animal models of HIV peripheral neuropathy

    PubMed Central

    Burdo, Tricia H; Miller, Andrew D

    2014-01-01

    The use of animal models in the study of HIV and AIDS has advanced our understanding of the underlying pathophysiologic mechanisms of infection. Of the multitude of HIV disease manifestations, peripheral neuropathy remains one of the most common long-term side effects. Several of the most important causes of peripheral neuropathy in AIDS patients include direct association with HIV infection with or without antiretroviral medication and infection with opportunistic agents. Because the pathogeneses of these diseases are difficult to study in human patients, animal models have allowed for significant advancement in the understanding of the role of viral infection and the immune system in disease genesis. This review focuses on rodent, rabbit, feline and rhesus models used to study HIV-associated peripheral neuropathies, focusing specifically on sensory neuropathy and antiretroviral-associated neuropathies. PMID:25214880

  17. Vitamin B supplementation for diabetic peripheral neuropathy

    PubMed Central

    Jayabalan, Bhavani; Low, Lian Leng

    2016-01-01

    Vitamin B12 deficiency has been associated with significant neurological pathology, especially peripheral neuropathy. This review aims to examine the existing evidence on the effectiveness of vitamin B12 supplementation for the treatment of diabetic peripheral neuropathy. A search of PubMed and the Cochrane Central Register of Controlled Trials for all relevant randomised controlled trials was conducted in December 2014. Any type of therapy using vitamin B12 or its coenzyme forms was assessed for efficacy and safety in diabetics with peripheral neuropathy. Changes in vibration perception thresholds, neuropathic symptoms and nerve conduction velocities, as well as the adverse effects of vitamin B12 therapy, were assessed. Four studies comprising 363 patients met the inclusion criteria. This review found no evidence that the use of oral vitamin B12 supplements is associated with improvement in the clinical symptoms of diabetic neuropathy. Furthermore, the majority of studies reported no improvement in the electrophysiological markers of nerve conduction. PMID:26892473

  18. The Escherichia coli Peripheral Inner Membrane Proteome*

    PubMed Central

    Papanastasiou, Malvina; Orfanoudaki, Georgia; Koukaki, Marina; Kountourakis, Nikos; Sardis, Marios Frantzeskos; Aivaliotis, Michalis; Karamanou, Spyridoula; Economou, Anastassios

    2013-01-01

    Biological membranes are essential for cell viability. Their functional characteristics strongly depend on their protein content, which consists of transmembrane (integral) and peripherally associated membrane proteins. Both integral and peripheral inner membrane proteins mediate a plethora of biological processes. Whereas transmembrane proteins have characteristic hydrophobic stretches and can be predicted using bioinformatics approaches, peripheral inner membrane proteins are hydrophilic, exist in equilibria with soluble pools, and carry no discernible membrane targeting signals. We experimentally determined the cytoplasmic peripheral inner membrane proteome of the model organism Escherichia coli using a multidisciplinary approach. Initially, we extensively re-annotated the theoretical proteome regarding subcellular localization using literature searches, manual curation, and multi-combinatorial bioinformatics searches of the available databases. Next we used sequential biochemical fractionations coupled to direct identification of individual proteins and protein complexes using high resolution mass spectrometry. We determined that the proposed cytoplasmic peripheral inner membrane proteome occupies a previously unsuspected ∼19% of the basic E. coli BL21(DE3) proteome, and the detected peripheral inner membrane proteome occupies ∼25% of the estimated expressed proteome of this cell grown in LB medium to mid-log phase. This value might increase when fleeting interactions, not studied here, are taken into account. Several proteins previously regarded as exclusively cytoplasmic bind membranes avidly. Many of these proteins are organized in functional or/and structural oligomeric complexes that bind to the membrane with multiple interactions. Identified proteins cover the full spectrum of biological activities, and more than half of them are essential. Our data suggest that the cytoplasmic proteome displays remarkably dynamic and extensive communication with

  19. [Continuous peripheral regional analgesia in children].

    PubMed

    Lacroix, F

    2007-06-01

    Continuous peripheral nerve blocks (CPNB) have important role in the therapeutic arsenal, anaesthetic or analgesic in children. Indications for CPNB depend on benefits/risks analysis for each patient. The indications include surgery associated with intense postoperative pain, surgery requiring painful physical therapy, and complex regional pain syndrome. CPNB are usually performed under sedation or general anaesthesia, and require appropriate equipment in order to decrease the risk of nerve injury. Nevertheless, CPNB may mask compartment syndrome in trauma or certain surgical procedure. Finally, ropivacaine, and perhaps levobupivacaine, appears to be the best local anaesthetic for continuous peripheral nerve blocks in children, requiring low flow rate with low concentration. PMID:17543494

  20. Peripheral phlebitis: a point-prevalence study.

    PubMed

    Washington, Georgita T; Barrett, Robin

    2012-01-01

    The purpose of this research study was to determine the factors influencing peripheral phlebitis in the adult medical-surgical population. The authors would then be able to use those data to determine whether a change in practice was warranted. Data collection and analysis of 188 intravenous sites revealed that females with higher doses of medications in intravenous sites of longer dwell times and suboptimal nutrition were at greater risk of developing peripheral phlebitis. The point prevalence was greater than the recommended 5%, which led the authors to review their facility's patient care and documentation practices. PMID:22759829

  1. Familial multiple symmetric lipomatosis with peripheral neuropathy.

    PubMed

    Chalk, C H; Mills, K R; Jacobs, J M; Donaghy, M

    1990-08-01

    We describe coexisting peripheral neuropathy and multiple symmetric lipomatosis in 4 of 7 siblings. The absence of either condition in 3 other generations of this family suggests autosomal recessive inheritance. None of the affected siblings were alcoholic, a factor some have proposed to explain the frequent occurrence of peripheral neuropathy in sporadic multiple symmetric lipomatosis. Serum lipid studies, including apoprotein A levels, were normal. Sural nerve biopsy from 1 patient showed nerve fiber loss, predominantly affecting large myelinated fibers. The relationship between myelin sheath thickness and axon diameter was normal, arguing that this neuropathy is not due to primary axonal atrophy. PMID:2166247

  2. Ultrasound-Guided Peripheral Nerve Procedures.

    PubMed

    Strakowski, Jeffrey A

    2016-08-01

    Ultrasound guidance allows real-time visualization of the needle in peripheral nerve procedures, improving accuracy and safety. Sonographic visualization of the peripheral nerve and surrounding anatomy can provide valuable information for diagnostic purposes and procedure enhancement. Common procedures discussed are the suprascapular nerve at the suprascapular notch, deep branch of the radial nerve at the supinator, median nerve at the pronator teres and carpal tunnel, lateral cutaneous nerve of the thigh, superficial fibular nerve at the leg, tibial nerve at the ankle, and interdigital neuroma. For each procedure, the indications, relevant anatomy, preprocedural scanning technique, and injection procedure itself are detailed. PMID:27468673

  3. β-Secretase-1 elevation in aged monkey and Alzheimer's disease human cerebral cortex occurs around vasculature in partnership with multisystem axon terminal pathogenesis and β-amyloid accumulation

    PubMed Central

    Cai, Yan; Xiong, Kun; Zhang, Xue-Mei; Cai, Huaibin; Luo, Xue-Gang; Feng, Jia-Chun; Clough, Richard W.; Struble, Robert G.; Patrylo, Peter R.; Chu, Yaping; Kordower, Jeffrey H.; Yan, Xiao-Xin

    2010-01-01

    Alzheimer's disease (AD) is the most common dementia-causing disorder in the elderly, which may relate to multiple risk factors and is pathologically featured by cerebral hypometabolism, paravascular β-amyloid (Aβ) plaques, neuritic dystrophy and intra-neuronal aggregation of phosphorylated-tau. To explore potential pathogenic link among some of these lesions, we examined β-secretase-1 (BACE1) alteration relative to Aβ deposition, neuritic pathology and vascular organization in aged monkey and AD human cerebral cortex. Western blot analyses detected increased levels of BACE1 proteins and β-site-cleavage amyloid precursor protein C-terminal fragments in plaque-bearing human and monkey cortex relative to controls. In immunohistochemistry, locally elevated BACE1 immunoreactivity (IR) occurred in AD but not in control human cortex, with a trend of increased overall density among cases with greater plaque pathology. In double labeling preparations, BACE1 IR colocalized with immunolabeling for Aβ but not for phosphorylated tau. In perfusion-fixed monkey cortex, locally increased BACE1 IR co-existed with intra-axonal and extracellular Aβ IR among virtually all neuritic plaques ranging from primitive to typical cored forms. This BACE1 labeling localized to swollen/sprouting axon terminals that might co-express one or another neuronal phenotype marker (GABAergic, glutamatergic, cholinergic or catecholaminergic). Importantly, these BACE1-labeled dystrophic axons resided near or in direct contact with blood vessels. These finds implicate that plaque formation in AD or normal aging primates relate to a multisystem axonal pathogenesis that occurs in partnership with potential vascular or metabolic deficit. The data provide a tangible mechanistic explanation as to why senile plaques are present preferentially near cerebral vasculature. PMID:20726888

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

    PubMed

    Foote, A P; Harmon, D L; Brown, K R; Strickland, J R; McLeod, K R; Bush, L P; Klotz, J L

    2012-05-01

    .31). Extrapolated maximum response was greatest in the saphenous vein for ergovaline, least for E+EXT, and intermediate for ALK (P < 0.0001). The E-EXT did not induce a contractile response in any vessel tested (P > 0.1). Data from this study indicate that ergovaline is largely responsible for the locally induced vasoconstriction of bovine vasculature observed with endophyte-infected tall fescue. PMID:22147482

  5. Endothelin-1-induced alterations in phenylephrine-induced contractile responses are largely additive in physiologically diverse rabbit vasculature.

    PubMed

    Gondré, M; Christ, G J

    1998-08-01

    , comparison of the "expected" contractile response with the "observed" response represents an important first step toward establishing a more uniform nomenclature for describing the physiological/pathophysiological effects of mixtures of drugs on diverse vasculature. PMID:9694914

  6. Autotaxin and LPA Receptors Represent Potential Molecular Targets for the Radiosensitization of Murine Glioma through Effects on Tumor Vasculature

    PubMed Central

    Linkous, Amanda G.; Hu, Rong; Leahy, Kathleen M.; Yazlovitskaya, Eugenia M.; Hallahan, Dennis E.

    2011-01-01

    Despite wide margins and high dose irradiation, unresectable malignant glioma (MG) is less responsive to radiation and is uniformly fatal. We previously found that cytosolic phospholipase A2 (cPLA2) is a molecular target for radiosensitizing cancer through the vascular endothelium. Autotaxin (ATX) and lysophosphatidic acid (LPA) receptors are downstream from cPLA2 and highly expressed in MG. Using the ATX and LPA receptor inhibitor, α-bromomethylene phosphonate LPA (BrP-LPA), we studied ATX and LPA receptors as potential molecular targets for the radiosensitization of tumor vasculature in MG. Treatment of Human Umbilical Endothelial cells (HUVEC) and mouse brain microvascular cells bEND.3 with 5 µmol/L BrP-LPA and 3 Gy irradiation showed decreased clonogenic survival, tubule formation, and migration. Exogenous addition of LPA showed radioprotection that was abrogated in the presence of BrP-LPA. In co-culture experiments using bEND.3 and mouse GL-261 glioma cells, treatment with BrP-LPA reduced Akt phosphorylation in both irradiated cell lines and decreased survival and migration of irradiated GL-261 cells. Using siRNA to knock down LPA receptors LPA1, LPA2 or LPA3 in HUVEC, we demonstrated that knockdown of LPA2 but neither LPA1 nor LPA3 led to increased viability and proliferation. However, knockdown of LPA1 and LPA3 but not LPA2 resulted in complete abrogation of tubule formation implying that LPA1 and LPA3 on endothelial cells are likely targets of BrP-LPA radiosensitizing effect. Using heterotopic tumor models of GL-261, mice treated with BrP-LPA and irradiation showed a tumor growth delay of 6.8 days compared to mice treated with irradiation alone indicating that inhibition of ATX and LPA receptors may significantly improve malignant glioma response to radiation therapy. These findings identify ATX and LPA receptors as molecular targets for the development of radiosensitizers for MG. PMID:21799791

  7. Radiation-induced malignant and atypical peripheral nerve sheath tumors

    SciTech Connect

    Foley, K.M.; Woodruff, J.M.; Ellis, F.T.; Posner, J.B.

    1980-04-01

    The reported peripheral nerve complications of therapeutic irradiation in humans include brachial and lumbar plexus fibrosis and cranial and peripheral nerve atrophy. We have encountered 9 patients with malignant (7) and atypical (2) peripheral nerve tumors occurring in an irradiated site suggesting that such tumors represent another delayed effect of radiation treatment on peripheral nerve. In all instances the radio-theray was within an acceptable radiation dosage, yet 3 patients developed local radiation-induced skin and bony abnormalities. The malignant peripheral nerve sheath tumors developed only in the radiation port. Animal studies support the clinical observation that malignant peripheral nerve sheath tumors can occur as a delayed effect of irradiation.

  8. Drugs for the treatment of peripheral neuropathies.

    PubMed

    Marmiroli, Paola; Cavaletti, Guido

    2016-01-01

    Peripheral neuropathies are frequent in association with systemic diseases as well as isolated disorders. Recent advances in the therapy of specific neuropathies led to the approval of new drugs/treatments. This review selected those peripheral neuropathies where the most recent approvals were provided and revised the potential future developments in diabetic and toxic-induced neuropathies, although they do not have a currently available causal therapy in view of their epidemiological and social relevance. Data have been extracted from the most important published trials and from clinical experience. In addition, data from the Food and Drug Administration and European Medicine Agency indications on the treatment of the selected peripheral neuropathies and from recently updated international guidelines have also been included. The website of the U.S. National Institutes of Health www.clinicaltrials.gov registry has been used as the reference database for phase III clinical trials not yet published or ongoing. This review gives a general overview of the most recent advances in the treatment of amyloid, inflammatory, and paraproteinemic peripheral neuropathies. Moreover, it briefly describes the unmet medical need in disabling and frequent conditions, such as diabetic and chemotherapy-induced neuropathy, highlighting the most promising therapeutic approaches to their treatment. PMID:26567516

  9. Massive exophytic malignant peripheral nerve sheath tumor.

    PubMed

    Khorsand, Derek; Porrino, Jack; Flaherty, Erin; Bandhlish, Anshu; Davidson, Darin

    2016-06-01

    We present a case of a solitary neurofibroma involving the right posterior shoulder of a 69-year-old man with degeneration into a massive, malignant peripheral nerve sheath tumor measuring more than 3 times the average reported size. The radiographic, magnetic resonance imaging, and computed tomographic features are compared with the gross appearance and pathology. PMID:27257459

  10. Peripheral Mechanisms of Pain and Analgesia

    PubMed Central

    Stein, Christoph; Clark, J. David; Oh, Uhtaek; Vasko, Michael R.; Wilcox, George L.; Overland, Aaron C.; Vanderah, Todd W.; Spencer, Robert H.

    2009-01-01

    This review summarizes recent findings on peripheral mechanisms underlying the generation and inhibition of pain. The focus is on events occurring in peripheral injured tissues that lead to the sensitization and excitation of primary afferent neurons, and on the modulation of such mechanisms. Primary afferent neurons are of particular interest from a therapeutic perspective because they are the initial generator of noxious impulses traveling towards relay stations in the spinal cord and the brain. Thus, if one finds ways to inhibit the sensitization and/or excitation of peripheral sensory neurons, subsequent central events such as wind-up, sensitization and plasticity may be prevented. Most importantly, if agents are found that selectively modulate primary afferent function and do not cross the blood-brain-barrier, centrally mediated untoward side effects of conventional analgesics (e.g. opioids, anticonvulsants) may be avoided. This article begins with the peripheral actions of opioids, turns to a discussion of the effects of adrenergic co-adjuvants, and then moves on to a discussion of pro-inflammatory mechanisms focusing on TRP channels and nerve growth factor, their signaling pathways and arising therapeutic perspectives. PMID:19150465

  11. Peripheral nerve regeneration and neurotrophic factors

    PubMed Central

    TERENGHI, GIORGIO

    1999-01-01

    The role of neurotrophic factors in the maintenance and survival of peripheral neuronal cells has been the subject of numerous studies. Administration of exogenous neurotrophic factors after nerve injury has been shown to mimic the effect of target organ-derived trophic factors on neuronal cells. After axotomy and during peripheral nerve regeneration, the neurotrophins NGF, NT-3 and BDNF show a well defined and selective beneficial effect on the survival and phenotypic expression of primary sensory neurons in dorsal root ganglia and of motoneurons in spinal cord. Other neurotrophic factors such as CNTF, GDNF and LIF also exert a variety of actions on neuronal cells, which appear to overlap and complement those of the neurotrophins. In addition, there is an indirect contribution of GGF to nerve regeneration. GGF is produced by neurons and stimulates proliferation of Schwann cells, underlining the close interaction between neuronal and glial cells during peripheral nerve regeneration. Different possibilities have been investigated for the delivery of growth factors to the injured neurons, in search of a suitable system for clinical applications. The studies reviewed in this article show the therapeutic potential of neurotrophic factors for the treatment of peripheral nerve injury and for neuropathies. PMID:10227662

  12. Legitimate Peripheral Participation and Home Education

    ERIC Educational Resources Information Center

    Safran, L.

    2010-01-01

    After a description of home education, Lave and Wenger's (1991) theory of legitimate peripheral participation (LPP) is applied to the situation of home educators who join a neighbourhood home education group, a community of practice. Then, it is argued that the theory of LPP, with suitable modification, can also apply to and illuminate the…

  13. Chapter 11: Tissue engineering of peripheral nerves.

    PubMed

    Battiston, Bruno; Raimondo, Stefania; Tos, Pierluigi; Gaidano, Valentina; Audisio, Chiara; Scevola, Anna; Perroteau, Isabelle; Geuna, Stefano

    2009-01-01

    Tissue engineering of peripheral nerves has seen an increasing interest over the last years and, similarly to many other fields of regenerative medicine, great expectations have risen within the general public to its potential clinical application in the treatment of damaged nerves. However, in spite of the scientific advancements, applications to the patients is still very limited and it appears that to optimize the strategy for the tissue engineering of the peripheral nerves in the clinical view, researchers have to strive for a new level of innovation which will bring together (in a multitranslational approach) the main pillars of tissue engineering: namely (1) microsurgery, (2) cell and tissue transplantation, (3) material science, and (4) gene transfer. This review paper provides an overview of these four key approaches to peripheral nerve tissue engineering. While some of these issues will also be specifically addressed in other papers in this special issue on peripheral nerve regeneration of the International Review of Neurobiology, in this paper we will focus on an example of successful translational research in tissue engineering, namely nerve reconstruction by muscle-vein-combined nerve scaffolds. PMID:19682640

  14. Reproducibility and repeatability of peripheral microvascular assessment using iontophoresis in conjunction with laser Doppler imaging.

    PubMed

    Jadhav, Sachin; Sattar, Naveed; Petrie, John R; Cobbe, Stuart M; Ferrell, William R

    2007-09-01

    Interrogation of peripheral vascular function is increasingly recognized as a noninvasive surrogate marker for coronary vascular function and carries with it important prognostic information regarding future cardiovascular risk. Laser Doppler imaging (LDI) is a completely noninvasive method for looking at peripheral microvascular function. We sought to look at reproducibility and repeatability of LDI-derived assessment of peripheral microvascular function between arms and 8 weeks apart. We used LDI in conjunction with iontophoretic application of ACh and SNP to look at endothelium-dependent and -independent microvascular function, respectively, in a mixture of women with cardiac syndrome X and healthy volunteers. We looked at variation between arms (n = 40) and variation at 8 weeks apart (n = 22). When measurements were corrected for skin resistance, there was nonsignificant variation between arms for ACh (2.7%) and SNP (3.8%) and nonsignificant temporal variation for ACh (3.5%) and SNP (4.7%). Construction of Bland-Altman plots reinforce that measurements have good repeatability. Elimination of the baseline perfusion response had deleterious effects on repeatability. LDI can be used to assess peripheral vascular response with good repeatability as long as measurements are corrected for skin resistance, which affects drug delivery. This has important implications for the future use of LDI. PMID:17878765

  15. Synthesis and comparative evaluation of novel (64)Cu-labeled high affinity cell-specific peptides for positron emission tomography imaging of tumor vasculature.

    PubMed

    Merrill, Joseph R; Krajewski, Krzysztof; Yuan, Hong; Frank, Jonathan E; Lalush, David S; Patterson, Cam; Veleva, Anka N

    2016-04-01

    Tumor angiogenesis, the formation of new tumor blood supply, has been recognized as a hallmark of cancer and represents an important target for clinical management of various angiogenesis-dependent solid tumors. Previously, by screening a bacteriophage peptide library we have discovered the FHT-peptide sequence that binds specifically to bone marrow-derived tumor vasculature with high affinity. Here in an effort to determine the potential of the FHT-peptide for in vivo positron emission tomography (PET) imaging of aggressive tumor vasculature we studied four FHT-derivatives: NOTA-FHT, NOTA-(FHT)2, NOTA-PEG-FHT, and NOTA-PEG-(FHT)2. These peptide analogs were synthesized, labeled with the PET radionuclide (64)Cu, and characterized side-by-side with small animal PET and computed tomography imaging (microPET/CT) at 1 h, 4 h, and 24 h post injection in a subcutaneous Lewis lung carcinoma (LLC) tumor model. Because of its excellent in vivo kinetic properties and high tumor-to-background ratio, the (64)Cu-NOTA-FHT radiopeptide was selected for more detailed evaluation. Blocking studies with excess of unlabeled peptide showed specific and peptide mediated (64)Cu-NOTA-FHT tumor uptake. Biodistribution experiments in the same tumor model confirmed microPET/CT imaging results. Human radiation absorbed dose extrapolated from rodent biodistribution of (64)Cu-NOTA-FHT revealed favorable dosimetry profile. The findings from this investigation warrant further development of (64)Cu-NOTA-FHT as a potential targeted diagnostic radiopharmaceutical for PET imaging of aggressive tumor vasculature. PMID:26839954

  16. Inflammatory Cytokines, Endothelial Function, and Chronic Allograft Vasculopathy in Children: An Investigation of the Donor and Recipient Vasculature After Heart Transplantation.

    PubMed

    Fenton, M; Simmonds, J; Shah, V; Brogan, P; Klein, N; Deanfield, J; Burch, M

    2016-05-01

    Chronic allograft vasculopathy (CAV) limits the lifespan of pediatric heart transplant recipients. We investigated blood markers of inflammation, endothelial dysfunction, and damage to both the native and transplanted vasculature in children after heart transplantation. Serum samples were taken from pediatric heart transplant recipients for markers of inflammation and endothelial activation. The systemic vasculature was investigated using brachial artery flow-mediated dilatation and carotid artery intima-medial hyperplasia. CAV was investigated using intravascular ultrasound. Mean intima-media thickness (mIMT) > 0.5 mm was used to define significant CAV. Forty-eight children (25 male) aged 8-18 years were enrolled in the study. Patients were a median (interquartile range) 4.1 (2.2-8.7) years after transplant. Patients had increased levels of circulating IL6 (3.86 [2.84-4.95] vs. 1.66 [1.22-2.63] p < 0.0001), vascular cell adhesion molecule 1 (539 [451-621] vs. 402 [342-487] p < 0.001), intracellular adhesion molecule 1 305 (247-346) vs. 256 (224-294) p = 0.002 and thrombomodulin (7.1 [5.5-8.1] vs. 3.57 [3.03-4.71] p < 0.0001) and decreased levels of tumor necrosis factor-α, E selectin, and P selectin, compared with controls. The systemic vasculature was unaffected. Patients with severe CAV had raised serum von Willebrand factor and decreased serum thrombomodulin. Posttransplant thrombomodulin levels are elevated after transplant but significantly lower in those with mIMT > 0.5 mm. This suggests that subclinical inflammation is present and that natural anticoagulant/thrombomodulin activity is important after transplant. PMID:26614396

  17. Rhythmic expression of cytochrome P450 epoxygenases CYP4x1 and CYP2c11 in the rat brain and vasculature.

    PubMed

    Carver, Koryn A; Lourim, David; Tryba, Andrew K; Harder, David R

    2014-12-01

    Mammals have circadian variation in blood pressure, heart rate, vascular tone, thrombotic tendency, and cerebral blood flow (CBF). These changes may be in part orchestrated by circadian variation in clock gene expression within cells comprising the vasculature that modulate blood flow (e.g., fibroblasts, cerebral vascular smooth muscle cells, astrocytes, and endothelial cells). However, the downstream mechanisms that underlie circadian changes in blood flow are unknown. Cytochrome P450 epoxygenases (Cyp4x1 and Cyp2c11) are expressed in the brain and vasculature and metabolize arachidonic acid (AA) to form epoxyeicosatrienoic acids (EETs). EETs are released from astrocytes, neurons, and vascular endothelial cells and act as potent vasodilators, increasing blood flow. EETs released in response to increases in neural activity evoke a corresponding increase in blood flow known as the functional hyperemic response. We examine the hypothesis that Cyp2c11 and Cyp4x1 expression and EETs production vary in a circadian manner in the rat brain and cerebral vasculature. RT-PCR revealed circadian/diurnal expression of clock and clock-controlled genes as well as Cyp4x1 and Cyp2c11, within the rat hippocampus, middle cerebral artery, inferior vena cava, hippocampal astrocytes and rat brain microvascular endothelial cells. Astrocyte and endothelial cell culture experiments revealed rhythmic variation in Cyp4x1 and Cyp2c11 gene and protein expression with a 12-h period and parallel rhythmic production of EETs. Our data suggest there is circadian regulation of Cyp4x1 and Cyp2c11 gene expression. Such rhythmic EETs production may contribute to circadian changes in blood flow and alter risk of adverse cardiovascular events throughout the day. PMID:25055826

  18. Endothelial Dysfunction in Mice with Streptozotocin-induced Type 1 Diabetes Is Opposed by Compensatory Overexpression of Cyclooxygenase-2 in the Vasculature

    PubMed Central

    Nacci, Carmela; Tarquinio, Mariela; De Benedictis, Leonarda; Mauro, Annamaria; Zigrino, Addolorata; Carratù, Maria Rosaria; Quon, Michael J.; Montagnani, Monica

    2009-01-01

    Cardiovascular complications of diabetes result from endothelial dysfunction secondary to persistent hyperglycemia. We investigated potential compensatory mechanisms in the vasculature that oppose endothelial dysfunction in diabetes. BALB/c mice were treated with streptozotocin (STZ) to induce type 1 diabetes (T1D). In mesenteric vascular beds (MVBs), isolated ex vivo from mice treated with STZ for 1 wk, dose-dependent vasorelaxation to acetylcholine (ACh) or sodium nitroprusside was comparable with that in age-matched control mice (CTRL). By contrast, MVBs from mice treated with STZ for 8 wk had severely impaired vasodilator responses to ACh consistent with endothelial dysfunction. Pretreatment of MVBs from CTRL mice with nitric oxide synthase inhibitor nearly abolished vasodilation to ACh. In MVB from 1-wk STZ-treated mice, vasodilation to ACh was only partially impaired by L-Nω-arginine methyl ester. Thus, vasculature of mice with T1D may have compensatory nitric oxide-independent mechanisms to augment vasodilation to ACh and oppose endothelial dysfunction. Indeed, pretreatment of MVBs isolated from 1-wk STZ-treated mice with NS-398 [selective cyclooxygenase (COX)-2 inhibitor] unmasked endothelial dysfunction not evident in CTRL mice pretreated without or with NS-398. Expression of COX-2 in MVBs, aortic endothelial cells, and aortic vascular smooth muscle cells from STZ-treated mice was significantly increased (vs. CTRL). Moreover, concentrations of the COX-2-dependent vasodilator 6-keto-prostaglandin F-1α was elevated in conditioned media from aorta of STZ-treated mice. We conclude that endothelial dysfunction in a mouse model of T1D is opposed by compensatory up-regulation of COX-2 expression and activity in the vasculature that may be relevant to developing novel therapeutic strategies for diabetes and its cardiovascular complications. PMID:18845644

  19. Decreased brain venous vasculature visibility on susceptibility-weighted imaging venography in patients with multiple sclerosis is related to chronic cerebrospinal venous insufficiency

    PubMed Central

    2011-01-01

    Background The potential pathogenesis between the presence and severity of chronic cerebrospinal venous insufficiency (CCSVI) and its relation to clinical and imaging outcomes in brain parenchyma of multiple sclerosis (MS) patients has not yet been elucidated. The aim of the study was to investigate the relationship between CCSVI, and altered brain parenchyma venous vasculature visibility (VVV) on susceptibility-weighted imaging (SWI) in patients with MS and in sex- and age-matched healthy controls (HC). Methods 59 MS patients, 41 relapsing-remitting and 18 secondary-progressive, and 33 HC were imaged on a 3T GE scanner using pre- and post-contrast SWI venography. The presence and severity of CCSVI was determined using extra-cranial and trans-cranial Doppler criteria. Apparent total venous volume (ATVV), venous intracranial fraction (VIF) and average distance-from-vein (DFV) were calculated for various vein mean diameter categories: < .3 mm, .3-.6 mm, .6-.9 mm and > .9 mm. Results CCSVI criteria were fulfilled in 79.7% of MS patients and 18.2% of HC (p < .0001). Patients with MS showed decreased overall ATVV, ATVV of veins with a diameter < .3 mm, and increased DFV compared to HC (all p < .0001). Subjects diagnosed with CCSVI had significantly increased DFV (p < .0001), decreased overall ATVV and ATVV of veins with a diameter < .3 mm (p < .003) compared to subjects without CCSVI. The severity of CCSVI was significantly related to decreased VVV in MS (p < .0001) on pre- and post-contrast SWI, but not in HC. Conclusions MS patients with higher number of venous stenoses, indicative of CCSVI severity, showed significantly decreased venous vasculature in the brain parenchyma. The pathogenesis of these findings has to be further investigated, but they suggest that reduced metabolism and morphological changes of venous vasculature may be taking place in patients with MS. PMID:22011402

  20. The choroid plexus response to a repeated peripheral inflammatory stimulus

    PubMed Central

    2009-01-01

    Background Chronic systemic inflammation triggers alterations in the central nervous system that may relate to the underlying inflammatory component reported in neurodegenerative disorders such as multiple sclerosis and Alzheimer's disease. However, it is far from being understood whether and how peripheral inflammation contributes to induce brain inflammatory response in such illnesses. As part of the barriers that separate the blood from the brain, the choroid plexus conveys inflammatory immune signals into the brain, largely through alterations in the composition of the cerebrospinal fluid. Results In the present study we investigated the mouse choroid plexus gene expression profile, using microarray analyses, in response to a repeated inflammatory stimulus induced by the intraperitoneal administration of lipopolysaccharide every two weeks for a period of three months; mice were sacrificed 3 and 15 days after the last lipopolysaccharide injection. The data show that the choroid plexus displays a sustained response to the repeated inflammatory stimuli by altering the expression profile of several genes. From a total of 24,000 probes, 369 are up-regulated and 167 are down-regulated 3 days after the last lipopolysaccharide injection, while at 15 days the number decreases to 98 and 128, respectively. The pathways displaying the most significant changes include those facilitating entry of cells into the cerebrospinal fluid, and those participating in the innate immune response to infection. Conclusion These observations contribute to a better understanding of the brain response to peripheral inflammation and pave the way to study their impact on the progression of several disorders of the central nervous system in which inflammation is known to be implicated. PMID:19922669