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Sample records for brain blood muscle

  1. Mercury in human brain, blood, muscle and toenails in relation to exposure: an autopsy study

    Directory of Open Access Journals (Sweden)

    Morild Inge

    2007-10-01

    Full Text Available Abstract Background The main forms of mercury (Hg exposure in the general population are methylmercury (MeHg from seafood, inorganic mercury (I-Hg from food, and mercury vapor (Hg0 from dental amalgam restorations. While the distribution of MeHg in the body is described by a one compartment model, the distribution of I-Hg after exposure to elemental mercury is more complex, and there is no biomarker for I-Hg in the brain. The aim of this study was to elucidate the relationships between on the one hand MeHg and I-Hg in human brain and other tissues, including blood, and on the other Hg exposure via dental amalgam in a fish-eating population. In addition, the use of blood and toenails as biological indicator media for inorganic and organic mercury (MeHg in the tissues was evaluated. Methods Samples of blood, brain (occipital lobe cortex, pituitary, thyroid, abdominal muscle and toenails were collected at autopsy of 30 deceased individuals, age from 47 to 91 years of age. Concentrations of total-Hg and I-Hg in blood and brain cortex were determined by cold vapor atomic fluorescence spectrometry and total-Hg in other tissues by sector field inductively coupled plasma-mass spectrometry (ICP-SFMS. Results The median concentrations of MeHg (total-Hg minus I-Hg and I-Hg in blood were 2.2 and 1.0 μg/L, and in occipital lobe cortex 4 and 5 μg/kg, respectively. There was a significant correlation between MeHg in blood and occipital cortex. Also, total-Hg in toenails correlated with MeHg in both blood and occipital lobe. I-Hg in both blood and occipital cortex, as well as total-Hg in pituitary and thyroid were strongly associated with the number of dental amalgam surfaces at the time of death. Conclusion In a fish-eating population, intake of MeHg via the diet has a marked impact on the MeHg concentration in the brain, while exposure to dental amalgam restorations increases the I-Hg concentrations in the brain. Discrimination between mercury species is

  2. Effects of Changes in Colored Light on Brain and Calf Muscle Blood Concentration and Oxygenation

    Directory of Open Access Journals (Sweden)

    J. Weinzirl

    2011-01-01

    Full Text Available Color light therapy is a therapeutic method in complementary medicine. In color therapy, light of two contrasting colors is often applied in a sequential order. The aim of this study was to investigate possible physiological effects, i.e., changes in the blood volume and oxygenation in the brain and calf muscle of healthy subjects who were exposed to red and blue light in sequential order. The hypothesis was that if a subject is first exposed to blue and then red light, the effect of the red light will be enhanced due to the contrastingly different characteristics of the two colors. The same was expected for blue light, if first exposing a subject to red and then to blue light. Twelve healthy volunteers (six male, six female were measured twice on two different days by near-infrared spectroscopy during exposure to colored light. Two sequences of colored light were applied in a controlled, randomized, crossover design: first blue, then red, and vice versa. For the brain and muscle, the results showed no significant differences in blood volume and oxygenation between the two sequences, and a high interindividual physiological variability. Thus, the hypothesis had to be rejected. Comparing these data to results from a previous study, where subjects were exposed to blue and red light without sequential color changes, shows that the results of the current study appear to be similar to those of red light exposure. This may indicate that the exposure to red light was preponderant and thus effects of blue light were outweighed.

  3. Effective atomic numbers for photon energy-absorption and photon interaction of some human organs and tissues such as blood-whole, adipose tissue, brain-grey/white matter, tissue-soft (four-component), lung tissue and muscle skeletal

    International Nuclear Information System (INIS)

    The present work aims at the accurate calculation of ZPEAeff values for some human organs and tissues such as blood-whole, adipose tissue, brain-grey/white matter, tissue-soft(four-component), lung tissue and muscle-skeletal in the energy region of 1 keV-20 MeV. The ZPEAeff values are compared with ZPIeff and the effective atomic number calculated using the program XMuDat and is denoted here by ZXMUDATeff

  4. SPECT of brain blood flow

    International Nuclear Information System (INIS)

    Morphological observation of the brain became possible by CT and various informations on vascularity and damages in brain blood barrier (BBB) became obtainable by the combined use of contrast medium. Then the appearance of MRI had enabled to discriminate the cortex and the medula of the brain and to perform MR angiography. However, it was still difficult to observe the cerebral tissue in detail. Recently, nuclear medical procedures have been developed and applied to diagnosis. SPECT images attributable to the distribution of γ-ray from a tracer, which monitors the blood flow and various metabolisms. Thus, investigations of cerebral functions including blood flow metabolism and neural transmission etc. became possible by the technique. Here, SPECT by Xe-133 clearance and 99mTc HMPAO methods were reviewed. For Xe-133 method, subjects positioned in SPECT instrument underwent bolus inhalation of Xe-133, 1850 Mbq followed by washout respiration of room air. During these treatment, cerebral projection and determination of the concentration of Xe-133 CO2 in the expired air were continuously carried out. And the blood flow level per pixel was estimated from SPECT images and the end-tidal Xe-133 concentration curve. This method was thought to be the most excellent method for the determination of local blood flow in respect of accuracy and reproducibility. The tracer distribution expressed the functional level of the stagnant state of blood flow. SPECT provides useful informations to investigate the physiological functions and pathology in the brain. (M.N.)

  5. MUSCLE METABOLISM WITH BLOOD FLOW RESTRICTION IN CHRONIC FATIGUE SYNDROME

    OpenAIRE

    McCully, Kevin K; Smith, Sinclair; Rajaei, Sheeva; Leigh, John S.; Natelson, Benjamin H

    2003-01-01

    The purpose of this study was to determine if chronic fatigue syndrome (CFS) is associated with reduced blood flow and muscle oxidative metabolism. Patients with CFS according to CDC criteria (n=19) were compared to normal sedentary subjects (n = 11). Muscle blood flow was measured in the femoral artery with Doppler ultrasound after exercise. Muscle metabolism was measured in the medial gastrocnemius muscle using 31P magnetic resonance spectroscopy (MRS). Muscle oxygen saturation and blood vo...

  6. The blood-brain barrier.

    Science.gov (United States)

    Obermeier, Birgit; Verma, Ajay; Ransohoff, Richard M

    2016-01-01

    In autoimmune neurologic disorders, the blood-brain barrier (BBB) plays a central role in immunopathogenesis, since this vascular interface is an entry path for cells and effector molecules of the peripheral immune system to reach the target organ, the central nervous system (CNS). The BBB's unique anatomic structure and the tightly regulated interplay of its cellular and acellular components allow for maintenance of brain homeostasis, regulation of influx and efflux, and protection from harm; these ensure an optimal environment for the neuronal network to function properly. In both health and disease, the BBB acts as mediator between the periphery and the CNS. For example, immune cell trafficking through the cerebral vasculature is essential to clear microbes or cell debris from neural tissues, while poorly regulated cellular transmigration can underlie or worsen CNS pathology. In this chapter, we focus on the specialized multicellular structure and function of the BBB/neurovascular unit and discuss how BBB breakdown can precede or be a consequence of neuroinflammation. We introduce the blood-cerebrospinal fluid barrier and include a brief aside about evolutionary aspects of barrier formation and refinements. Lastly, since restoration of barrier function is considered key to ameliorate neurologic disease, we speculate about new therapeutic avenues to repair a damaged BBB. PMID:27112670

  7. Blood-borne revitalization of the aged brain

    Science.gov (United States)

    Castellano, Joseph M.; Kirby, Elizabeth D.; Wyss-Coray, Tony

    2016-01-01

    In the modern medical era, more diverse and effective treatment options have translated into increased life expectancy. With this increased lifespan comes increased age-associated disease and the dire need to understand the underlying causes so that therapies can be designed to mitigate the burden to health and the economy. Aging exacts a seemingly inevitable, multi-system deterioration of function that acts as a risk factor for a variety of age-related disorders, including those that devastate organs of limited regenerative potential such as the brain. Rather than studying the brain and mechanisms that govern its aging in isolation from other organ systems, an emerging approach is to understand the relatively unappreciated communication existing between the brain and the systemic environment. Revisiting classical methods of experimental physiology in animal models has uncovered surprising regenerative activity within young blood with translational implications for aging liver, muscle, brain and other organs. Surprisingly, soluble factors present in young or aged blood are sufficient to improve or impair cognitive function, respectively, suggesting an aging continuum of brain-relevant systemic factors. The age-associated plasma chemokine CCL11 has been shown to impair young brain function while GDF11 has been reported to increase the generation of neurons in aged mice. However, the identities of specific factors mediating memory-enhancing effects of young blood and their mechanisms of action remain enigmatic. Here we review recent brain rejuvenation studies in the broader context of systemic rejuvenation research. We discuss putative mechanisms for blood-borne brain rejuvenation while suggesting promising avenues for future research and development of therapies. PMID:26237737

  8. Blood-Borne Revitalization of the Aged Brain.

    Science.gov (United States)

    Castellano, Joseph M; Kirby, Elizabeth D; Wyss-Coray, Tony

    2015-10-01

    In the modern medical era, more diverse and effective treatment options have translated to increased life expectancy. With this increased life span comes increased age-associated disease and the dire need to understand underlying causes so that therapies can be designed to mitigate the burden to health and the economy. Aging exacts a seemingly inevitable multisystem deterioration of function that acts as a risk factor for a variety of age-related disorders, including those that devastate organs of limited regenerative potential, such as the brain. Rather than studying the brain and mechanisms that govern its aging in isolation from other organ systems, an emerging approach is to understand the relatively unappreciated communication that exists between the brain and systemic environment. Revisiting classical methods of experimental physiology in animal models has uncovered surprising regenerative activity in young blood with translational implications for the aging liver, muscle, brain, and other organs. Soluble factors present in young or aged blood are sufficient to improve or impair cognitive function, respectively, suggesting an aging continuum of brain-relevant systemic factors. The age-associated plasma chemokine CCL11 has been shown to impair young brain function while GDF11 has been reported to increase the generation of neurons in aged mice. However, the identities of specific factors mediating memory-enhancing effects of young blood and their mechanisms of action are enigmatic. Here we review brain rejuvenation studies in the broader context of systemic rejuvenation research. We discuss putative mechanisms for blood-borne brain rejuvenation and suggest promising avenues for future research and development of therapies. PMID:26237737

  9. Markers for blood-brain barrier integrity

    DEFF Research Database (Denmark)

    Saunders, Norman R; Dziegielewska, Katarzyna M; Møllgård, Kjeld;

    2015-01-01

    In recent years there has been a resurgence of interest in brain barriers and various roles their intrinsic mechanisms may play in neurological disorders. Such studies require suitable models and markers to demonstrate integrity and functional changes at the interfaces between blood, brain, and...... cerebrospinal fluid. Studies of brain barrier mechanisms and measurements of plasma volume using dyes have a long-standing history, dating back to the late nineteenth-century. Their use in blood-brain barrier studies continues in spite of their known serious limitations in in vivo applications. These were well...... known when first introduced, but seem to have been forgotten since. Understanding these limitations is important because Evans blue is still the most commonly used marker of brain barrier integrity and those using it seem oblivious to problems arising from its in vivo application. The introduction of...

  10. Laser Unlocks Blood-Brain Barrier for Chemotherapy, Study Shows

    Science.gov (United States)

    ... nlm.nih.gov/medlineplus/news/fullstory_157444.html Laser Unlocks Blood-Brain Barrier for Chemotherapy, Study Shows ... 24, 2016 WEDNESDAY, Feb. 24, 2016 (HealthDay News) -- Laser surgery can open the protective blood-brain barrier, ...

  11. Medulloblastoma Genotype Dictates Blood Brain Barrier Phenotype.

    Science.gov (United States)

    Phoenix, Timothy N; Patmore, Deanna M; Boop, Scott; Boulos, Nidal; Jacus, Megan O; Patel, Yogesh T; Roussel, Martine F; Finkelstein, David; Goumnerova, Liliana; Perreault, Sebastien; Wadhwa, Elizabeth; Cho, Yoon-Jae; Stewart, Clinton F; Gilbertson, Richard J

    2016-04-11

    The childhood brain tumor, medulloblastoma, includes four subtypes with very different prognoses. Here, we show that paracrine signals driven by mutant β-catenin in WNT-medulloblastoma, an essentially curable form of the disease, induce an aberrant fenestrated vasculature that permits the accumulation of high levels of intra-tumoral chemotherapy and a robust therapeutic response. In contrast, SHH-medulloblastoma, a less curable disease subtype, contains an intact blood brain barrier, rendering this tumor impermeable and resistant to chemotherapy. The medulloblastoma-endothelial cell paracrine axis can be manipulated in vivo, altering chemotherapy permeability and clinical response. Thus, medulloblastoma genotype dictates tumor vessel phenotype, explaining in part the disparate prognoses among medulloblastoma subtypes and suggesting an approach to enhance the chemoresponsiveness of other brain tumors. PMID:27050100

  12. Recent advances in the brain-to-blood efflux transport across the blood-brain barrier.

    Science.gov (United States)

    Hosoya, Ken-ichi; Ohtsuki, Sumio; Terasaki, Tetsuya

    2002-11-01

    Elucidating the details of the blood-brain barrier (BBB) transport mechanism is a very important step towards successful drug targeting to the brain and understanding what happens in the brain. Although several brain uptake methods have been developed to characterize transport at the BBB, these are mainly useful for investigating influx transport across the BBB. In 1992, P-glycoprotein was found to act as an efflux pump for anti-cancer drugs at the BBB using primary cultured bovine brain endothelial cells. In order to determine the direct efflux transport from the brain to the circulating blood of exogenous compounds in vivo, the Brain Efflux Index method was developed to characterize several BBB efflux transport systems. Recently, we have established conditionally immortalized rat (TR-BBB) and mouse (TM-BBB) brain capillary endothelial cell lines from transgenic rats and mice harboring temperature-sensitive simian virus 40 large T-antigen gene to characterize the transport mechanisms at the BBB in vitro. TR-BBB and TM-BBB cells possess certain in vivo transport functions and express mRNAs for the BBB. Using a combination of newly developed in vivo and in vitro methods, we have elucidated the efflux transport mechanism at the BBB for neurosteroids, excitatory neurotransmitters, suppressive neurotransmitters, amino acids, and other organic anions to understand the physiological role played by the BBB as a detoxifying organ for the brain. PMID:12429456

  13. Blood-Brain Barrier Genomics, Proteomics, and New Transporter Discovery

    OpenAIRE

    Shusta, Eric V.

    2005-01-01

    Summary: The blood-brain barrier (BBB) is an impermeable cellular interface that physically separates the blood from the interstices of the brain. The endothelial cells lining the brain blood vessels form the principle barrier, and their unique phenotype is a consequence of dynamic interactions with several perivascular cell types present in the brain parenchyma. In addition, BBB dysfunction has been observed in the large majority of neurological diseases, but the causes of aberrant vascular ...

  14. Xenon-133 determination of muscle blood flow in electrical injury

    International Nuclear Information System (INIS)

    Xe-133 washout determination of muscle blood flow (MBF) was used to detect muscle ischemia in electrical injury of an experimental animal model and three patients. The control MBF of rabbit hindlimbs, which averaged 11.29 +- 1.07 cc/min/100 gm, was significantly reduced by electrical injury, to 5.82 +- 1.49 cc/min/100 gm (p less than 0.001). An electrical injury of 4,000 watt-seconds or greater was associated with uniform MBF less than 1.00 cc/min/100 gm and with histopathologic alterations of muscle necrosis. Thenar MBF less than 1.00 cc/min/100 gm in two patients was associated with muscle necrosis requiring distal arm amputation. The remaining patient with sequential muscle blood flows above this level had uneventful healing of hand electrical injuries. Xe-133 determination of MBF may be a useful objective technique to determine the extent of electrical injury in muscle

  15. Acute effects of electromagnetic stimulation of the brain on cortical activity, cortical blood flow, blood pressure and heart rate in the cat: an evaluation of safety.

    OpenAIRE

    Eyre, J A; Flecknell, P. A.; Kenyon, B R; Koh, T H; Miller, S.

    1990-01-01

    The influence of repeated high intensity electromagnetic stimulation of the brain on cortical activity, cortical blood flow, blood pressure and heart rate has been investigated in the cat, to evaluate the safety of the method. The observations have been made in preparations under propofol anaesthesia before, during and after periods of anoxia. Electromagnetic stimulation of the brain evoked activity in descending motor pathways and was recorded by activity in the median nerve and by muscle tw...

  16. Regulation of the skeletal muscle blood flow in humans

    DEFF Research Database (Denmark)

    Mortensen, Stefan; Saltin, Bengt

    2014-01-01

    hyperaemia whereas the role of ATP remains uncertain due to lack of specific purinergic receptor blockers for human use. The purpose of this review is to address the interaction between vasodilator systems and to discuss the multiple proposed roles of ATP in human skeletal muscle blood flow regulation......In humans, skeletal muscle blood flow is regulated by an interaction between several locally formed vasodilators including nitric oxide (NO) and prostaglandins. In plasma, ATP is a potent vasodilator that stimulates the formation of NO and prostaglandins and very importantly can offset local...... sympathetic vasoconstriction. ATP is released into plasma from erythrocytes and endothelial cells and the plasma concentration increases in both the feeding artery and the vein draining the contracting skeletal muscle. Adenosine also stimulates the formation of NO and prostaglandins, but the plasma adenosine...

  17. Vasodilator interactions in skeletal muscle blood flow regulation

    DEFF Research Database (Denmark)

    Hellsten, Ylva; Nyberg, Michael Permin; Jensen, Lasse Gliemann;

    2012-01-01

    During exercise, oxygen delivery to skeletal muscle is elevated to meet the increased oxygen demand. The increase in blood flow to skeletal muscle is achieved by vasodilators formed locally in the muscle tissue, either on the intraluminal or the extraluminal side of the blood vessels. A number...... vasodilators are both stimulated by several compounds, eg. adenosine, ATP, acetylcholine, bradykinin, and are affected by mechanically induced signals, such as shear stress. NO and prostacyclin have also been shown to interact in a redundant manner where one system can take over when formation of the other...... is compromised. Although numerous studies have examined the role of single and multiple pharmacological inhibition of different vasodilator systems, and important vasodilators and interactions have been identified, a large part of the exercise hyperemic response remains unexplained. It is plausible...

  18. 65zinc uptake from blood into brain and other tissues in the rat

    International Nuclear Information System (INIS)

    Zinc is essential for normal growth, development and brain function although little is known about brain zinc homeostasis. Therefore, in this investigation we have studied 65Zn uptake from blood into brain and other tissues and have measured the blood-brain barrier permeability to 65Zn in the anaesthetized rat in vivo. Adult male Wistar rats within the weight range 500-600 g were used. 65ZnCl2 and [125I]albumin, the latter serving as a vascular marker, were injected in a bolus of normal saline I.V. Sequential arterial blood samples were taken during experiments that lasted between 5 min and 5 hr. At termination, samples from the liver, spleen, pancreas, lung, heart, muscle, kidney, bone, testis, ileum, blood cells, csf, and whole brain were taken and analysed for radio-isotope activity. Data have been analysed by Graphical Analysis which suggests 65Zn uptake from blood by all tissues sampled was unidirectional during this experimental period except brain, where at circulation times less than 30 min, 65Zn fluxes were bidirectional. In addition to the blood space, the brain appears to contain a rapidly exchanging compartment(s) for 65Zn of about 4 ml/100g which is not csf

  19. Reduced blood flow to contracting skeletal muscle in ageing humans

    DEFF Research Database (Denmark)

    Nyberg, Michael Permin; Hellsten, Ylva

    2016-01-01

    The ability to sustain a given absolute submaximal workload declines with advancing age likely due to a lower level of blood flow and O2 delivery to the exercising muscles. Given that physical inactivity mimics many of the physiological changes associated with ageing, separating the physiological...... the O2 demand of the active skeletal muscle of aged individuals during conditions where systemic blood flow is not limited by cardiac output seems to a large extent to be related to the level of physical activity. This article is protected by copyright. All rights reserved....... consequences of ageing and physical inactivity can be challenging; yet, observations from cross-sectional and longitudinal studies on the effects of physical activity have provided some insight. Physical activity has the potential to offset the age-related decline in blood flow to contracting skeletal muscle...... during exercise where systemic blood flow is not limited by cardiac output, thereby improving O2 delivery and allowing for an enhanced energy production from oxidative metabolism. The mechanisms underlying the increase in blood flow with regular physical activity include improved endothelial function...

  20. Legs and Trunk Muscle Hypertrophy Following Walk Training with Restricted Leg Muscle Blood Flow

    OpenAIRE

    Mikako Sakamaki; Bemben, Michael G.; Takashi Abe

    2011-01-01

    We examined the effect of walk training combined with blood flow restriction (BFR) on the size of blood flow-restricted distal muscles, as well as, on the size of non-restricted muscles in the proximal limb and trunk. Nine men performed walk training with BFR and 8 men performed walk training alone. Training was conducted two times a day, 6 days/wk, for 3 wk using five sets of 2-min bouts (treadmill speed at 50 m/min), with a 1-min rest between bouts. After walk training with BFR, MRI-measure...

  1. Brain and skeletal muscle bioenergetic failure in familial hypobetalipoproteinaemia.

    OpenAIRE

    Lodi, R; R. Rinaldi; Gaddi, A.; Iotti, S; D'Alessandro, R.(INFN Sezione di Firenze, Firenze, Italy); Scoz, N; Battino, M; Carelli, V; Azzimondi, G; Zaniol, P; Barbiroli, B.

    1997-01-01

    OBJECTIVE: To determine whether a multisystemic bioenergetic deficit is an underlying feature of familial hypobetalipoproteinaemia. METHODS: Brain and skeletal muscle bioenergetics were studied by in vivo phosphorus MR spectroscopy (31P-MRS) in two neurologically affected members (mother and son) and in one asymptomatic member (daughter) of a kindred with familial hypobetalipoproteinaemia. Plasma concentrations of vitamin E and coenzyme Q10 (CoQ10) were also assessed. RESULTS: Brain 31P-MRS d...

  2. Blood-brain barrier permeability imaging using perfusion computed tomography

    Directory of Open Access Journals (Sweden)

    Avsenik Jernej

    2015-06-01

    Full Text Available Background. The blood-brain barrier represents the selective diffusion barrier at the level of the cerebral microvascular endothelium. Other functions of blood-brain barrier include transport, signaling and osmoregulation. Endothelial cells interact with surrounding astrocytes, pericytes and neurons. These interactions are crucial to the development, structural integrity and function of the cerebral microvascular endothelium. Dysfunctional blood-brain barrier has been associated with pathologies such as acute stroke, tumors, inflammatory and neurodegenerative diseases.

  3. Brain and muscle Arnt-like 1 promotes skeletal muscle regeneration through satellite cell expansion

    Energy Technology Data Exchange (ETDEWEB)

    Chatterjee, Somik [Center for Diabetes Research, Department of Medicine, Houston Methodist Research Institute, Houston, TX 77030 (United States); Yin, Hongshan [Center for Diabetes Research, Department of Medicine, Houston Methodist Research Institute, Houston, TX 77030 (United States); Department of Cardiovascular Medicine, Third Affiliated Hospital, Hebei Medical University, Shijiazhuang 050051, Hebei (China); Nam, Deokhwa [Center for Diabetes Research, Department of Medicine, Houston Methodist Research Institute, Houston, TX 77030 (United States); Li, Yong [Department of Pediatric Surgery, Center for Stem Cell Research and Regenerative Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030 (United States); Ma, Ke, E-mail: kma@houstonmethodist.org [Center for Diabetes Research, Department of Medicine, Houston Methodist Research Institute, Houston, TX 77030 (United States)

    2015-02-01

    Circadian clock is an evolutionarily conserved timing mechanism governing diverse biological processes and the skeletal muscle possesses intrinsic functional clocks. Interestingly, although the essential clock transcription activator, Brain and muscle Arnt-like 1 (Bmal1), participates in maintenance of muscle mass, little is known regarding its role in muscle growth and repair. In this report, we investigate the in vivo function of Bmal1 in skeletal muscle regeneration using two muscle injury models. Bmal1 is highly up-regulated by cardiotoxin injury, and its genetic ablation significantly impairs regeneration with markedly suppressed new myofiber formation and attenuated myogenic induction. A similarly defective regenerative response is observed in Bmal1-null mice as compared to wild-type controls upon freeze injury. Lack of satellite cell expansion accounts for the regeneration defect, as Bmal1{sup −/−} mice display significantly lower satellite cell number with nearly abolished induction of the satellite cell marker, Pax7. Furthermore, satellite cell-derived primary myoblasts devoid of Bmal1 display reduced growth and proliferation ex vivo. Collectively, our results demonstrate, for the first time, that Bmal1 is an integral component of the pro-myogenic response that is required for muscle repair. This mechanism may underlie its role in preserving adult muscle mass and could be targeted therapeutically to prevent muscle-wasting diseases. - Highlights: • Bmal1 is highly inducible by muscle injury and myogenic stimuli. • Genetic ablation of Bmal1 significantly impairs muscle regeneration. • Bmal1 promotes satellite cell expansion during muscle regeneration. • Bmal1-deficient primary myoblasts display attenuated growth and proliferation.

  4. Brain and muscle Arnt-like 1 promotes skeletal muscle regeneration through satellite cell expansion

    International Nuclear Information System (INIS)

    Circadian clock is an evolutionarily conserved timing mechanism governing diverse biological processes and the skeletal muscle possesses intrinsic functional clocks. Interestingly, although the essential clock transcription activator, Brain and muscle Arnt-like 1 (Bmal1), participates in maintenance of muscle mass, little is known regarding its role in muscle growth and repair. In this report, we investigate the in vivo function of Bmal1 in skeletal muscle regeneration using two muscle injury models. Bmal1 is highly up-regulated by cardiotoxin injury, and its genetic ablation significantly impairs regeneration with markedly suppressed new myofiber formation and attenuated myogenic induction. A similarly defective regenerative response is observed in Bmal1-null mice as compared to wild-type controls upon freeze injury. Lack of satellite cell expansion accounts for the regeneration defect, as Bmal1−/− mice display significantly lower satellite cell number with nearly abolished induction of the satellite cell marker, Pax7. Furthermore, satellite cell-derived primary myoblasts devoid of Bmal1 display reduced growth and proliferation ex vivo. Collectively, our results demonstrate, for the first time, that Bmal1 is an integral component of the pro-myogenic response that is required for muscle repair. This mechanism may underlie its role in preserving adult muscle mass and could be targeted therapeutically to prevent muscle-wasting diseases. - Highlights: • Bmal1 is highly inducible by muscle injury and myogenic stimuli. • Genetic ablation of Bmal1 significantly impairs muscle regeneration. • Bmal1 promotes satellite cell expansion during muscle regeneration. • Bmal1-deficient primary myoblasts display attenuated growth and proliferation

  5. Adipose tissue and skeletal muscle blood flow during mental stress

    International Nuclear Information System (INIS)

    Mental stress [a modified Stroop color word conflict test (CWT)] increased adipose tissue blood flow (ATBF; 133Xe clearance) by 70% and reduced adipose tissue vascular resistance (ATR) by 25% in healthy male volunteers. The vasculatures of adipose tissue (abdomen as well as thigh), skeletal muscle of the calf (133Xe clearance), and the entire calf (venous occlusion plethysmography) responded similarly. Arterial epinephrine (Epi) and glycerol levels were approximately doubled by stress. Beta-Blockade by metoprolol (beta 1-selective) or propranolol (nonselective) attenuated CWT-induced tachycardia similarly. Metoprolol attenuated stress-induced vasodilation in the calf and tended to do so in adipose tissue. Propranolol abolished vasodilation in the calf and resulted in vasoconstriction during CWT in adipose tissue. Decreases in ATR, but not in skeletal muscle or calf vascular resistances, were correlated to increases in arterial plasma glycerol (r = -0.42, P less than 0.05), whereas decreases in skeletal muscle and calf vascular resistances, but not in ATR, were correlated to increases in arterial Epi levels (r = -0.69, P less than 0.01; and r = -0.43, P less than 0.05, respectively). The results suggest that mental stress increases nutritive blood flow in adipose tissue and skeletal muscle considerably, both through the elevation of perfusion pressure and via vasodilatation. Withdrawal of vasoconstrictor nerve activity, vascular beta 2-adrenoceptor stimulation by circulating Epi, and metabolic mechanisms (in adipose tissue) may contribute to the vasodilatation

  6. Adipose tissue and skeletal muscle blood flow during mental stress

    Energy Technology Data Exchange (ETDEWEB)

    Linde, B.; Hjemdahl, P.; Freyschuss, U.; Juhlin-Dannfelt, A.

    1989-01-01

    Mental stress (a modified Stroop color word conflict test (CWT)) increased adipose tissue blood flow (ATBF; 133Xe clearance) by 70% and reduced adipose tissue vascular resistance (ATR) by 25% in healthy male volunteers. The vasculatures of adipose tissue (abdomen as well as thigh), skeletal muscle of the calf (133Xe clearance), and the entire calf (venous occlusion plethysmography) responded similarly. Arterial epinephrine (Epi) and glycerol levels were approximately doubled by stress. Beta-Blockade by metoprolol (beta 1-selective) or propranolol (nonselective) attenuated CWT-induced tachycardia similarly. Metoprolol attenuated stress-induced vasodilation in the calf and tended to do so in adipose tissue. Propranolol abolished vasodilation in the calf and resulted in vasoconstriction during CWT in adipose tissue. Decreases in ATR, but not in skeletal muscle or calf vascular resistances, were correlated to increases in arterial plasma glycerol (r = -0.42, P less than 0.05), whereas decreases in skeletal muscle and calf vascular resistances, but not in ATR, were correlated to increases in arterial Epi levels (r = -0.69, P less than 0.01; and r = -0.43, P less than 0.05, respectively). The results suggest that mental stress increases nutritive blood flow in adipose tissue and skeletal muscle considerably, both through the elevation of perfusion pressure and via vasodilatation. Withdrawal of vasoconstrictor nerve activity, vascular beta 2-adrenoceptor stimulation by circulating Epi, and metabolic mechanisms (in adipose tissue) may contribute to the vasodilatation.

  7. Glial and neuronal control of brain blood flow

    DEFF Research Database (Denmark)

    Attwell, David; Buchan, Alastair M; Charpak, Serge;

    2010-01-01

    Blood flow in the brain is regulated by neurons and astrocytes. Knowledge of how these cells control blood flow is crucial for understanding how neural computation is powered, for interpreting functional imaging scans of brains, and for developing treatments for neurological disorders. It is now...

  8. The transport of L-6-fluorodopa and its metabolites from blood to cerebrospinal fluid and brain.

    Science.gov (United States)

    Hammerstad, J P; Pate, B D; Hewitt, K A; Chan, G L; Ruth, T J; Calne, D B

    1993-10-01

    The transport of L-6-fluorodopa and its major metabolites from the blood to the brain, cerebrospinal fluid (CSF), and muscle was studied in carbidopa-pretreated cynomolgus monkeys. A bolus intravenous injection of 18F-L-6-fluorodopa was followed by serial positron emission tomography scans and sampling of cisternal CSF and arterial blood. The relative concentrations of L-6-fluorodopa and its metabolites were determined in blood plasma and CSF by high-performance liquid chromatography. Raising the blood concentration of phenylalanine by intraperitoneal injection markedly reduced the accumulation of tracer in the brain. This indicates that L-6-fluorodopa and 3-O-methylfluorodopa, like native L-dopa and its O-methylated derivative, are transported at the brain capillary by the large neutral amino acid carrier-mediated system, which is subject to saturation and competition by other large neutral amino acids (such as phenylalanine) at physiological plasma concentrations. In contrast, administration of phenylalanine had no effect on the accumulation of tracer either in muscle, or as L-6-fluorodopa and 3-O-methylfluorodopa, in CSF. This suggests that the transport of L-dopa and its derivatives at the blood-CSF barrier differs from the transport at the blood-brain barrier and also that measurement of CSF L-dopa is not a good index of the transport and pharmacokinetics of L-dopa in the brain. However, the effect of phenylalanine administration in reducing the concentration of fluorohomovanillic acid in the CSF suggests that the concentration of homovanillic acid in the CSF is an accurate reflection of dopamine turnover in the brain. PMID:8215248

  9. Blood-Brain Barrier Integrity and Breast Cancer Metastasis to the Brain

    OpenAIRE

    Hava Karsenty Avraham; Shalom Avraham; Christopher Sy; Lili Wang; Farheen Arshad

    2011-01-01

    Brain metastasis, an important cause of cancer morbidity and mortality, occurs in at least 30% of patients with breast cancer. A key event of brain metastasis is the migration of cancer cells through the blood-brain barrier (BBB). Although preventing brain metastasis is immensely important for survival, very little is known about the early stage of transmigration and the molecular mechanisms of breast tumor cells penetrating the BBB. The brain endothelium plays an important role in brain meta...

  10. The Blood-Brain Barrier: An Engineering Perspective

    Directory of Open Access Journals (Sweden)

    Andrew eWong

    2013-08-01

    Full Text Available It has been more than 100 years since Paul Ehrlich reported that various water-soluble dyes injected into the circulation did not enter the brain. Since Ehrlich’s first experiments, only a small number of molecules, such as alcohol and caffeine have been found to cross the blood-brain barrier, and it remains the major roadblock to treatment of many central nervous system diseases. At the same time, many central nervous system diseases are associated with disruption of the blood-brain barrier that can lead to changes in permeability, modulation of immune cell transport, and trafficking of pathogens into the brain. Therefore advances in our understanding of the structure and function of the blood-brain barrier are key to advances in treatment of a wide range of central nervous system diseases. Over the past 10 years it has become recognized that the blood-brain barrier is a complex dynamic system that involves biomechanical and biochemical signaling between the vascular system and the brain. Here we reconstruct the structure, function, and transport properties of the blood-brain barrier from an engineering perspective. New insight into the physics of the blood-brain barrier could ultimately lead to clinical advances in the treatment of central nervous system diseases.

  11. Solubility of inert gases in dog blood and skeletal muscle.

    Science.gov (United States)

    Meyer, M; Tebbe, U; Piiper, J

    1980-03-01

    Solubility of H2, Ar, CH4 and SF6 was determined at 310 K (37 degrees C) in water, in saline (0.154 mol NaCl/l H2O), in plasma and whole blood of dogs, and in homogenates of the dog gastrocnemius muscle. The liquids were equilibrated with pure gases, and the dissolved gases were extracted and measured by gas chromatography as described previously (Meyer, M.: Pflügers Arch. 375, 161--165, 1978). In saline, the solubilities were 4% (SF6) to 15% (Ar) lower than in water. For dog blood the following mean values for the solubility coefficient (in mumol . 1(-1) . kPa-1) were found: for H2, 6.44; for Ar, 9.94; for CH4, 11.44; for SF6, 2.62. The red cell/plasma and the muscle/blood solubility ratios were near unity for H2, Ar and CH4 (ranging from 0.9 to 1.3); for SF6, however, they were much higher (about 2.1), apparently due to the high solubility of SF6 in hydrophobic substances (lipids). PMID:6247698

  12. KINESTHETIC IMAGERY TRAINING OF FORCEFUL MUSCLE CONTRACTIONS INCREASES BRAIN SIGNAL AND MUSCLE STRENGTH

    Directory of Open Access Journals (Sweden)

    Wan X Yao

    2013-09-01

    Full Text Available The purpose of this study was to compare the effect of training using internal imagery (IMI; also known as kinesthetic imagery or first person imagery with that of external imagery (EMI; also known as third-person visual imagery of strong muscle contractions on voluntary muscle strengthening. Eighteen young, healthy subjects were randomly assigned to one of three groups (6 in each group: internal motor imagery (IMI, external motor imagery (EMI, or a no-practice control (CTRL group. Training lasted for 6 weeks (~15 min/day, 5 days/week. The participants’ right arm elbow-flexion strength, muscle electrical activity and movement-related cortical potential (MRCP were evaluated before and after training. Only the IMI group showed significant strength gained (10.8% while the EMI (4.8% and CTRL (-3.3% groups did not. Only the IMI group showed a significant elevation in MRCP on scalp locations over both the primary motor (M1 and supplementary motor cortices (EMI group over M1 only and this increase was significantly greater than that of EMI and CTRL groups. These results suggest that training by IMI of forceful muscle contractions was effective in improving voluntary muscle strength without physical exercise. We suggest that the IMI training likely strengthened brain-to-muscle (BTM command that may have improved motor unit recruitment and activation, and led to greater muscle output. Training by internal motor imagery of forceful muscle contractions may change the activity level of cortical motor control network, which may translate into greater descending command to the target muscle and increase its strength.

  13. Mathematical modelling of blood-brain barrier failure and edema

    Science.gov (United States)

    Waters, Sarah; Lang, Georgina; Vella, Dominic; Goriely, Alain

    2015-11-01

    Injuries such as traumatic brain injury and stroke can result in increased blood-brain barrier permeability. This increase may lead to water accumulation in the brain tissue resulting in vasogenic edema. Although the initial injury may be localised, the resulting edema causes mechanical damage and compression of the vasculature beyond the original injury site. We employ a biphasic mixture model to investigate the consequences of blood-brain barrier permeability changes within a region of brain tissue and the onset of vasogenic edema. We find that such localised changes can indeed result in brain tissue swelling and that the type of damage that results (stress damage or strain damage) depends on the ability of the brain to clear edema fluid.

  14. Role of the Blood-Brain Barrier in the Formation of Brain Metastases

    OpenAIRE

    Krizbai, István A.; János Haskó; Csilla Fazakas; Judit Molnár; Imola Wilhelm

    2013-01-01

    The majority of brain metastases originate from lung cancer, breast cancer and malignant melanoma. In order to reach the brain, parenchyma metastatic cells have to transmigrate through the endothelial cell layer of brain capillaries, which forms the morphological basis of the blood-brain barrier (BBB). The BBB has a dual role in brain metastasis formation: it forms a tight barrier protecting the central nervous system from entering cancer cells, but it is also actively involved in protecting ...

  15. MRI of the brain in muscle-eye-brain (MEB) disease

    International Nuclear Information System (INIS)

    Muscle-eye-brain (MEB) disease belongs to the spectrum of rare congenital syndromes with migration disorders of the brain and muscular dystrophy, along with the Walker-Warburg syndrome and Fukuyama congenital muscular dystrophy. Their features overlap, and differential diagnosis presents some difficulties. We examined the brain of 10 patients with MEB using high-field MRI and found a uniform pattern consisting of a pachygyria-type cortical migration disorder, septal and corpus callosum defects and severe hypoplasia of the pons in 7 of them. (orig.)

  16. Hemodynamic measurements in rat brain and human muscle using diffuse near-infrared absorption and correlation spectroscopies

    Science.gov (United States)

    Yu, Guoqiang; Durduran, Turgut; Furuya, D.; Lech, G.; Zhou, Chao; Chance, Britten; Greenberg, J. H.; Yodh, Arjun G.

    2003-07-01

    Measurement of concentration, oxygenation, and flow characteristics of blood cells can reveal information about tissue metabolism and functional heterogeneity. An improved multifunctional hybrid system has been built on the basis of our previous hybrid instrument that combines two near-infrared diffuse optical techniques to simultaneously monitor the changes of blood flow, total hemoglobin concentration (THC) and blood oxygen saturation (StO2). Diffuse correlation spectroscopy (DCS) monitors blood flow (BF) by measuring the optical phase shifts caused by moving blood cells, while diffuse photon density wave spectroscopy (DPDW) measures tissue absorption and scattering. Higher spatial resolution, higher data acquisition rate and higher dynamic range of the improved system allow us to monitor rapid hemodynamic changes in rat brain and human muscles. We have designed two probes with different source-detector pairs and different separations for the two types of experiments. A unique non-contact probe mounted on the back of a camera, which allows continuous measurements without altering the blood flow, was employed to in vivo monitor the metabolic responses in rat brain during KCl induced cortical spreading depression (CSD). A contact probe was used to measure changes of blood flow and oxygenation in human muscle during and after cuff occlusion or exercise, where the non-contact probe is not appropriate for monitoring the moving target. The experimental results indicate that our multifunctional hybrid system is capable of in vivo and non-invasive monitoring of the hemodynamic changes in different tissues (smaller tissues in rat brain, larger tissues in human muscle) under different conditions (static versus moving). The time series images of flow during CSD obtained by our technique revealed spatial and temporal hemodynamic changes in rat brain. Two to three fold longer recovery times of flow and oxygenation after cuff occlusion or exercise from calf flexors in a

  17. Intracerebral transplants of primary muscle cells: a potential 'platform' for transgene expression in the brain

    Science.gov (United States)

    Jiao, S.; Schultz, E.; Wolff, J. A.

    1992-01-01

    After the transplantation of rat primary muscle cells into the caudate or cortex of recipient rats, the muscle cells were able to persist for at least 6 months. Muscle cells transfected with expression plasmids prior to transplantation were able to express reporter genes in the brains for at least 2 months. These results suggest that muscle cells might be a useful 'platform' for transgene expression in the brain.

  18. Brain magnetic resonance imaging with contrast dependent on blood oxygenation

    International Nuclear Information System (INIS)

    Paramagnetic deoxyhemoglobin in venous blood is a naturally occurring contrast agent for magnetic resonance imaging (MRI). By accentuating the effects of this agent through the use of gradient-echo techniques in high yields, the authors demonstrate in vivo images of brain microvasculature with image contrast reflecting the blood oxygen level. This blood oxygenation level-dependent (BOLD) contrast follows blood oxygen changes induced by anesthetics, by insulin-induced hypoglycemia, and by inhaled gas mixtures that alter metabolic demand or blood flow. The results suggest that BOLD contrast can be used to provide in vivo real-time maps of blood oxygenation in the brain under normal physiological conditions. BOLD contrast adds an additional feature to magnetic resonance imaging and complement other techniques that are attempting to provide position emission tomography-like measurements related to regional neural activity

  19. Brain magnetic resonance imaging with contrast dependent on blood oxygenation

    Energy Technology Data Exchange (ETDEWEB)

    Ogawa, S.; Lee, T.M.; Kay, A.R.; Tank, D.W. (AT and T Bell Laboratories, Murray Hill, NJ (United States))

    1990-12-01

    Paramagnetic deoxyhemoglobin in venous blood is a naturally occurring contrast agent for magnetic resonance imaging (MRI). By accentuating the effects of this agent through the use of gradient-echo techniques in high yields, the authors demonstrate in vivo images of brain microvasculature with image contrast reflecting the blood oxygen level. This blood oxygenation level-dependent (BOLD) contrast follows blood oxygen changes induced by anesthetics, by insulin-induced hypoglycemia, and by inhaled gas mixtures that alter metabolic demand or blood flow. The results suggest that BOLD contrast can be used to provide in vivo real-time maps of blood oxygenation in the brain under normal physiological conditions. BOLD contrast adds an additional feature to magnetic resonance imaging and complement other techniques that are attempting to provide position emission tomography-like measurements related to regional neural activity.

  20. Blood-brain transfer of Pittsburgh compound B in humans

    DEFF Research Database (Denmark)

    Gjedde, Albert; Aanerud, Joel; Braendgaard, Hans;

    2013-01-01

    In the labeled form, the Pittsburgh compound B (2-(4'-{N-methyl-[(11)C]}methyl-aminophenyl)-6-hydroxy-benzothiazole, [(11)C]PiB), is used as a biomarker for positron emission tomography (PET) of brain β-amyloid deposition in Alzheimer's disease (AD). The permeability of [(11)C]PiB in the blood......-brain barrier is held to be high but the permeability-surface area product and extraction fractions in patients or healthy volunteers are not known. We used PET to determine the clearance associated with the unidrectional blood-brain transfer of [(11)C]PiB and the corresponding cerebral blood flow rates in......-brain clearances of [(11)C]PiB in the patients....

  1. Cerebrospinal fluid aquaporin-4-immunoglobulin G disrupts blood brain barrier.

    Science.gov (United States)

    Asgari, Nasrin; Berg, Carsten Tue; Mørch, Marlene Thorsen; Khorooshi, Reza; Owens, Trevor

    2015-08-01

    To clarify the significance of immunoglobulin G autoantibody specific for the astrocyte water channel aquaporin-4 in cerebrospinal fluid, aquaporin-4-immunoglobulin G from a neuromyelitis optica patient was administered intrathecally to naïve mice, and the distribution and pathogenic impact was evaluated. A distinct distribution pattern of aquaporin-4-immunoglobulin G deposition was observed in the subarachnoid and subpial spaces where vessels penetrate the brain parenchyma, via a paravascular route with intraparenchymal perivascular deposition. Perivascular astrocyte-destructive lesions were associated with blood-borne horseradish peroxidase leakage indicating blood-brain barrier breakdown. The cerebrospinal fluid aquaporin-4-immunoglobulin G therefore distributes widely in brain to initiate astrocytopathy and blood-brain barrier breakdown. PMID:26339679

  2. Blood Brain Barrier: A Challenge for Effectual Therapy of Brain Tumors

    OpenAIRE

    Arijit Bhowmik; Rajni Khan; Mrinal Kanti Ghosh

    2015-01-01

    Brain tumors are one of the most formidable diseases of mankind. They have only a fair to poor prognosis and high relapse rate. One of the major causes of extreme difficulty in brain tumor treatment is the presence of blood brain barrier (BBB). BBB comprises different molecular components and transport systems, which in turn create efflux machinery or hindrance for the entry of several drugs in brain. Thus, along with the conventional techniques, successful modification of drug delivery and n...

  3. Glutamate Efflux at the Blood-Brain Barrier

    DEFF Research Database (Denmark)

    Cederberg-Helms, Hans Christian; Uhd-Nielsen, Carsten; Brodin, Birger

    2014-01-01

    L-Glutamate is considered the most important excitatory amino acid in the mammalian brain. Strict control of its concentration in the brain interstitial fluid is important to maintain neurotransmission and avoid excitotoxicity. The role of astrocytes in handling L-glutamate transport and metabolism...... is well known, however endothelial cells may also play an important role through mediating brain-to-blood L-glutamate efflux. Expression of excitatory amino acid transporters has been demonstrated in brain endothelial cells of bovine, human, murine, rat and porcine origin. These can account for high...... affinity concentrative uptake of L-glutamate from the brain interstitial fluid into the capillary endothelial cells. The mechanisms in between L-glutamate uptake in the endothelial cells and L-glutamate appearing in the blood are still unclear and may involve a luminal transporter for L...

  4. Regulation of skeletal muscle blood flow during exercise in ageing humans.

    Science.gov (United States)

    Hearon, Christopher M; Dinenno, Frank A

    2016-04-15

    The regulation of skeletal muscle blood flow and oxygen delivery to contracting skeletal muscle is complex and involves the mechanical effects of muscle contraction; local metabolic, red blood cell and endothelium-derived substances; and the sympathetic nervous system (SNS). With advancing age in humans, skeletal muscle blood flow is typically reduced during dynamic exercise and this is due to a lower vascular conductance, which could ultimately contribute to age-associated reductions in aerobic exercise capacity, a primary predictor of mortality in both healthy and diseased ageing populations. Recent findings have highlighted the contribution of endothelium-derived substances to blood flow control in contracting muscle of older adults. With advancing age, impaired nitric oxide availability due to scavenging by reactive oxygen species, in conjunction with elevated vasoconstrictor signalling via endothelin-1, reduces the local vasodilatory response to muscle contraction. Additionally, ageing impairs the ability of contracting skeletal muscle to blunt sympathetic vasoconstriction (i.e. 'functional sympatholysis'), which is critical for the proper regulation of tissue blood flow distribution and oxygen delivery, and could further reduce skeletal muscle perfusion during high intensity and/or large muscle mass exercise in older adults. We propose that initiation of endothelium-dependent hyperpolarization is the underlying signalling event necessary to properly modulate sympathetic vasoconstriction in contracting muscle, and that age-associated impairments in red blood cell adenosine triphosphate release and stimulation of endothelium-dependent vasodilatation may explain impairments in both local vasodilatation and functional sympatholysis with advancing age in humans. PMID:26332887

  5. Acute strength exercise and the involvement of small or large muscle mass on plasma brain-derived neurotrophic factor levels

    Directory of Open Access Journals (Sweden)

    Paulo Roberto Correia

    2010-01-01

    Full Text Available OBJECTIVE: Blood neurotrophins, such as the brain-derived neurotrophic factor, are considered to be of great importance in mediating the benefits of physical exercise. In this study, the effect of acute strength exercise and the involvement of small versus large muscle mass on the levels of plasma brain-derived neurotrophic factor were evaluated in healthy individuals. METHODS: The concentric strengths of knee (large and elbow (small flexor and extensor muscles were measured on two separate days. Venous blood samples were obtained from 16 healthy subjects before and after exercise. RESULTS: The levels of brain-derived neurotrophic factor in the plasma did not significantly increase after both arm and leg exercise. There was no significant difference in the plasma levels of the brain-derived neurotrophic factor in the arms and legs. CONCLUSION: The present results demonstrate that acute strength exercise does not induce significant alterations in the levels of brain-derived neurotrophic factor plasma concentrations in healthy individuals. Considering that its levels may be affected by various factors, such as exercise, these findings suggest that the type of exercise program may be a decisive factor in altering peripheral brain-derived neurotrophic factor.

  6. Inclusion body myositis, muscle blood vessel and cardiac amyloidosis, and transthyretin Val122Ile allele.

    Science.gov (United States)

    Askanas, V; Engel, W K; Alvarez, R B; Frangione, B; Ghiso, J; Vidal, R

    2000-04-01

    Typical of sporadic inclusion body myositis muscle biopsies are vacuolated muscle fibers containing intracellular amyloid deposits and accumulations of "Alzheimer-characteristic" proteins. There is no muscle blood vessel or cardiac amyloidosis. We report on a 70-year-old African-American man homozygous for the transthyretin Val122Ile allele who has both sporadic inclusion body myositis and cardiac amyloidosis. His unique pathological features included transthyretin immunoreactivity in prominent muscle blood vessel amyloid and congophilic amyloid deposits within vacuolated muscle fibers. PMID:10762172

  7. Postmortem Quetiapine Reference Concentrations in Brain and Blood

    DEFF Research Database (Denmark)

    Skov, Louise; Johansen, Sys Stybe; Linnet, Kristian

    2015-01-01

    range of 2.08 –6.05, which correspond to those of the nontoxic concentrations. A single case, where quetiapine was ruled as the sole cause of death, a suicide by quetiapine overdose, had an even higher value of 25.74 mg/kg in brain tissue. The blood concentration was 8.99 mg/kg, giving a brain......Brain tissue is a useful alternative to blood in postmortem forensic investigations, but scarcity of information on reference concentrations in brain tissue makes interpretation challenging. Here we present a study of 43 cases where the antipsychotic drug quetiapine was quantified in brain tissue...... and related to concentrations in postmortem blood. For cases, where quetiapine was unrelated to the cause of death (N 5 36), the 10–90 percentiles for quetiapine concentrations in brain tissue were 0.030 – 1.54 mg/kg (median 0.48 mg/kg, mean 0.79 mg/kg). Corresponding blood 10 –90 percentile values...

  8. Mapping blood flow directionality in the human brain.

    Science.gov (United States)

    Park, Sung-Hong; Do, Won-Joon; Choi, Seung Hong; Zhao, Tiejun; Bae, Kyongtae Ty

    2016-07-01

    Diffusion properties of tissue are often expressed on the basis of directional variance, i.e., diffusion tensor imaging. In comparison, common perfusion-weighted imaging such as arterial spin labeling yields perfusion in a scalar quantity. The purpose of this study was to test the feasibility of mapping cerebral blood flow directionality using alternate ascending/descending directional navigation (ALADDIN), a recently-developed arterial spin labeling technique with sensitivity to blood flow directions. ALADDIN was applied along 3 orthogonal directions to assess directional blood flow in a vector form and also along 6 equally-spaced directions to extract blood flow tensor matrix (P) based on a blood flow ellipsoid model. Tensor elements (eigenvalues, eigenvectors, etc) were calculated to investigate characteristics of the blood flow tensor, in comparison with time-of-flight MR angiogram. While the directions of the main eigenvectors were heterogeneous throughout the brain, regional clusters of blood flow directionality were reproducible across subjects. The technique could show heterogeneous blood flow directionality within and around brain tumor, which was different from that of the contralateral normal side. The proposed method is deemed to provide information of blood flow directionality, which has not been demonstrated before. The results warrant further studies to assess changes in the directionality map as a function of scan parameters, to understand the signal sources, to investigate the possibility of mapping local blood perfusion directionality, and to evaluate its usefulness for clinical diagnosis. PMID:26968145

  9. Noninvasive optical quantification of absolute blood flow, blood oxygenation, and oxygen consumption rate in exercising skeletal muscle

    OpenAIRE

    Gurley, Katelyn; Shang, Yu; Yu, Guoqiang

    2012-01-01

    This study investigates a method using novel hybrid diffuse optical spectroscopies [near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS)] to obtain continuous, noninvasive measurement of absolute blood flow (BF), blood oxygenation, and oxygen consumption rate (V˙O2) in exercising skeletal muscle. Healthy subjects (n=9) performed a handgrip exercise to increase BF and V˙O2 in forearm flexor muscles, while a hybrid optical probe on the skin surface directly monitored oxy...

  10. Relationship between muscle oxygenation by NIRS and blood lactate

    International Nuclear Information System (INIS)

    The aim of the study was to investigate the relationship of muscle oxygenation in term of oxy-hemoglobin concentration change (ΔHbO2) by NIRS and blood lactate (BLA) in local skeletal muscle and evaluate the capability of NIRS in the research of exercise physiology Twenty-three athlete in the national fin-swimming team took the increasing load training on the power bicycle while their ΔHbO2 and BLA were simultaneously recorded. The initial powers used in the training were set as 100 w for males and 40 w for females. During the experiment, the power kept constant for 3 min before each abrupt increment of 30 w until the limit of the athlete's capability. Statistical analysis and data visualization were performed. Following the increasing load training, ΔHbO2 step-likely increased in the phase of aerobic metabolism but linearly decreased in the phase of anaerobic metabolism. The variation tendency of BLA was the same as ΔHbO2 and the concurrency of crucial turning points between ΔHbO2 and BLA was revealed. This relationship between ΔHbO2 and BLA presented in the increasing load training suggested that ΔHbO2 might be capable for taking the place of the invasively measured parameter BLA. Considering that ΔHbO2 can be noninvasively measured by NIRS, ΔHbO2 has the potential in the evaluation of athletes' physiological function and training effect on the athletes and accordingly NIRS can be well used in this field.

  11. Relationship between muscle oxygenation by NIRS and blood lactate

    Energy Technology Data Exchange (ETDEWEB)

    Xu Guodong [School of Physical Education, Jianghan University, Hubei Wuhan 430056 (China); Mao Zongzhen; Ye Yanjie; Lv Kunru, E-mail: xguodong@wipe.edu.cn [School of Health Sciences, Wuhan Institute of Physical Education, Hubei Wuhan 430079 (China)

    2011-01-01

    The aim of the study was to investigate the relationship of muscle oxygenation in term of oxy-hemoglobin concentration change ({Delta}HbO{sub 2}) by NIRS and blood lactate (BLA) in local skeletal muscle and evaluate the capability of NIRS in the research of exercise physiology Twenty-three athlete in the national fin-swimming team took the increasing load training on the power bicycle while their {Delta}HbO{sub 2} and BLA were simultaneously recorded. The initial powers used in the training were set as 100 w for males and 40 w for females. During the experiment, the power kept constant for 3 min before each abrupt increment of 30 w until the limit of the athlete's capability. Statistical analysis and data visualization were performed. Following the increasing load training, {Delta}HbO{sub 2} step-likely increased in the phase of aerobic metabolism but linearly decreased in the phase of anaerobic metabolism. The variation tendency of BLA was the same as {Delta}HbO{sub 2} and the concurrency of crucial turning points between {Delta}HbO{sub 2} and BLA was revealed. This relationship between {Delta}HbO{sub 2} and BLA presented in the increasing load training suggested that {Delta}HbO{sub 2} might be capable for taking the place of the invasively measured parameter BLA. Considering that {Delta}HbO{sub 2} can be noninvasively measured by NIRS, {Delta}HbO{sub 2} has the potential in the evaluation of athletes' physiological function and training effect on the athletes and accordingly NIRS can be well used in this field.

  12. Structure and blood supply of motion neuro-muscles endings of skeletal muscles of rats of a different age

    Directory of Open Access Journals (Sweden)

    Popel S.L.

    2012-01-01

    Full Text Available Purpose of work consists in the study of structure ofthe neuro-muscles endings and their blood supply in ontogenesis. It is shown that at the level of the neuro-muscles endings there is the expressed blood-nerve barrier which is deter-mined by the structural features of wall of blood microvessels. In the early period of ontogenesis of structure of blood-nerve barrier immature, and his functional insufficiency is compensated by made distance of sources of blood supply, that provides the sufficient morphological isolation of axons from albumens and cellular components of blood. With age structure of blood-nerve barrier destruction as a result of strengthening and generalization reverse development processes which pass by apoptos. Intracellulary alteration of neurolemocytes during ontogenesis testifies to their active trophic function, and concentration of synaps blisters in the cytoplasm of separate terminals neurolemocytes requires сomprehension of their role in functioning of blood supply barrier at the level of neuro-muscles endings.

  13. Blood and Brain Glutamate Levels in Children with Autistic Disorder

    Science.gov (United States)

    Hassan, Tamer H.; Abdelrahman, Hadeel M.; Fattah, Nelly R. Abdel; El-Masry, Nagda M.; Hashim, Haitham M.; El-Gerby, Khaled M.; Fattah, Nermin R. Abdel

    2013-01-01

    Despite of the great efforts that move forward to clarify the pathophysiologic mechanisms in autism, the cause of this disorder, however, remains largely unknown. There is an increasing body of literature concerning neurochemical contributions to the pathophysiology of autism. We aimed to determine blood and brain levels of glutamate in children…

  14. Brain energy metabolism and blood flow differences in healthy aging

    DEFF Research Database (Denmark)

    Aanerud, Joel; Borghammer, Per; Chakravarty, M Mallar; Vang, Kim; Rodell, Anders B; Jónsdottir, Kristjana Y; Møller, Arne; Ashkanian, Mahmoud; Vafaee, Manouchehr S; Iversen, Peter; Johannsen, Peter; Gjedde, Albert

    2012-01-01

    Cerebral metabolic rate of oxygen consumption (CMRO(2)), cerebral blood flow (CBF), and oxygen extraction fraction (OEF) are important indices of healthy aging of the brain. Although a frequent topic of study, changes of CBF and CMRO(2) during normal aging are still controversial, as some authors...

  15. Blood-brain distribution of morphine-6-glucuronide in sheep

    DEFF Research Database (Denmark)

    Villesen, H H; Foster, D J R; Upton, R N;

    2006-01-01

    At present there are few data regarding the rate and extent of brain-blood partitioning of the opioid active metabolite of morphine, morphine-6-glucuronide (M6G). In this study the cerebral kinetics of M6G were determined, after a short-term intravenous infusion, in chronically instrumented...

  16. Gliomas and the vascular fragility of the blood brain barrier

    Directory of Open Access Journals (Sweden)

    Luiz Gustavo eDubois

    2014-12-01

    Full Text Available Astrocytes, members of the glial family, interact through the exchange of soluble factors or by directly contacting neurons and other brain cells, such as microglia and endothelial cells. Astrocytic projections interact with vessels and act as additional elements of the Blood Brain Barrier (BBB. By mechanisms not fully understood, astrocytes can undergo oncogenic transformation and give rise to gliomas. The tumors take advantage of the BBB to ensure survival and continuous growth. A glioma can develop into a very aggressive tumor, the glioblastoma (GBM, characterized by a highly heterogeneous cell population (including tumor stem cells, extensive proliferation and migration. Nevertheless, gliomas can also give rise to slow growing tumors and in both cases, the afflux of blood, via BBB is crucial. Glioma cells migrate to different regions of the brain guided by the extension of blood vessels, colonizing the healthy adjacent tissue. In the clinical context, GBM can lead to tumor-derived seizures, which represent a challenge to patients and clinicians, since drugs used for its treatment must be able to cross the BBB. Uncontrolled and fast growth also leads to the disruption of the chimeric and fragile vessels in the tumor mass resulting in peritumoral edema. Although hormonal therapy is currently used to control the edema, it is not always efficient. In this review we comment the points cited above, considering the importance of the blood brain barrier and the concerns that arise when this barrier is affected.

  17. Cerebral autoregulation control of blood flow in the brain

    CERN Document Server

    Payne, Stephen

    2016-01-01

    This Brief provides a comprehensive introduction to the control of blood flow in the brain. Beginning with the basic physiology of autoregulation, the author goes on to discuss measurement techniques, mathematical models, methods of analysis, and relevant clinical conditions, all within this single volume. The author draws together this disparate field, and lays the groundwork for future research directions. The text gives an up-to-date review of the state of the art in cerebral autoregulation, which is particularly relevant as cerebral autoregulation moves from the laboratory to the bedside. Cerebral Autoregulation will be useful to researchers in the physical sciences such as mathematical biology, medical physics, and biomedical engineering whose work is concerned with the brain. Researchers in the medical sciences and clinicians dealing with the brain and blood flow, as well as industry professionals developing techniques such as ultrasound, MRI, and CT will also find this Brief of interest.

  18. Direct and indirect assessment of skeletal muscle blood flow in chronic congestive heart failure

    Energy Technology Data Exchange (ETDEWEB)

    LeJemtel, T.H.; Scortichini, D.; Katz, S.

    1988-09-09

    In patients with chronic congestive heart failure (CHF), skeletal muscle blood flow can be measured directly by the continuous thermodilution technique and by the xenon-133 clearance method. The continuous thermodilution technique requires retrograde catheterization of the femoral vein and, thus, cannot be repeated conveniently in patients during evaluation of pharmacologic interventions. The xenon-133 clearance, which requires only an intramuscular injection, allows repeated determination of skeletal muscle blood flow. In patients with severe CHF, a fixed capacity of the skeletal muscle vasculature to dilate appears to limit maximal exercise performance. Moreover, the changes in peak skeletal muscle blood flow noted during long-term administration of captopril, an angiotensin-converting enzyme inhibitor, appears to correlate with the changes in aerobic capacity. In patients with CHF, resting supine deep femoral vein oxygen content can be used as an indirect measurement of resting skeletal muscle blood flow. The absence of a steady state complicates the determination of peak skeletal muscle blood flow reached during graded bicycle or treadmill exercise in patients with chronic CHF. Indirect assessments of skeletal muscle blood flow and metabolism during exercise performed at submaximal work loads are currently developed in patients with chronic CHF.

  19. Hydrophilic solute transport across the rat blood-brain barrier

    International Nuclear Information System (INIS)

    Brain capillary permeability-surface area products (PS) of hydrophilic solutes ranging in size from 180 to 5,500 Daltons were measured in rats according to the method of Ohno, Pettigrew and Rapoport. The distribution volume of 70 KD dextran at 10 minutes after i.v. injection was also measured to determine the residual volume of blood in brain tissue at the time of sacrifice. Small test solutes were injected in pairs in order to elucidate whether their transfer into the brain proceeds by diffusion through water- or lipid-filled channels or by vesicular transport. This issue was examined in rats whose blood-brain barrier (BBB) was presumed to be intact (untreated) and in rats that received intracarotid infusions to open the BBB (isosmotic salt (ISS) and hyperosmolar arabinose). Ohno PS values of 3H-inulin and 14C-L-glucose in untreated rats were found to decrease as the labelling time was lengthened. This was evidence that a rapidly equilibrating compartment exists between blood and brain that renders the Ohno two-compartment model inadequate for computing true transfer rate constants. When the data were reanalyzed using a multi-compartment graphical analysis, solutes with different molecular radii were found to enter the brain at approximately equal rates. Furthermore, unidirectional transport is likely to be initiated by solute adsorption to a glycocalyx coat on the luminal surface of brain capillary endothelium. Apparently, more inulin than L-glucose was adsorbed, which may account for its slightly faster transfer across the BBB. After rats were treated with intracarotid infusions of ISS or hyperosmolar arabinose, solute PS values were significantly increased, but the ratio of PS for each of the solute pairs approached that of their free-diffusion coefficients

  20. Establishment of rat model of opening blood-brain barrier with conventional whole-brain irradiation

    International Nuclear Information System (INIS)

    Objective: To establish a rat model of opening blood-brain barrier with conventional whole-brain irradiation. Methods: According to different dosage of irradiation, a hundred Sprague-Dowley rats were randomly assigned into five groups, the control group (no irradiation), and four irradiated groups at 10 grays, 20 grays, 30 grays and 40 grays. The rats were administered to conventional fraction irradiation (2 Gy/day and 5 days a week) with routine 60Co gamma-rays. The intake of feed and autonomic activities were observed every day. Changes in skin and hair in the irradiated field, body weight, and center nervous system symptoms and signs were examined and recorded every week during irradiation. The neurological status was ranked on a scale based on the Mickley's Scale. Ultrastructure changes of blood-brain barrier at 16 hours after the last irradiation were examined with electron microscope using lanthanum trace labeling. Results: Neither abnormal nervous sign, nor change of feed intake, skin and hair was observed in all the rats. No statistically significant difference of body weight was observed among the five groups (P>0.05). The effect that radiation can directly damage the function and structure of blood-brain barrier was proportional to irradiation doses. Conclusion: This rat model is a suitable for study on blood-brain barrier pathophysiology and molecular biology after conventional whole-brain irradiation. (authors)

  1. Blood brain barrier and brain tissue injury by Gd-DTPA in uremia-induced rabbits

    International Nuclear Information System (INIS)

    An experimental study was carried out to evaluate the morphological changes in the blood brain barrier and neighbouring brain tissue caused by Gd-DTPA in uremia-induced rabbits. Bilateral renal arteries and veins of ten rabbits were ligated. Gd-DTPA(0.2mmol/kg) was intravenously injected into seven rabbits immediately after ligation. After MRI, they were sacrificed 2 or 3 days after ligation in order to observe light and electron microscopic changes in the blood brain barrier and brain tissue. MRI findings were normal, except for enhancement of the superior and inferior sagittal sinuses on T1 weighted images in uremia-induced rabbits injected with Gd-DTPA. On light microscopic examination, these rabbits showed perivascular edema and glial fibrillary acidic protein expression: electron microscopic examination showed separation of tight junctions of endothelial cells, duplication/rarefaction of basal lamina, increased lysosomes of neurons with neuronal death, demyelination of myelin, and extravasation of red blood cells. Uremia-induced rabbits injected with Gd-DTPA showed more severe changes than those without Gd-DTPA injection. Injuries to the blood brain barrier and neighbouring brain tissue were aggravated by Gd-DTPA administration in uremia-induced rabbits. These findings appear to be associated with the neurotoxicity of Gd-DTPA

  2. Spatiotemporal changes in blood-brain barrier permeability, cerebral blood flow, T2 and diffusion following mild traumatic brain injury.

    Science.gov (United States)

    Li, Wei; Watts, Lora; Long, Justin; Zhou, Wei; Shen, Qiang; Jiang, Zhao; Li, Yunxia; Duong, Timothy Q

    2016-09-01

    The blood-brain barrier (BBB) can be impaired following traumatic brain injury (TBI), however the spatiotemporal dynamics of BBB leakage remain incompletely understood. In this study, we evaluated the spatiotemporal evolution of BBB permeability using dynamic contrast-enhanced MRI and measured the volume transfer coefficient (K(trans)), a quantitative measure of contrast agent leakage across the blood and extravascular compartment. Measurements were made in a controlled cortical impact (CCI) model of mild TBI in rats from 1h to 7 days following TBI. The results were compared with cerebral blood flow, T2 and diffusion MRI from the same animal. Spatially, K(trans) changes were localized to superficial cortical layers within a 1mm thickness, which was dramatically different from the changes in cerebral blood flow, T2 and diffusion, which were localized to not only the superficial layers but also to brain regions up to 2.2mm from the cortical surface. Temporally, K(trans) changes peaked at day 3, similar to CBF and ADC changes, but differed from T2 and FA, whose changes peaked on day 2. The pattern of superficial cortical layer localization of K(trans) was consistent with patterns revealed by Evans Blue extravasation. Collectively, these results suggest that BBB disruption, edema formation, blood flow disturbance and diffusion changes are related to different components of the mechanical impact, and may play different roles in determining injury progression and tissue fate processes following TBI. PMID:27208495

  3. Blood-brain barrier and blood-cerebrospinal fluid barrier in normal and pathological conditions.

    Science.gov (United States)

    Ueno, Masaki; Chiba, Yoichi; Murakami, Ryuta; Matsumoto, Koichi; Kawauchi, Machi; Fujihara, Ryuji

    2016-04-01

    Blood-borne substances can invade into the extracellular spaces of the brain via endothelial cells in sites without the blood-brain barrier (BBB), and can travel through the interstitial fluid (ISF) of the brain parenchyma adjacent to non-BBB sites. It has been shown that cerebrospinal fluid (CSF) drains directly into the blood via the arachnoid villi and also into lymph nodes via the subarachnoid spaces of the brain, while ISF drains into the cervical lymph nodes through perivascular drainage pathways. In addition, the glymphatic pathway of fluids, characterized by para-arterial pathways, aquaporin4-dependent passage through astroglial cytoplasm, interstitial spaces, and paravenous routes, has been established. Meningeal lymphatic vessels along the superior sagittal sinus were very recently discovered. It is known that, in mice, blood-borne substances can be transferred to areas with intact BBB function, such as the medial regions of the hippocampus, presumably through leaky vessels in non-BBB sites. In the present paper, we review the clearance mechanisms of interstitial substances, such as amyloid-β peptides, as well as summarize models of BBB deterioration in response to different types of insults, including acute ischemia followed by reperfusion, hypertension, and chronic hypoperfusion. Lastly, we discuss the relationship between perivascular clearance and brain disorders. PMID:26920424

  4. Blood flow and oxygenation in peritendinous tissue and calf muscle during dynamic exercise in humans

    DEFF Research Database (Denmark)

    Boushel, Robert Christopher; Langberg, H; Green, Sara Marie Ehrenreich;

    2000-01-01

    1. Circulation around tendons may act as a shunt for muscle during exercise. The perfusion and oxygenation of Achilles' peritendinous tissue was measured in parallel with that of calf muscle during exercise to determine (1) whether blood flow is restricted in peritendinous tissue during exercise...... output by dye dilution, arterial pressure by an arterial catheter-transducer, and muscle and peritendinous O2 saturation by spatially resolved spectroscopy (SRS). 3. Calf blood flow rose 20-fold with exercise, reaching 44 +/- 7 ml (100 g)-1 min-1 (mean +/- s.e.m. ) at 9 W, while Achilles' peritendinous...... with a rise in leg vascular conductance and microvascular haemoglobin volume, despite elevated systemic vascular resistance. 4. The parallel rise in calf muscle and peritendinous blood flow and fall in O2 saturation during exercise indicate that blood flow is coupled to oxidative metabolism in both...

  5. Increased blood pressure can reduce fatigue of thenar muscles paralyzed after spinal cord injury

    NARCIS (Netherlands)

    Butler, JE; Ribot-Ciscar, E; Zijdewind, Inge; Thomas, CK

    2004-01-01

    The aim of this study was to evaluate whether increases in blood pressure, and presumably muscle perfusion pressure, improve the endurance of thenar muscles paralyzed chronically by cervical spinal cord injury (SCI). Resting mean arterial pressure (MAP) was low in all eight subjects (64 +/- 2 mmHg).

  6. Noninvasive optical characterization of muscle blood flow, oxygenation, and metabolism in women with fibromyalgia

    OpenAIRE

    Shang, Yu; Gurley, Katelyn; Symons, Brock; Long, Douglas; Srikuea, Ratchakrit; Crofford., Leslie J.; Peterson, Charlotte A.; Yu, Guoqiang

    2012-01-01

    Introduction Women with fibromyalgia (FM) have symptoms of increased muscular fatigue and reduced exercise tolerance, which may be associated with alterations in muscle microcirculation and oxygen metabolism. This study used near-infrared diffuse optical spectroscopies to noninvasively evaluate muscle blood flow, blood oxygenation and oxygen metabolism during leg fatiguing exercise and during arm arterial cuff occlusion in post-menopausal women with and without FM. Methods Fourteen women with...

  7. Noninvasive optical quantification of absolute blood flow, blood oxygenation, and oxygen consumption rate in exercising skeletal muscle

    Science.gov (United States)

    Gurley, Katelyn; Shang, Yu; Yu, Guoqiang

    2012-07-01

    This study investigates a method using novel hybrid diffuse optical spectroscopies [near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS)] to obtain continuous, noninvasive measurement of absolute blood flow (BF), blood oxygenation, and oxygen consumption rate (\\Vdot O2) in exercising skeletal muscle. Healthy subjects (n=9) performed a handgrip exercise to increase BF and \\Vdot O2 in forearm flexor muscles, while a hybrid optical probe on the skin surface directly monitored oxy-, deoxy-, and total hemoglobin concentrations ([HbO2], [Hb], and THC), tissue oxygen saturation (StO2), relative BF (rBF), and relative oxygen consumption rate (r\\Vdot O2). The rBF and r\\Vdot O2 signals were calibrated with absolute baseline BF and \\Vdot O2 obtained through venous and arterial occlusions, respectively. Known problems with muscle-fiber motion artifacts in optical measurements during exercise were mitigated using a novel gating algorithm that determined muscle contraction status based on control signals from a dynamometer. Results were consistent with previous findings in the literature. This study supports the application of NIRS/DCS technology to quantitatively evaluate hemodynamic and metabolic parameters in exercising skeletal muscle and holds promise for improving diagnosis and treatment evaluation for patients suffering from diseases affecting skeletal muscle and advancing fundamental understanding of muscle and exercise physiology.

  8. Muscle fatigue in fibromyalgia is in the brain, not in the muscles

    DEFF Research Database (Denmark)

    Bandak, Elisabeth; Amris, Kirstine; Bliddal, Henning;

    2013-01-01

    To investigate relationships between perceived and objectively measured muscle fatigue during exhausting muscle contractions in women with fibromyalgia (FM) compared with healthy controls (HC).......To investigate relationships between perceived and objectively measured muscle fatigue during exhausting muscle contractions in women with fibromyalgia (FM) compared with healthy controls (HC)....

  9. Peripheral blood brain-derived neurotrophic factor in bipolar disorder

    DEFF Research Database (Denmark)

    Munkholm, K; Vinberg, M; Kessing, L V

    2016-01-01

    Peripheral blood brain-derived neurotrophic factor (BDNF) has been proposed as a potential biomarker related to disease activity and neuroprogression in bipolar disorder, speculated to mirror alterations in brain expression of BDNF. The research area is rapidly evolving; however, recent...... investigations have yielded conflicting results with substantial variation in outcomes, highlighting the need to critically assess the state of current evidence. The aims of the study were to investigate differences in peripheral blood BDNF concentrations between bipolar disorder patients and healthy control...... subjects and between affective states in bipolar disorder patients, including assessment of the effect of treatment of acute episodes on BDNF levels. A systematic review of English language studies without considering publication status was conducted in PubMed (January 1950-November 2014), Embase (1974...

  10. Estrogen and insulin transport through the blood-brain barrier.

    Science.gov (United States)

    May, Aaron A; Bedel, Nicholas D; Shen, Ling; Woods, Stephen C; Liu, Min

    2016-09-01

    Obesity is associated with insulin resistance and reduced transport of insulin through the blood-brain barrier (BBB). Reversal of high-fat diet-induced obesity (HFD-DIO) by dietary intervention improves the transport of insulin through the BBB and the sensitivity of insulin in the brain. Although both insulin and estrogen (E2), when given alone, reduce food intake and body weight via the brain, E2 actually renders the brain relatively insensitive to insulin's catabolic action. The objective of these studies was to determine if E2 influences the ability of insulin to be transported into the brain, since the receptors for both E2 and insulin are found in BBB endothelial cells. E2 (acute or chronic) was systemically administered to ovariectomized (OVX) female rats and male rats fed a chow or a high-fat diet. Food intake, body weight and other metabolic parameters were assessed along with insulin entry into the cerebrospinal fluid (CSF). Acute E2 treatment in OVX female and male rats reduced body weight and food intake, and chronic E2 treatment prevented or partially reversed high-fat diet-induced obesity. However, none of these conditions increased insulin transport into the CNS; rather, chronic E2 treatment was associated less-effective insulin transport into the CNS relative to weight-matched controls. Thus, the reduction of brain insulin sensitivity by E2 is unlikely to be mediated by increasing the amount of insulin entering the CNS. PMID:27182046

  11. Electrical Stimulation of the Suprahyoid Muscles in Brain-injured Patients with Dysphagia: A Pilot Study

    OpenAIRE

    Beom, Jaewon; Kim, Sang Jun; Han, Tai Ryoon

    2011-01-01

    Objective To investigate the therapeutic effects of repetitive electrical stimulation of the suprahyoid muscles in brain-injured patients with dysphagia. Method Twenty-eight brain-injured patients who showed reduced laryngeal elevation and supraglottic penetration or subglottic aspiration during a videofluoroscopic swallowing study (VFSS) were selected. The patients received either conventional dysphagia management (CDM) or CDM with repetitive electrical stimulation of the suprahyoid muscles ...

  12. SHIFTING OF ACTIVATION CENTER IN THE BRAIN DURING MUSCLE FATIGUE: AN EXPLANATION OF MINIMAL CENTRAL FATIGUE?

    OpenAIRE

    Liu, Jing Z; Lewandowski, Beth; Karakasis, Chris; Yao, Bing; Siemionow, Vlodek; Sahgal, Vinod; Yue, Guang H

    2007-01-01

    Accumulating evidence suggests that the overall level of cortical activation controlling a voluntary motor task that leads to significant muscle fatigue does not decrease as much as the activation level of the motoneuron pool projecting to the muscle. One possible explanation for this “muscle fatigue>cortical fatigue” phenomenon is that the brain is an organ with built-in redundancies: it has multiple motor centers and parallel pathways, and the center of activation may shift from one locatio...

  13. Gliomas and the vascular fragility of the blood brain barrier

    Science.gov (United States)

    Dubois, Luiz Gustavo; Campanati, Loraine; Righy, Cassia; D’Andrea-Meira, Isabella; Spohr, Tania Cristina Leite de Sampaio e; Porto-Carreiro, Isabel; Pereira, Claudia Maria; Balça-Silva, Joana; Kahn, Suzana Assad; DosSantos, Marcos F.; Oliveira, Marcela de Almeida Rabello; Ximenes-da-Silva, Adriana; Lopes, Maria Celeste; Faveret, Eduardo; Gasparetto, Emerson Leandro; Moura-Neto, Vivaldo

    2014-01-01

    Astrocytes, members of the glial family, interact through the exchange of soluble factors or by directly contacting neurons and other brain cells, such as microglia and endothelial cells. Astrocytic projections interact with vessels and act as additional elements of the Blood Brain Barrier (BBB). By mechanisms not fully understood, astrocytes can undergo oncogenic transformation and give rise to gliomas. The tumors take advantage of the BBB to ensure survival and continuous growth. A glioma can develop into a very aggressive tumor, the glioblastoma (GBM), characterized by a highly heterogeneous cell population (including tumor stem cells), extensive proliferation and migration. Nevertheless, gliomas can also give rise to slow growing tumors and in both cases, the afflux of blood, via BBB is crucial. Glioma cells migrate to different regions of the brain guided by the extension of blood vessels, colonizing the healthy adjacent tissue. In the clinical context, GBM can lead to tumor-derived seizures, which represent a challenge to patients and clinicians, since drugs used for its treatment must be able to cross the BBB. Uncontrolled and fast growth also leads to the disruption of the chimeric and fragile vessels in the tumor mass resulting in peritumoral edema. Although hormonal therapy is currently used to control the edema, it is not always efficient. In this review we comment the points cited above, considering the importance of the BBB and the concerns that arise when this barrier is affected. PMID:25565956

  14. Effects of intravascular contrast media on blood-brain barrier

    International Nuclear Information System (INIS)

    The effects upon the rabbit blood-brain barrier after intracarotid injection of two non-ionic contrast media, iopentol (a monomer) and iodixanol (a dimer) were compared. Iothalamate and iohexol were used as reference substances. 99Tcm-DTPA, 125I-HSA and Trypsin blue were used as tracers in order to demonstrate various degrees of damage to the barrier. Injection of iothalamate led to large extravasation of 99Tcm-DTPA, 125I-HSA and Trypan blue which means severe damage of the blood-brain barrier. Injection of iopentol and iohexol resulted in some extravasation of all three tracers used, whereas injection of iodixanol only led to extravasation of the small molecule tracer 99Tcm-DTPA demonstrating minor changes of the barrier. At computed tomography of the brain with intravascular contrast medium enhancement it is safer to use iodixanol than iothalamate. Iodixanol is expected to cause even less adverse effects to the brain after intraarterial injection than iopentol and iohexol. (orig.)

  15. Drug transport across the blood-brain barrier.

    Science.gov (United States)

    Pardridge, William M

    2012-11-01

    The blood-brain barrier (BBB) prevents the brain uptake of most pharmaceuticals. This property arises from the epithelial-like tight junctions within the brain capillary endothelium. The BBB is anatomically and functionally distinct from the blood-cerebrospinal fluid barrier at the choroid plexus. Certain small molecule drugs may cross the BBB via lipid-mediated free diffusion, providing the drug has a molecular weight hydrogen bonds. These chemical properties are lacking in the majority of small molecule drugs, and all large molecule drugs. Nevertheless, drugs can be reengineered for BBB transport, based on the knowledge of the endogenous transport systems within the BBB. Small molecule drugs can be synthesized that access carrier-mediated transport (CMT) systems within the BBB. Large molecule drugs can be reengineered with molecular Trojan horse delivery systems to access receptor-mediated transport (RMT) systems within the BBB. Peptide and antisense radiopharmaceuticals are made brain-penetrating with the combined use of RMT-based delivery systems and avidin-biotin technology. Knowledge on the endogenous CMT and RMT systems expressed at the BBB enable new solutions to the problem of BBB drug transport. PMID:22929442

  16. Role of the Blood-Brain Barrier in the Formation of Brain Metastases

    Directory of Open Access Journals (Sweden)

    István A. Krizbai

    2013-01-01

    Full Text Available The majority of brain metastases originate from lung cancer, breast cancer and malignant melanoma. In order to reach the brain, parenchyma metastatic cells have to transmigrate through the endothelial cell layer of brain capillaries, which forms the morphological basis of the blood-brain barrier (BBB. The BBB has a dual role in brain metastasis formation: it forms a tight barrier protecting the central nervous system from entering cancer cells, but it is also actively involved in protecting metastatic cells during extravasation and proliferation in the brain. The mechanisms of interaction of cancer cells and cerebral endothelial cells are largely uncharacterized. Here, we provide a comprehensive review on our current knowledge about the role of junctional and adhesion molecules, soluble factors, proteolytic enzymes and signaling pathways mediating the attachment of tumor cells to brain endothelial cells and the transendothelial migration of metastatic cells. Since brain metastases represent a great therapeutic challenge, it is indispensable to understand the mechanisms of the interaction of tumor cells with the BBB in order to find targets of prevention of brain metastasis formation.

  17. Distribution of blood flow in the muscles of conscious animals during exercise

    International Nuclear Information System (INIS)

    This study reviews the recent research on the distribution of blood flow within and among skeletal muscles in conscious animals during locomotory exercise. A brief description of the technique that has been used in these studies, the radiolabeled microsphere method, is presented, including a short discussion of the assumptions that must be met in using the methodology. Distinct patterns of flow distribution occur in the muscles during exercise that are related to the fiber-type composition of the muscles or muscle parts (and, presumably, the patterns of fiber recruitment) and the intensity of the exercise. The mechanisms that regulate the differential elevations in blood flow within and among the muscles at the initiation of exercise have not been elucidated. However, studies on the conscious animal model indicate that the control cannot be totally explained by local metabolic factors, sympathetic influences or mechanical effects

  18. A correlation study of the expression of resistin and glycometabolism in muscle tissue after traumatic brain injury in rats

    Directory of Open Access Journals (Sweden)

    Jin Peng

    2014-06-01

    Full Text Available Objective:To investigate the expression pattern of resistin (RSTN in skeletal muscle tissue and its influence on glycometabolism in rats with traumatic brain injury (TBI. Methods:Seventy-eight SD rats were randomly divided into traumatic group (n=36, RSTN group (n=36 and sham operation group (n=6. Fluid percussion TBI model was developed in traumatic and RSTN groups and the latter received additional 1 mg RSTN antibody treatment for each rat. At respectively 12 h, 24 h, 72 h, 1 w, 2 w, and 4 w after operation, venous blood was collected and the right hind leg skeletal muscle tissue was sampled. We used real-time PCR to determine mRNA expression of RSTN in skeletal muscles, western blot to determine RSTN protein expression and ELISA to assess serum insulin as well as fasting blood glucose (FBG levels. Calculation of the quantitative insulin sensitivity check index (Q value was also conducted. The above mentioned indicators and their correction were statistically analyzed. Results:Compared with sham operation group, the RSTN expression in the skeletal muscle as well as serum insulin and FBG levels revealed significant elevation (P<0.05, and reduced Q value (P<0.05 in traumatic group. Single factor linear correlation analysis showed a significant negative correlation between RSTN expression and Q values (P<0.001 in traumatic group. Conclusion:The expression of RSTN has been greatly increased in the muscular tissue of TBI rats and it was closely related to the index of glycometabolism. RSTN may play an important role in the process of insulin resistance after TBI. Key words: Brain injuries; Resistin; Insulin resistance; Blood glucose; Insulin sensitivity

  19. Effects of High-Intensity Blood Flow Restriction Exercise on Muscle Fatigue

    Directory of Open Access Journals (Sweden)

    Neto Gabriel R.

    2014-07-01

    Full Text Available Strength training combined with blood flow restriction (BFR have been used to improve the levels of muscle adaptation. The aim of this paper was to investigate the acute effect of high intensity squats with and without blood flow restriction on muscular fatigue levels. Twelve athletes (aged 25.95 ± 0.84 years were randomized into two groups: without Blood Flow Restriction (NFR, n = 6 and With Blood Flow Restriction (WFR, n = 6 that performed a series of free weight squats with 80% 1-RM until concentric failure. The strength of the quadriceps extensors was assessed in a maximum voluntary isometric contraction integrated to signals from the surface electromyogram. The average frequency showed significant reductions in the WFR group for the vastus lateralis and vastus medialis muscles, and intergroup only for the vastus medialis. In conclusion, a set of squats at high intensity with BFR could compromise muscle strength immediately after exercise, however, differences were not significant between groups.

  20. Nanoparticle-mediated brain drug delivery: Overcoming blood-brain barrier to treat neurodegenerative diseases.

    Science.gov (United States)

    Saraiva, Cláudia; Praça, Catarina; Ferreira, Raquel; Santos, Tiago; Ferreira, Lino; Bernardino, Liliana

    2016-08-10

    The blood-brain barrier (BBB) is a vital boundary between neural tissue and circulating blood. The BBB's unique and protective features control brain homeostasis as well as ion and molecule movement. Failure in maintaining any of these components results in the breakdown of this specialized multicellular structure and consequently promotes neuroinflammation and neurodegeneration. In several high incidence pathologies such as stroke, Alzheimer's (AD) and Parkinson's disease (PD) the BBB is impaired. However, even a damaged and more permeable BBB can pose serious challenges to drug delivery into the brain. The use of nanoparticle (NP) formulations able to encapsulate molecules with therapeutic value, while targeting specific transport processes in the brain vasculature, may enhance drug transport through the BBB in neurodegenerative/ischemic disorders and target relevant regions in the brain for regenerative processes. In this review, we will discuss BBB composition and characteristics and how these features are altered in pathology, namely in stroke, AD and PD. Additionally, factors influencing an efficient intravenous delivery of polymeric and inorganic NPs into the brain as well as NP-related delivery systems with the most promising functional outcomes will also be discussed. PMID:27208862

  1. Skeletal muscle fiber, nerve, and blood vessel breakdown in space-flown rats

    Science.gov (United States)

    Riley, D. A.; Ilyina-Kakueva, E. I.; Ellis, S.; Bain, J. L.; Slocum, G. R.; Sedlak, F. R.

    1990-01-01

    Histochemical and ultrastructural analyses were performed postflight on hind limb skeletal muscles of rats orbited for 12.5 days aboard the unmanned Cosmos 1887 biosatellite and returned to Earth 2 days before sacrifice. The antigravity adductor longus (AL), soleus, and plantaris muscles atrophied more than the non-weight-bearing extensor digitorum longus, and slow muscle fibers were more atrophic than fast fibers. Muscle fiber segmental necrosis occurred selectively in the AL and soleus muscles; primarily, macrophages and neutrophils infiltrated and phagocytosed cellular debris. Granule-rich mast cells were diminished in flight AL muscles compared with controls, indicating the mast cell secretion contributed to interstitial tissue edema. Increased ubiquitination of disrupted myofibrils implicated ubiquitin in myofilament degradation. Mitochondrial content and succinic dehydrogenase activity were normal, except for subsarcolemmal decreases. Myofibrillar ATPase activity of flight AL muscle fibers shifted toward the fast type. Absence of capillaries and extravasation of red blood cells indicated failed microcirculation. Muscle fiber regeneration from activated satellite cells was detected. About 17% of the flight AL end plates exhibited total or partial denervation. Thus, skeletal muscle weakness associated with spaceflight can result from muscle fiber atrophy and segmental necrosis, partial motor denervation, and disruption of the microcirculation.

  2. Brain and muscle oxygenation monitoring using near-infrared spectroscopy (NIRS) during all-night sleep

    Science.gov (United States)

    Zhang, Zhongxing; Khatami, Ramin

    2013-03-01

    The hemodynamic changes during natural human sleep are still not well understood. NIRS is ideally suited for monitoring the hemodynamic changes during sleep due to the properties of local measurement, totally safe application and good tolerance to motion. Several studies have been conducted using NIRS in both normal subjects and patients with various sleep disorders during sleep to characterize the hemodynamic changing patterns during different sleep stages and during different symptoms such as obstructive apneas. Here we assessed brain and muscle oxygenation changes in 7 healthy adults during all-night sleep with combined polysomnography measurement to test the notion if hemodynamic changes in sleep are indeed brain specific. We found that muscle and brain showed similar hemodynamic changes during sleep initiation. A decrease in HbO2 and tissue oxygenation index (TOI) while an increase in HHb was observed immediately after sleep onset, and an opposite trend was found after transition with progression to deeper slow-wave sleep (SWS) stage. Spontaneous low frequency oscillations (LFO) and very low frequency oscillations (VLFO) were smaller (Levene's test, psleep (LS) and rapid-eye-movement (REM) sleep in both brain and muscle. Spectral analysis of the NIRS signals measured from brain and muscle also showed reductions in VLFO and LFO powers during SWS with respect to LS and REM sleep. These results indicate a systemic attenuation rather than local cerebral reduction of spontaneous hemodynamic activity in SWS. A systemic physiological mechanism may exist to regulate the hemodynamic changes in brain and muscle during sleep.

  3. Brain blood vessel segmentation using line-shaped profiles

    International Nuclear Information System (INIS)

    Segmentation of cerebral blood vessels is of great importance in diagnostic and clinical applications, especially for embolization of cerebral aneurysms and arteriovenous malformations (AVMs). In order to perform embolization of the AVM, the structural and geometric information of blood vessels from 3D images is of utmost importance. For this reason, the in-depth segmentation of cerebral blood vessels is usually done as a fusion of different segmentation techniques, often requiring extensive user interaction. In this paper we introduce the idea of line-shaped profiling with an application to brain blood vessel and AVM segmentation, efficient both in terms of resolving details and in terms of computation time. Our method takes into account both local proximate and wider neighbourhood of the processed pixel, which makes it efficient for segmenting large blood vessel tree structures, as well as fine structures of the AVMs. Another advantage of our method is that it requires selection of only one parameter to perform segmentation, yielding very little user interaction. (paper)

  4. Blood-brain barrier permeability and brain uptake mechanism of kainic Acid and dihydrokainic Acid

    DEFF Research Database (Denmark)

    Gynther, Mikko; Petsalo, Aleksanteri; Hansen, Steen Honoré;

    2015-01-01

    tools in various in vivo central nervous system disease models in rodents, as well as being templates in the design of novel ligands affecting the glutamatergic system. Both molecules are highly polar but yet capable of crossing the blood-brain barrier (BBB). We used an in situ rat brain perfusion...... low, 0.25 × 10(-6) and 0.28 × 10(-6) cm/s for KA and DHK, respectively. In addition, the brain uptake is mediated by passive diffusion, and not by active transport. Furthermore, the non-specific plasma and brain protein binding of KA and DHK was determined to be low, which means that the unbound drug...

  5. A novel transgenic zebrafish model for blood-brain and blood-retinal barrier development

    Directory of Open Access Journals (Sweden)

    Sugimoto Masahiko

    2010-07-01

    Full Text Available Abstract Background Development and maintenance of the blood-brain and blood-retinal barrier is critical for the homeostasis of brain and retinal tissue. Despite decades of research our knowledge of the formation and maintenance of the blood-brain (BBB and blood-retinal (BRB barrier is very limited. We have established an in vivo model to study the development and maintenance of these barriers by generating a transgenic zebrafish line that expresses a vitamin D-binding protein fused with enhanced green fluorescent protein (DBP-EGFP in blood plasma, as an endogenous tracer. Results The temporal establishment of the BBB and BRB was examined using this transgenic line and the results were compared with that obtained by injection of fluorescent dyes into the sinus venosus of embryos at various stages of development. We also examined the expression of claudin-5, a component of tight junctions during the first 4 days of development. We observed that the BBB of zebrafish starts to develop by 3 dpf, with expression of claudin-5 in the central arteries preceding it at 2 dpf. The hyaloid vasculature in the zebrafish retina develops a barrier function at 3 dpf, which endows the zebrafish with unique advantages for studying the BRB. Conclusion Zebrafish embryos develop BBB and BRB function simultaneously by 3 dpf, which is regulated by tight junction proteins. The Tg(l-fabp:DBP-EGFP zebrafish will have great advantages in studying development and maintenance of the blood-neural barrier, which is a new application for the widely used vertebrate model.

  6. Impact of migraine attacks on the blood-brain barrier

    Institute of Scientific and Technical Information of China (English)

    GAO Hong-mei; LI Le; ZHANG Ke-ling; CHEN Xu-hui; TIAN Shu-qing; ZHANG Zhong-ling

    2010-01-01

    Background Cortical spreading depression can cause migraine attack, and up-regulate matrix metalloproteinase-9 (MMP-9) expression in animal. This study aimed to determine the impact on the structure and function of the blood-brain barrier by measuring plasma MMP-9 levels in patients at the acute and late stages of migraine attacks in order to elucidate the pathological mechanisms involved.Methods We recruited a case-control cohort of 38 adult migraine patients and 20 age- and gender-matched healthy control subjects. Five milliliter blood samples were collected at the acute and late stages of migraine (days 1-7), and also from the control subjects. Solid phase double antibody sandwich enzyme-linked immunosorbent assay was used to determine plasma MMP-9 levels. Statistical analysis was performed using the SAS version 9.1.Results Initial plasma MMP-9 levels of migraine patients were significantly higher than those of controls ((12.612±0.016)μg/L vs. (6.069±0.023) μg/L, respectively, P 0.05); in addition, levels were not correlated with degree of headache pain (P >0.05).Conclusions We hypothesize that migraine could lead to increased plasma MMP-9 levels resulting in blood-brain barrier damage. MMP-9 levels increase during days 1-6 of migraine attacks, peaking on day 3. Therefore, MMP-9 could be used as a biological marker to guide treatment of migraine attacks.

  7. Measurement of brain perfusion, blood volume, and blood-brain barrier permeability, using dynamic contrast-enhanced T(1)-weighted MRI at 3 tesla

    DEFF Research Database (Denmark)

    Larsson, Henrik B W; Courivaud, Frédéric; Rostrup, Egill;

    2009-01-01

    Assessment of vascular properties is essential to diagnosis and follow-up and basic understanding of pathogenesis in brain tumors. In this study, a procedure is presented that allows concurrent estimation of cerebral perfusion, blood volume, and blood-brain permeability from dynamic T(1)-weighted...

  8. Prostaglandin E2 metabolism in rat brain: Role of the blood-brain interfaces

    Directory of Open Access Journals (Sweden)

    Strazielle Nathalie

    2008-03-01

    Full Text Available Abstract Background Prostaglandin E2 (PGE2 is involved in the regulation of synaptic activity and plasticity, and in brain maturation. It is also an important mediator of the central response to inflammatory challenges. The aim of this study was to evaluate the ability of the tissues forming the blood-brain interfaces to act as signal termination sites for PGE2 by metabolic inactivation. Methods The specific activity of 15-hydroxyprostaglandin dehydrogenase was measured in homogenates of microvessels, choroid plexuses and cerebral cortex isolated from postnatal and adult rat brain, and compared to the activity measured in peripheral organs which are established signal termination sites for prostaglandins. PGE2 metabolites produced ex vivo by choroid plexuses were identified and quantified by HPLC coupled to radiochemical detection. Results The data confirmed the absence of metabolic activity in brain parenchyma, and showed that no detectable activity was associated with brain microvessels forming the blood-brain barrier. By contrast, 15-hydroxyprostaglandin dehydrogenase activity was measured in both fourth and lateral ventricle choroid plexuses from 2-day-old rats, albeit at a lower level than in lung or kidney. The activity was barely detectable in adult choroidal tissue. Metabolic profiles indicated that isolated choroid plexus has the ability to metabolize PGE2, mainly into 13,14-dihydro-15-keto-PGE2. In short-term incubations, this metabolite distributed in the tissue rather than in the external medium, suggesting its release in the choroidal stroma. Conclusion The rat choroidal tissue has a significant ability to metabolize PGE2 during early postnatal life. This metabolic activity may participate in signal termination of centrally released PGE2 in the brain, or function as an enzymatic barrier acting to maintain PGE2 homeostasis in CSF during the critical early postnatal period of brain development.

  9. Changes in tissue blood flow and beta-receptor density of skeletal muscle in rats treated with the beta2-adrenoceptor agonist clenbuterol.

    OpenAIRE

    Rothwell, N. J.; Stock, M J; Sudera, D. K.

    1987-01-01

    Rats injected with the beta2-adrenoceptor agonist clenbuterol (2 mg kg-1 per day) for 18 days gained significantly more weight than controls. Tissue blood flow assessed 24 h after the last injection from the distribution of radiolabelled microspheres was increased in white (5 fold) and brown (3 fold) adipose tissue of clenbuterol-treated rats but was unaffected in kidney, brain and diaphragm, and was reduced by about 80% in skeletal muscle. Acute injection of clenbuterol one hour before measu...

  10. Perlecan and the Blood-Brain Barrier: Beneficial Proteolysis?

    Directory of Open Access Journals (Sweden)

    Jill eRoberts

    2012-08-01

    Full Text Available The cerebral microvasculature is important for maintaining brain homeostasis. This is achieved via the blood-brain barrier (BBB, composed of endothelial cells with specialized tight junctions, astrocytes and a basement membrane. Prominent components of the basement membrane extracellular matrix (ECM include fibronectin, laminin, collagen IV and perlecan, all of which regulate cellular processes via signal transduction through various cell membrane bound ECM receptors. Expression and proteolysis of these ECM components can be rapidly altered during pathological states of the central nervous system. In particular, proteolysis of perlecan, a heparan sulfate proteoglycan, occurs within hours following ischemia induced by experimental stroke. Proteolysis of ECM components following stroke results in the degradation of the basement membrane and further disruption of the BBB. While it is clear that such proteolysis has negative consequences for the BBB, we propose that it also may lead to generation of ECM protein fragments, including the C-terminal domain V (DV of perlecan, that potentially have a positive influence on other aspects of CNS health. Indeed, perlecan DV has been shown to be persistently generated after stroke and beneficial as a neuroprotective molecule and promoter of post-stroke brain repair. This mini-review will discuss beneficial roles of perlecan protein fragment generation within the brain during stroke.

  11. Blood flow and oxygenation in peritendinous tissue and calf muscle during dynamic exercise in humans

    DEFF Research Database (Denmark)

    Boushel, R; Langberg, Henning; Green, Stefan Mathias; Skovgaard, D; Bulow, J; Kjaer, M

    1. Circulation around tendons may act as a shunt for muscle during exercise. The perfusion and oxygenation of Achilles' peritendinous tissue was measured in parallel with that of calf muscle during exercise to determine (1) whether blood flow is restricted in peritendinous tissue during exercise...... output by dye dilution, arterial pressure by an arterial catheter-transducer, and muscle and peritendinous O2 saturation by spatially resolved spectroscopy (SRS). 3. Calf blood flow rose 20-fold with exercise, reaching 44 +/- 7 ml (100 g)-1 min-1 (mean +/- s.e.m. ) at 9 W, while Achilles' peritendinous...... flow increased (7-fold) to 14 +/- 4 ml (100 g)-1 min-1, which was 18 % of the maximal flow established during reactive hyperaemia. SRS-O2 saturation fell both in muscle (from 66 +/- 2 % at rest to 57 +/- 3 %, P <0.05) and in peritendinous regions (58 +/- 4 to 52 +/- 4 %, P <0.05) during exercise along...

  12. Evaluation of sedentary women’s ambulatory blood pressure and its relation to muscle strength

    Directory of Open Access Journals (Sweden)

    Ramires Alsamir Tibana

    2012-09-01

    Full Text Available Objective: To compare the ambulatory blood pressure in women with different values of relative muscle strength. Methods: Data from 21 (aged 33.8±8.0 years sedentary women from Vila Telebrasília was collected during the period of November 2010 to July 2011. The volunteers were submitted to the evaluation of the handgrip strength and ambulatory monitoring of blood pressure (AMBP for a 72-hour period. Following the evaluation of handgrip strength to determine the absolute muscle strength, an adjustment in the body mass was made, in order to determine the relative muscle strength. Based on the relative value of muscular strength, the sample was divided into tertiles to compare systolic, diastolic and mean blood pressure during the periods of 24 hours, daytime and night-time, by using an one-way ANOVA, followed by Bonferroni test when appropriate, with a significance level of p<0.05. Results: Significant differences were found for systolic blood pressure between tertile 1 (99.3±12.2 and tertile 3 (106.8±11.1 in the night-time (P<0.05. Values of mean blood pressure were also significantly different between tertile 1 (70.2±6.3 and tertile 3 (80.3 ± 8.8 in the night-time (p<0,05. Conclusion: Women with higher relative muscle strength present lower values of blood pressure during night-time

  13. Blood-brain barrier shuttle peptides: an emerging paradigm for brain delivery.

    Science.gov (United States)

    Oller-Salvia, Benjamí; Sánchez-Navarro, Macarena; Giralt, Ernest; Teixidó, Meritxell

    2016-08-22

    Brain delivery is one of the major challenges in drug development because of the high number of patients suffering from neural diseases and the low efficiency of the treatments available. Although the blood-brain barrier (BBB) prevents most drugs from reaching their targets, molecular vectors - known as BBB shuttles - offer great promise to safely overcome this formidable obstacle. In recent years, peptide shuttles have received growing attention because of their lower cost, reduced immunogenicity, and higher chemical versatility than traditional Trojan horse antibodies and other proteins. PMID:27188322

  14. Muscle and Blood Metabolites during a Soccer Game: Implications for Sprint Performance

    DEFF Research Database (Denmark)

    Krustrup, Peter; Mohr, Magni; Steensberg, Adam;

    2006-01-01

    Abstract: Purpose: To examine muscle and blood metabolites during soccer match play and relate it to possible changes in sprint performance. Methods: Thirty-one Danish fourth division players took part in three friendly games. Blood samples were collected frequently during the game, and muscle...... biopsies were taken before and after the game as well as immediately after an intense period in each half. The players performed five 30-m sprints interspersed by 25-s recovery periods before the game and immediately after each half (N = 11) or after an intense exercise period in each half (N = 20...... decreased (P < 0.05) from 449 +/- 23 to 255 +/- 22 mmol[middle dot]kg-1 d.w. during the game, with 47 +/- 7% of the muscle fibers being completely or almost empty of glycogen after the game. Blood glucose remained elevated during the game, whereas plasma FFA increased (P < 0.05) from 0.45 +/- 0.05 to 1...

  15. Multiscale modeling and simulation of brain blood flow

    Science.gov (United States)

    Perdikaris, Paris; Grinberg, Leopold; Karniadakis, George Em

    2016-02-01

    The aim of this work is to present an overview of recent advances in multi-scale modeling of brain blood flow. In particular, we present some approaches that enable the in silico study of multi-scale and multi-physics phenomena in the cerebral vasculature. We discuss the formulation of continuum and atomistic modeling approaches, present a consistent framework for their concurrent coupling, and list some of the challenges that one needs to overcome in achieving a seamless and scalable integration of heterogeneous numerical solvers. The effectiveness of the proposed framework is demonstrated in a realistic case involving modeling the thrombus formation process taking place on the wall of a patient-specific cerebral aneurysm. This highlights the ability of multi-scale algorithms to resolve important biophysical processes that span several spatial and temporal scales, potentially yielding new insight into the key aspects of brain blood flow in health and disease. Finally, we discuss open questions in multi-scale modeling and emerging topics of future research.

  16. Multiscale modeling and simulation of brain blood flow

    International Nuclear Information System (INIS)

    The aim of this work is to present an overview of recent advances in multi-scale modeling of brain blood flow. In particular, we present some approaches that enable the in silico study of multi-scale and multi-physics phenomena in the cerebral vasculature. We discuss the formulation of continuum and atomistic modeling approaches, present a consistent framework for their concurrent coupling, and list some of the challenges that one needs to overcome in achieving a seamless and scalable integration of heterogeneous numerical solvers. The effectiveness of the proposed framework is demonstrated in a realistic case involving modeling the thrombus formation process taking place on the wall of a patient-specific cerebral aneurysm. This highlights the ability of multi-scale algorithms to resolve important biophysical processes that span several spatial and temporal scales, potentially yielding new insight into the key aspects of brain blood flow in health and disease. Finally, we discuss open questions in multi-scale modeling and emerging topics of future research

  17. Multiscale modeling and simulation of brain blood flow

    Energy Technology Data Exchange (ETDEWEB)

    Perdikaris, Paris, E-mail: parisp@mit.edu [Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 (United States); Grinberg, Leopold, E-mail: leopoldgrinberg@us.ibm.com [IBM T.J Watson Research Center, 1 Rogers St, Cambridge, Massachusetts 02142 (United States); Karniadakis, George Em, E-mail: george-karniadakis@brown.edu [Division of Applied Mathematics, Brown University, Providence, Rhode Island 02912 (United States)

    2016-02-15

    The aim of this work is to present an overview of recent advances in multi-scale modeling of brain blood flow. In particular, we present some approaches that enable the in silico study of multi-scale and multi-physics phenomena in the cerebral vasculature. We discuss the formulation of continuum and atomistic modeling approaches, present a consistent framework for their concurrent coupling, and list some of the challenges that one needs to overcome in achieving a seamless and scalable integration of heterogeneous numerical solvers. The effectiveness of the proposed framework is demonstrated in a realistic case involving modeling the thrombus formation process taking place on the wall of a patient-specific cerebral aneurysm. This highlights the ability of multi-scale algorithms to resolve important biophysical processes that span several spatial and temporal scales, potentially yielding new insight into the key aspects of brain blood flow in health and disease. Finally, we discuss open questions in multi-scale modeling and emerging topics of future research.

  18. Protective effects of taurine in traumatic brain injury via mitochondria and cerebral blood flow.

    Science.gov (United States)

    Wang, Qin; Fan, Weijia; Cai, Ying; Wu, Qiaoli; Mo, Lidong; Huang, Zhenwu; Huang, Huiling

    2016-09-01

    In mammalian tissues, taurine is an important natural component and the most abundant free amino acid in the heart, retina, skeletal muscle, brain, and leukocytes. This study is to examine the taurine's protective effects on neuronal ultrastructure, the function of the mitochondrial respiratory chain complex, and on cerebral blood flow (CBF). The model of traumatic brain injury (TBI) was made for SD rats by a fluid percussion device, with taurine (200 mg/kg) administered by tail intravenous injection once daily for 7 days after TBI. It was found that CBF was improved for both left and right brain at 30 min and 7 days post-injury by taurine. Reaction time was prolonged relative to the TBI-only group. Neuronal damage was prevented by 7 days taurine. Mitochondrial electron transport chain complexes I and II showed greater activity with the taurine group. The improvement by taurine of CBF may alleviate edema and elevation in intracranial pressure. Importantly taurine improved the hypercoagulable state. PMID:27156064

  19. Regional blood flow and skeletal muscle energy status in endotoxemic rats

    International Nuclear Information System (INIS)

    Endotoxins induce muscle wasting in part as a result of depressed protein synthesis. To investigate whether these changes reflect impaired energy transduction, blood flow, O2 extraction, and high-energy phosphates in muscle and whole-body O2 consumption (Vo2) have been measured. Vo2 was measured for 6 h after an initial sublethal dose of endotoxin (Escherichia coli lipopolysaccharide 0.3 mg/100 g body wt sc) or saline and during 6 h after a second dose 24 h later. In fed or fasted rats, Vo2 was either increased or better maintained after endotoxin. In anesthetized fed rats 3-4 h after the second dose of endotoxin Vo2 was increased, and this was accompanied by increased blood flow measured by 57Co-labelled microspheres to liver (hepatic arterial supply), kidney, and perirenal brown adipose tissue and a 57 and 64% decrease in flow to back and hindlimb muscle, respectively, with no change in any other organ. Hindlimb arteriovenous O2 was unchanged, indicating markedly decreased aerobic metabolism in muscle, and the contribution of the hindlimb to whole-body Vo2 decreased by 46%. Adenosine 5'-triphosphate levels in muscle were unchanged in endotoxin-treated rats, and this was confirmed by topical nuclear magnetic resonance spectroscopy, which also showed muscle pH to be unchanged. These results show that, although there is decreased blood flow and aerobic oxidation in muscle, adenosine 5'-triphosphate availability does not appear to be compromised so that the endotoxin-induced muscle catabolism and decreased protein synthesis must reflex some other mechanism

  20. Skeletal muscle blood flow responses to hypoperfusion at rest and during rhythmic exercise in humans

    OpenAIRE

    Casey, Darren P.; Joyner, Michael J.

    2009-01-01

    We evaluated the contribution of changes in systemic arterial pressure and local vasodilation to blood flow restoration in contracting human muscles during acute hypoperfusion. Healthy subjects (n = 10) performed rhythmic forearm exercise (10% and 20% of maximum) while a balloon in the brachial artery located above the elbow was inflated. Each trial included 3 min of rest, exercise, exercise with balloon inflation, and exercise after balloon deflation. Forearm blood flow (FBF) was measured us...

  1. A Functional Requirement for Astroglia in Promoting Blood Vessel Development in the Early Postnatal Brain

    OpenAIRE

    Shang Ma; Hyo Jun Kwon; Zhen Huang

    2012-01-01

    Astroglia are a major cell type in the brain and play a key role in many aspects of brain development and function. In the adult brain, astrocytes are known to intimately ensheath blood vessels and actively coordinate local neural activity and blood flow. During development of the neural retina, blood vessel growth follows a meshwork of astrocytic processes. Several genes have also been implicated in retinal astrocytes for regulating vessel development. This suggests a role of astrocytes in p...

  2. Calcium-activated potassium channels mediated blood-brain tumor barrier opening in a rat metastatic brain tumor model

    OpenAIRE

    2007-01-01

    Background The blood-brain tumor barrier (BTB) impedes the delivery of therapeutic agents to brain tumors. While adequate delivery of drugs occurs in systemic tumors, the BTB limits delivery of anti-tumor agents into brain metastases. Results In this study, we examined the function and regulation of calcium-activated potassium (KCa) channels in a rat metastatic brain tumor model. We showed that intravenous infusion of NS1619, a KCa channel agonist, and bradykinin selectively enhanced BTB perm...

  3. Stroke and Drug Delivery—In Vitro Models of the Ischemic Blood-Brain Barrier

    DEFF Research Database (Denmark)

    Tornabene, Erica; Brodin, Birger

    2016-01-01

    Stroke is a major cause of death and disability worldwide. Both cerebral hypoperfusion and focal cerebral infarcts are caused by a reduction of blood flow to the brain, leading to stroke and subsequent brain damage. At present, only few medical treatments of stroke are available, with the Food and...... permeation pathways across the barrier in ischemic and postischemic brain endothelium is important for development of new medical treatments. The blood-brain barrier, that is, the endothelial monolayer lining the brain capillaries, changes properties during an ischemic event. In vitro models of the blood...

  4. In vivo interactions of magnetic nanoparticles with the blood-brain barrier

    International Nuclear Information System (INIS)

    Targeted drug delivery to the brain parenchyma, i.e., in brain tumor patients, by means of magnetically supported carrier delivery through the tight vascular endothelium of the blood-brain barrier is of critical biomedical importance. We were interested in delineating the first steps in successful brain drug delivery, which focuses on the interactions between magnetically guided yet freely blood circulating nanoparticles and the blood-brain barrier. We employed an in vivo model to quantitatively determine changes in cerebrovascular flow rate and volume during magnetically guided exposure of circulating nanoparticles.

  5. Electroporation of Brain Endothelial Cells on Chip toward Permeabilizing the Blood-Brain Barrier.

    Science.gov (United States)

    Bonakdar, Mohammad; Wasson, Elisa M; Lee, Yong W; Davalos, Rafael V

    2016-01-19

    The blood-brain barrier, mainly composed of brain microvascular endothelial cells, poses an obstacle to drug delivery to the brain. Controlled permeabilization of the constituent brain endothelial cells can result in overcoming this barrier and increasing transcellular transport across it. Electroporation is a biophysical phenomenon that has shown potential in permeabilizing and overcoming this barrier. In this study we developed a microengineered in vitro model to characterize the permeabilization of adhered brain endothelial cells to large molecules in response to applied pulsed electric fields. We found the distribution of affected cells by reversible and irreversible electroporation, and quantified the uptaken amount of naturally impermeable molecules into the cells as a result of applied pulse magnitude and number of pulses. We achieved 81 ± 1.7% (N = 6) electroporated cells with 17 ± 8% (N = 5) cell death using an electric-field magnitude of ∼580 V/cm and 10 pulses. Our results provide the proper range for applied electric-field intensity and number of pulses for safe permeabilization without significantly compromising cell viability. Our results demonstrate that it is possible to permeabilize the endothelial cells of the BBB in a controlled manner, therefore lending to the feasibility of using pulsed electric fields to increase drug transport across the BBB through the transcellular pathway. PMID:26789772

  6. Combined inhibition of nitric oxide and prostaglandins reduces human skeletal muscle blood flow during exercise

    DEFF Research Database (Denmark)

    Boushel, Robert Christopher; Langberg, Henning; Gemmer, Carsten;

    2002-01-01

    The vascular endothelium is an important mediator of tissue vasodilatation, yet the role of the specific substances, nitric oxide (NO) and prostaglandins (PG), in mediating the large increases in muscle perfusion during exercise in humans is unclear. Quadriceps microvascular blood flow was quanti...

  7. Skeletal muscle signaling and the heart rate and blood pressure response to exercise

    DEFF Research Database (Denmark)

    Mortensen, Stefan P; Svendsen, Jesper H; Ersbøll, Mads;

    2013-01-01

    Endurance training lowers heart rate and blood pressure responses to exercise, but the mechanisms and consequences remain unclear. To determine the role of skeletal muscle for the cardioventilatory response to exercise, 8 healthy young men were studied before and after 5 weeks of 1-legged knee-ex...... was ≈ 15 bpm lower during exercise with the trained leg (P...

  8. Role of adenosine in regulating the heterogeneity of skeletal muscle blood flow during exercise in humans

    DEFF Research Database (Denmark)

    Heinonen, Ilkka; Nesterov, Sergey V; Kemppainen, Jukka;

    2007-01-01

    Evidence from both animal and human studies suggests that adenosine plays a role in the regulation of exercise hyperemia in skeletal muscle. We tested whether adenosine also plays a role in the regulation of blood flow (BF) distribution and heterogeneity among and within quadriceps femoris (QF...

  9. Association between blood pressure levels over time and brain atrophy in the elderly

    NARCIS (Netherlands)

    den Heijer, T; Skoog, [No Value; Oudkerk, M; de Leeuw, FE; de Groot, JC; Hofman, A; Breteler, MMB

    2003-01-01

    The relation between blood pressure level and degree of global brain atrophy is equivocal. We evaluated past and present blood pressure levels and change in blood pressure over 20 years in relation to the degree of cortical atrophy on magnetic resonance imaging (MRI). In 1995-1996, we measured blood

  10. Blood flow restricted and traditional resistance training performed to fatigue produce equal muscle hypertrophy.

    Science.gov (United States)

    Farup, J; de Paoli, F; Bjerg, K; Riis, S; Ringgard, S; Vissing, K

    2015-12-01

    This study investigated the hypertrophic potential of load-matched blood-flow restricted resistance training (BFR) vs free-flow traditional resistance training (low-load TRT) performed to fatigue. Ten healthy young subjects performed unilateral BFR and contralateral low-load TRT elbow flexor dumbbell curl with 40% of one repetition maximum until volitional concentric failure 3 days per week for 6 weeks. Prior to and at 3 (post-3) and 10 (post-10) days post-training, magnetic resonance imaging (MRI) was used to estimate elbow flexor muscle volume and muscle water content accumulation through training. Acute changes in muscle thickness following an early vs a late exercise bout were measured with ultrasound to determine muscle swelling during the immediate 0-48 h post-exercise. Total work was threefold lower for BFR compared with low-load TRT (P BRF and low-load TRT increased muscle volume by approximately 12% at post-3 and post-10 (P BRF (P < 0.05) in the early training phase. In conclusion, BFR and low-load TRT, when performed to fatigue, produce equal muscle hypertrophy, which may partly rely on transient exercise-induced increases in muscle water content. PMID:25603897

  11. Transactivating-transduction protein-polyethylene glycol modified liposomes traverse the blood-spinal cord and blood-brain barriers

    Institute of Scientific and Technical Information of China (English)

    Xianhu Zhou; Chunyuan Wang; Shiqing Feng; Jin Chang; Xiaohong Kong; Yang Liu; Shijie Gao

    2012-01-01

    Naive liposomes can cross the blood-brain barrier and blood-spinal cord barrier in small amounts. Liposomes modified by a transactivating-transduction protein can deliver antibiotics for the treatment of acute bacterial infection-induced brain inflammation. Liposomes conjugated with polyethylene glycol have the capability of long-term circulation. In this study we prepared transactivating-transduction protein-polyethylene glycol-modified liposomes labeled with fluorescein isothiocyanate. Thus, liposomes were characterized by transmembrane, long-term circulation and fluorescence tracing. Uptake, cytotoxicity, and the ability of traversing blood-spinal cord and blood-brain barriers were observed following coculture with human breast adenocarcinoma cells (MCF-7). Results demonstrated that the liposomes had good biocompatibility, and low cytotoxicity when cocultured with human breast adenocarcinoma cells. Liposomes could traverse cell membranes and entered the central nervous system and neurocytes through the blood-spinal cord and blood-brain barriers of rats via the systemic circulation. These results verified that fluorescein isothiocyanate-modified transactivating-transduction protein-polyethylene glycol liposomes have the ability to traverse the blood-spinal cord and blood-brain barriers.

  12. A quantitative MRI method for imaging blood-brain barrier leakage in experimental traumatic brain injury.

    Directory of Open Access Journals (Sweden)

    Wei Li

    Full Text Available Blood-brain barrier (BBB disruption is common following traumatic brain injury (TBI. Dynamic contrast enhanced (DCE MRI can longitudinally measure the transport coefficient Ktrans which reflects BBB permeability. Ktrans measurements however are not widely used in TBI research because it is generally considered to be noisy and possesses low spatial resolution. We improved spatiotemporal resolution and signal sensitivity of Ktrans MRI in rats by using a high-sensitivity surface transceiver coil. To overcome the signal drop off profile of the surface coil, a pre-scan module was used to map the flip angle (B1 field and magnetization (M0 distributions. A series of T1-weighted gradient echo images were acquired and fitted to the extended Kety model with reversible or irreversible leakage, and the best model was selected using F-statistics. We applied this method to study the rat brain one hour following controlled cortical impact (mild to moderate TBI, and observed clear depiction of the BBB damage around the impact regions, which matched that outlined by Evans Blue extravasation. Unlike the relatively uniform T2 contrast showing cerebral edema, Ktrans shows a pronounced heterogeneous spatial profile in and around the impact regions, displaying a nonlinear relationship with T2. This improved Ktrans MRI method is also compatible with the use of high-sensitivity surface coil and the high-contrast two-coil arterial spin-labeling method for cerebral blood flow measurement, enabling more comprehensive investigation of the pathophysiology in TBI.

  13. Use of the Structure of Blood Vessel for Detection of Brain Aneurysm and Route Search to Brain Aneurysm

    Directory of Open Access Journals (Sweden)

    Toshihide Miyagi

    2013-08-01

    Full Text Available In this research, we constructed functions that are necessary for the operation simulation system which assists medical students to inhibit brain aneurysm from exploding. The system reported in this paper is "detection of blood vessels", "detection of brain aneurysm" and "route planning to brain aneurysm". Not only the detection method but also the method to reduce the miss detection is realized for the detection of blood vessel. Finally, the future work will be shown including construction of head model consisting of artery, vein, brain and cranium.

  14. Blood BDNF concentrations reflect brain-tissue BDNF levels across species

    DEFF Research Database (Denmark)

    Klein, Anders B; Williamson, Rebecca; Santini, Martin A;

    2011-01-01

    Brain-derived neurotrophic factor (BDNF) is involved in synaptic plasticity, neuronal differentiation and survival of neurons. Observations of decreased serum BDNF levels in patients with neuropsychiatric disorders have highlighted the potential of BDNF as a biomarker, but so far there have been no...... studies directly comparing blood BDNF levels to brain BDNF levels in different species. We examined blood, serum, plasma and brain-tissue BDNF levels in three different mammalian species: rat, pig, and mouse, using an ELISA method. As a control, we included an analysis of blood and brain tissue from...... conditional BDNF knockout mice and their wild-type littermates. Whereas BDNF could readily be measured in rat blood, plasma and brain tissue, it was undetectable in mouse blood. In pigs, whole-blood levels of BDNF could not be measured with a commercially available ELISA kit, but pig plasma BDNF levels (mean...

  15. Measurement of blood flow volume of ocular muscles by Xe-133 clearance method

    International Nuclear Information System (INIS)

    The blood flow volume of the ocular muscles was measured in 8 normal volunteers and 12 cases with miscellaneous opthalmic diseases by Xe-133 clearance method. The average of blood flow volume in the normal subjects was 7.45 ± 2.07 ml/min/100 g, and the blood flow volume ratio of right eye to left eye was 0.94 ± 0.07. The blood flow volume of the ocular muscles was decreased in the cases with stenosis of the internal carotid artery (n = 4, 4.3 ± 2.1 ml/min/100 g), glaucoma (n = 3, 4.7 ± 4.1 ml/min/100 g), arterial scleroses (n = 2, 3.8 ± 0.2 ml/min/100 g) and Takayasu's disease (n = 2, 5.6 ± 0.4 ml/min/100 g), and was increased in the acute inflammatory disease (n = 2, 21.5 ± 2.5 ml/min/100 g). Measurement of the blood flow volume of the ocular muscles using Xe-133 clearance method is useful to evaluate the circulatory abnormality in the ophthalmic diseases. (author)

  16. Transporter protein and drug-conjugated gold nanoparticles capable of bypassing the blood-brain barrier.

    Science.gov (United States)

    Zhang, Yanhua; Walker, Janelle Buttry; Minic, Zeljka; Liu, Fangchao; Goshgarian, Harry; Mao, Guangzhao

    2016-01-01

    Drug delivery to the central nervous system (CNS) is challenging due to the inability of many drugs to cross the blood-brain barrier (BBB). Here, we show that wheat germ agglutinin horse radish peroxidase (WGA-HRP) chemically conjugated to gold nanoparticles (AuNPs) can be transported to the spinal cord and brainstem following intramuscular injection into the diaphragm of rats. We synthesized and determined the size and chemical composition of a three-part nanoconjugate consisting of WGA-HRP, AuNPs, and drugs for the treatment of diaphragm paralysis associated with high cervical spinal cord injury (SCI). Upon injection into the diaphragm muscle of rats, we show that the nanoconjugate is capable of delivering the drug at a much lower dose than the unconjugated drug injected systemically to effectively induce respiratory recovery in rats following SCI. This study not only demonstrates a promising strategy to deliver drugs to the CNS bypassing the BBB but also contributes a potential nanotherapy for the treatment of respiratory muscle paralysis resulted from cervical SCI. PMID:27180729

  17. Biologic TNFα-inhibitors that cross the human blood-brain barrier

    OpenAIRE

    Pardridge, William M.

    2010-01-01

    Tumor necrosis factor (TNF)α inhibitors (TNFI) are a major class of biologic therapeutics, and include decoy receptor and monoclonal antibody (MAb) therapeutics that block TNFα action. TNFα is a pro-inflammatory cytokine in brain disease, such as stroke, brain or spinal cord injury, or Alzheimer disease. However, the biologic TNFIs cannot be developed for the brain, because these large molecules do not cross the blood-brain barrier (BBB). Brain penetrating forms of TNFα decoy receptors or ant...

  18. Non-viral liposome-mediated transfer of brain-derived neurotrophic factor across the blood-brain barrier

    Institute of Scientific and Technical Information of China (English)

    Ying Xing; Chun-yan Wen; Song-tao Li; Zong-xin Xia

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) plays an important role in the repair of central nervous system injury, but cannot directly tra-verse the blood-brain barrier. Liposomes are a new type of non-viral vector, able to carry macromolecules across the blood-brain barrier and into the brain. Here, we investigate whether BDNF could be transported across the blood-brain barrier by tail-vein injection of lipo-somes conjugated to transferrin (Tf) and polyethylene glycol (PEG), and carrying BDNF modiifed with cytomegalovirus promoter (pCMV) or glial ifbrillary acidic protein promoter (pGFAP) (Tf-pCMV-BDNF-PEG and Tf-pGFAP-BDNF-PEG, respectively). Both liposomes were able to traverse the blood-brain barrier, and BDNF was mainly expressed in the cerebral cortex. BDNF expression in the cerebral cortex was higher in the Tf-pGFAP-BDNF-PEG group than in the Tf-pCMV-BDNF-PEG group. This study demonstrates the successful construction of a non-virus targeted liposome, Tf-pGFAP-BDNF-PEG, which crosses the blood-brain barrier and is distributed in the cerebral cortex. Our work provides an experimental basis for BDNF-related targeted drug delivery in the brain.

  19. Differentiation of smooth muscle progenitor cells in peripheral blood and its application in tissue engineered blood vessels

    Institute of Scientific and Technical Information of China (English)

    Shang-zhe XIE; Ning-tao FANG; Shui LIU; Ping ZHOU; Yi ZHANG; Song-mei WANG; Hong-yang GAO; Luan-feng PAN

    2008-01-01

    Background: A major shortcoming in tissue engineered blood vessels (TEBVs) is the lack of healthy and easily attainable smooth muscle cells (SMCs). Smooth muscle progenitor cells (SPCs), especially from peripheral blood, may offer an alternative cell source for tissue engineering involving a less invasive harvesting technique. Methods: SPCs were isolated from 5-ml fresh rat peripheral blood by density-gradient centrifugation and cultured for 3 weeks in endothelial growth medium-2-MV (EGM-2-MV) medium containing platelet-derived growth factor-BB (PDGF BB). Before seeded on the synthesized scaffold, SPC-derived smooth muscle outgrowth cell (SOC) phenotypes were assessed by immuno-fluorescent staining, Western blot analysis, and reverse transcription polymerase chain reaction (RT-PCR). The cells were seeded onto the silk fibroin-modified poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (SF-PHBHHx) scaffolds by 6×104 cells/cm'2 and cultured under the static con-dition for 3 weeks. The growth and proliferation of the seeded cells on the scaffold were analyzed by 3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide (MTT) assay, scanning electron microscope (SEM), and 4,6-diamidino-2-phenylindole (DAPI) staining. Results: SOCs displayed specific "hill and valley" morphology, expressed the specific markers of the SMC lineage: protein, and extracellular matrix components elastin and matrix Gla protein (MGP), as well as vascular endothelial growth factor (VEGF). After seeded on the SF-PHBHHx scaffold, the cells showed excellent metabolic activity and proliferation. Conclusion: SPCs isolated from peripheral blood can be differentiated into the SMCs in vitro and have an impressive growth potential in the biodegradable synthesized scaffold. Thus, SPCs may be a promising cell source for constructing TEBVs.

  20. Dyslipidemia and Blood-Brain Barrier Integrity in Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Gene L. Bowman

    2012-01-01

    Full Text Available Background. Blood-brain barrier (BBB dysfunction may have a significant role in the pathogenesis of Alzheimer's disease (AD. Modifiable factors associated with BBB function may have therapeutic implication. This study tested the hypothesis that dyslipidemia is associated with BBB impairment in mild-to-moderate AD. Methods. Thirty-six subjects with AD were followed for 1 year. Fasting CSF and plasma were collected with clinical assessments at baseline and 12 months. BBB impairment was defined as CSF albumin index ≥9. Independent t-tests and linear regression assessed the relationship between plasma lipoproteins and BBB integrity. Results. Dyslipidemia was prevalent in 47% of the population, and in 75% of those with BBB impairment. Subjects with BBB impairment had significantly higher mean plasma triglyceride and lower HDL cholesterol (TG, P=0.007; HDL, P=0.043. Plasma triglycerides explained 22% of the variance in BBB integrity and remained significant after controlling for age, gender, ApoE-4 genotype, blood pressure, and statin use. Conclusion. Dyslipidemia is more prevalent in AD subjects with BBB impairment. Plasma triglyceride and HDL cholesterol may have a role in maintaining BBB integrity in mild-to-moderate Alzheimer's disease.

  1. Acute responses of muscle protein metabolism to reduced blood flow reflect metabolic priorities for homeostasis.

    Science.gov (United States)

    Zhang, Xiao-Jun; Irtun, Oivind; Chinkes, David L; Wolfe, Robert R

    2008-03-01

    The present experiment was designed to measure the synthetic and breakdown rates of muscle protein in the hindlimb of rabbits with or without clamping the femoral artery. l-[ring-(13)C(6)]phenylalanine was infused as a tracer for measurement of muscle protein kinetics by means of an arteriovenous model, tracer incorporation, and tracee release methods. The ultrasonic flowmeter, dye dilution, and microsphere methods were used to determine the flow rates in the femoral artery, in the leg, and in muscle capillary, respectively. The femoral artery flow accounted for 65% of leg flow. A 50% reduction in the femoral artery flow reduced leg flow by 28% and nutritive flow by 26%, which did not change protein synthetic or breakdown rate in leg muscle. Full clamp of the femoral artery reduced leg flow by 42% and nutritive flow by 59%, which decreased (P < 0.05) both the fractional synthetic rate from 0.19 +/- 0.05 to 0.14 +/- 0.03%/day and fractional breakdown rate from 0.28 +/- 0.07 to 0.23 +/- 0.09%/day of muscle protein. Neither the partial nor full clamp reduced (P = 0.27-0.39) the intracellular phenylalanine concentration or net protein balance in leg muscle. We conclude that the flow threshold to cause a fall of protein turnover rate in leg muscle was a reduction of 30-40% of the leg flow. The acute responses of muscle protein kinetics to the reductions in blood flow reflected the metabolic priorities to maintain muscle homeostasis. These findings cannot be extrapolated to more chronic conditions without experimental validation. PMID:18089763

  2. Heart Failure Impairs Muscle Blood Flow and Endurance Exercise Tolerance in COPD.

    Science.gov (United States)

    Oliveira, Mayron F; Arbex, Flavio F; Alencar, Maria Clara; Souza, Aline; Sperandio, Priscila A; Medeiros, Wladimir M; Mazzuco, Adriana; Borghi-Silva, Audrey; Medina, Luiz A; Santos, Rita; Hirai, Daniel M; Mancuso, Frederico; Almeida, Dirceu; O'Donnell, Denis E; Neder, J Alberto

    2016-08-01

    Heart failure, a prevalent and disabling co-morbidity of COPD, may impair cardiac output and muscle blood flow thereby contributing to exercise intolerance. To investigate the role of impaired central and peripheral hemodynamics in limiting exercise tolerance in COPD-heart failure overlap, cycle ergometer exercise tests at 20% and 80% peak work rate were performed by overlap (FEV1 = 56.9 ± 15.9% predicted, ejection fraction = 32.5 ± 6.9%; N = 16), FEV1-matched COPD (N = 16), ejection fraction-matched heart failure patients (N = 15) and controls (N = 12). Differences (Δ) in cardiac output (impedance cardiography) and vastus lateralis blood flow (indocyanine green) and deoxygenation (near-infrared spectroscopy) between work rates were expressed relative to concurrent changes in muscle metabolic demands (ΔO2 uptake). Overlap patients had approximately 30% lower endurance exercise tolerance than COPD and heart failure (p COPD. Blunted limb perfusion was related to greater muscle deoxygenation and lactate concentration in overlap (r = 0.78 and r = 0.73, respectively; p COPD and heart failure add to decrease exercising cardiac output and skeletal muscle perfusion to a greater extent than that expected by heart failure alone. Treatment strategies that increase muscle O2 delivery and/or decrease O2 demand may be particularly helpful to improve exercise tolerance in COPD patients presenting heart failure as co-morbidity. PMID:26790095

  3. Impairment of brain endothelial glucose transporter by methamphetamine causes blood-brain barrier dysfunction

    Directory of Open Access Journals (Sweden)

    Murrin L Charles

    2011-03-01

    Full Text Available Abstract Background Methamphetamine (METH, an addictive psycho-stimulant drug with euphoric effect is known to cause neurotoxicity due to oxidative stress, dopamine accumulation and glial cell activation. Here we hypothesized that METH-induced interference of glucose uptake and transport at the endothelium can disrupt the energy requirement of the blood-brain barrier (BBB function and integrity. We undertake this study because there is no report of METH effects on glucose uptake and transport across the blood-brain barrier (BBB to date. Results In this study, we demonstrate that METH-induced disruption of glucose uptake by endothelium lead to BBB dysfunction. Our data indicate that a low concentration of METH (20 μM increased the expression of glucose transporter protein-1 (GLUT1 in primary human brain endothelial cell (hBEC, main component of BBB without affecting the glucose uptake. A high concentration of 200 μM of METH decreased both the glucose uptake and GLUT1 protein levels in hBEC culture. Transcription process appeared to regulate the changes in METH-induced GLUT1 expression. METH-induced decrease in GLUT1 protein level was associated with reduction in BBB tight junction protein occludin and zonula occludens-1. Functional assessment of the trans-endothelial electrical resistance of the cell monolayers and permeability of dye tracers in animal model validated the pharmacokinetics and molecular findings that inhibition of glucose uptake by GLUT1 inhibitor cytochalasin B (CB aggravated the METH-induced disruption of the BBB integrity. Application of acetyl-L-carnitine suppressed the effects of METH on glucose uptake and BBB function. Conclusion Our findings suggest that impairment of GLUT1 at the brain endothelium by METH may contribute to energy-associated disruption of tight junction assembly and loss of BBB integrity.

  4. Nitric oxide and prostaglandins influence local skeletal muscle blood flow during exercise in humans: coupling between local substrate uptake and blood flow

    DEFF Research Database (Denmark)

    Kalliokoski, Kari K; Langberg, Henning; Ryberg, Ann Kathrine; Scheede-Bergdahl, Celena; Doessing, Simon; Kjaer, Andreas; Kjaer, Michael; Boushel, Robert

    2006-01-01

    Synergic action of nitric oxide (NO) and prostaglandins (PG) in the regulation of muscle blood flow during exercise has been demonstrated. In the present study, we investigated whether these vasodilators also regulate local blood flow, flow heterogeneity, and glucose uptake within the exercising ...... regions of vastus lateralis muscle but do not influence regional glucose uptake. The findings suggest that local substrate uptake in skeletal muscle can be regulated independently of regional changes in blood flow.......Synergic action of nitric oxide (NO) and prostaglandins (PG) in the regulation of muscle blood flow during exercise has been demonstrated. In the present study, we investigated whether these vasodilators also regulate local blood flow, flow heterogeneity, and glucose uptake within the exercising...... skeletal muscle. Skeletal muscle blood flow was measured in seven healthy young men using near-infrared spectroscopy and indocyanine green and muscle glucose uptake using positron emission tomography and 2-fluoro-2-deoxy-D-[(18)F]glucose without and with local blockade of NO and PG at rest and during one...

  5. Pharmacokinetic modeling of subcutaneous heroin and its metabolites in blood and brain of mice.

    Science.gov (United States)

    Boix, Fernando; Andersen, Jannike M; Mørland, Jørg

    2013-01-01

    High blood-brain permeability and effective delivery of morphine to the brain have been considered as explanations for the high potency of heroin. Results from Andersen et al. indicate that 6-monoacetylmorphine (6-MAM), and not morphine, is the active metabolite responsible for the acute effects observed for heroin. Here, we use pharmacokinetic modeling on data from the aforementioned study to calculate parameters of the distribution of heroin, 6-MAM and morphine in blood and brain tissue after subcutaneous heroin administration in mice. The estimated pharmacokinetic parameters imply that the very low heroin and the high 6-MAM levels observed both in blood and brain in the original experiment are likely to be caused by a very high metabolic rate of heroin in blood. The estimated metabolic rate of heroin in brain was much lower and cannot account for the low heroin and high 6-MAM levels in the brain, which would primarily reflect the concentrations of these compounds in blood. The very different metabolic rates for heroin in blood and brain calculated by the model were confirmed by in vitro experiments. These results show that heroin's fast metabolism in blood renders high concentrations of 6-MAM which, due to its relatively good blood-brain permeability, results in high levels of this metabolite in the brain. Thus, it is the high blood metabolism rate of heroin and the blood-brain permeability to 6-MAM, and not to heroin, which could account for the highly efficient delivery of active metabolites to the brain after heroin administration. PMID:21481103

  6. Stress does not increase blood-brain barrier permeability in mice.

    Science.gov (United States)

    Roszkowski, Martin; Bohacek, Johannes

    2016-07-01

    Several studies have reported that exposure to acute psychophysiological stressors can lead to an increase in blood-brain barrier permeability, but these findings remain controversial and disputed. We thoroughly examined this issue by assessing the effect of several well-established paradigms of acute stress and chronic stress on blood-brain barrier permeability in several brain areas of adult mice. Using cerebral extraction ratio for the small molecule tracer sodium fluorescein (NaF, 376 Da) as a sensitive measure of blood-brain barrier permeability, we find that neither acute swim nor restraint stress lead to increased cerebral extraction ratio. Daily 6-h restraint stress for 21 days, a model for the severe detrimental impact of chronic stress on brain function, also does not alter cerebral extraction ratio. In contrast, we find that cold forced swim and cold restraint stress both lead to a transient, pronounced decrease of cerebral extraction ratio in hippocampus and cortex, suggesting that body temperature can be an important confounding factor in studies of blood-brain barrier permeability. To additionally assess if stress could change blood-brain barrier permeability for macromolecules, we measured cerebral extraction ratio for fluorescein isothiocyanate-dextran (70 kDa). We find that neither acute restraint nor cold swim stress affected blood-brain barrier permeability for macromolecules, thus corroborating our findings that various stressors do not increase blood-brain barrier permeability. PMID:27146513

  7. Combined inhibition of nitric oxide and prostaglandins reduces human skeletal muscle blood flow during exercise

    Science.gov (United States)

    Boushel, Robert; Langberg, Henning; Gemmer, Carsten; Olesen, Jens; Crameri, Regina; Scheede, Celena; Sander, Michael; Kjær, Michael

    2002-01-01

    The vascular endothelium is an important mediator of tissue vasodilatation, yet the role of the specific substances, nitric oxide (NO) and prostaglandins (PG), in mediating the large increases in muscle perfusion during exercise in humans is unclear. Quadriceps microvascular blood flow was quantified by near infrared spectroscopy and indocyanine green in six healthy humans during dynamic knee extension exercise with and without combined pharmacological inhibition of NO synthase (NOS) and PG by l-NAME and indomethacin, respectively. Microdialysis was applied to determine interstitial release of PG. Compared to control, combined blockade resulted in a 5- to 10-fold lower muscle interstitial PG level. During control incremental knee extension exercise, mean blood flow in the quadriceps muscles rose from 10 ± 0.8 ml (100 ml tissue)−1 min−1 at rest to 124 ± 19, 245 ± 24, 329 ± 24 and 312 ± 25 ml (100 ml tissue)−1 min−1 at 15, 30, 45 and 60 W, respectively. During inhibition of NOS and PG, blood flow was reduced to 8 ± 0.5 ml (100 ml tissue)−1 min−1 at rest, and 100 ± 13, 163 ± 21, 217 ± 23 and 256 ± 28 ml (100 ml tissue)−1 min−1 at 15, 30, 45 and 60 W, respectively (P < 0.05 vs. control). In conclusion, combined inhibition of NOS and PG reduced muscle blood flow during dynamic exercise in humans. These findings demonstrate an important synergistic role of NO and PG for skeletal muscle vasodilatation and hyperaemia during muscular contraction. PMID:12205200

  8. Protection of the blood-brain barrier by hypercapnia during acute hypertension

    International Nuclear Information System (INIS)

    The purpose of this study was to examine effects of hypercapnia on susceptibility of the blood-brain barrier to disruption during acute hypertension. Two methods were used to test the hypothesis that cerebral vasodilation during hypercapnia increases disruption of the blood-brain barrier. First, permeability of the blood-brain barrier was measured in anesthetized cats with 125I-labeled serum albumin. Severe hypertension markedly increased permeability of the blood-brain barrier during normocapnia, but not during hypercapnia. The protective effect of hypercapnia was not dependent on sympathetic nerves. Second, in anesthetized rats, permeability of the barrier was quantitated by clearance of fluorescent dextran. Disruption of the blood-brain barrier during hypertension was decreased by hypercapnia. Because disruption of the blood-brain barrier occurred primarily in pial venules, the authors also measured pial venular diameter and pressure. Acute hypertension increased pial venular pressure and diameter in normocapnic rats. Hypercapnia alone increased pial venular pressure and pial venular diameter, and acute hypertension during hypercapnia further increased venular pressure. The magnitude of increase in pial venular pressure during acute hypertension was significantly less in hypercapnic than in normocapnic rats. They conclude that hypercapnia protects the blood-brain barrier. Possible mechanisms of this effect include attenuation of the incremental increase in pial venular pressure by hypercapnia or a direct effect on the blood-brain barrier not related to venous pressure

  9. Post-warm-up muscle temperature maintenance: blood flow contribution and external heating optimisation

    OpenAIRE

    Raccuglia, Margherita; Lloyd, Alex; Filingeri, Davide; Faulkner, Steve H; Hodder, Simon; Havenith, George

    2015-01-01

    Purpose Passive muscle heating has been shown to reduce the drop in post-warm-up muscle temperature (T m) by about 25 % over 30 min, with concomitant sprint/power performance improvements. We sought to determine the role of leg blood flow in this cooling and whether optimising the heating procedure would further benefit post-warm-up T m maintenance. Methods Ten male cyclists completed 15-min sprint-based warm-up followed by 30 min recovery. Vastus lateralis T m (T mvl) was measured at deep-, ...

  10. Neurosurgical Techniques for Disruption of the Blood-Brain Barrier for Glioblastoma Treatment.

    Science.gov (United States)

    Rodriguez, Analiz; Tatter, Stephen B; Debinski, Waldemar

    2015-01-01

    The blood-brain barrier remains a main hurdle to drug delivery to the brain. The prognosis of glioblastoma remains grim despite current multimodal medical management. We review neurosurgical technologies that disrupt the blood-brain barrier (BBB). We will review superselective intra-arterial mannitol infusion, focused ultrasound, laser interstitial thermotherapy, and non-thermal irreversible electroporation (NTIRE). These technologies can lead to transient BBB and blood-brain tumor barrier disruption and allow for the potential of more effective local drug delivery. Animal studies and preliminary clinical trials show promise for achieving this goal. PMID:26247958

  11. Aquaporin 4 expression and ultrastructure of the blood-brain barrier following cerebral contusion injury

    Institute of Scientific and Technical Information of China (English)

    Xinjun Li; Yangyun Han; Hong Xu; Zhongshu Sun; Zengjun Zhou; Xiaodong Long; Yumin Yang; Linbo Zou

    2013-01-01

    This study aimed to investigate aquaporin 4 expression and the ultrastructure of the blood-brain barrier at 2–72 hours following cerebral contusion injury, and correlate these changes to the formation of brain edema. Results revealed that at 2 hours after cerebral contusion and laceration injury, aquaporin 4 expression significantly increased, brain water content and blood-brain barrier permeability increased, and the number of pinocytotic vesicles in cerebral microvascular endothelial cells increased. In addition, the mitochondrial accumulation was observed. As contusion and laceration injury became aggravated, aquaporin 4 expression continued to increase, brain water content and blood-brain barrier permeability gradually increased, brain capillary endothelial cells and astrocytes swelled, and capillary basement membrane injury gradually increased. The above changes were most apparent at 12 hours after injury, after which they gradually attenuated. Aquaporin 4 expression positively correlated with brain water content and the blood-brain barrier index. Our experimental findings indicate that increasing aquaporin 4 expression and blood-brain barrier permeability after cerebral contusion and laceration injury in humans is involved in the formation of brain edema.

  12. Middle cerebral artery flow velocity and blood flow during exercise and muscle ischemia in humans

    DEFF Research Database (Denmark)

    Jørgensen, L G; Perko, M; Hanel, B; Schroeder, T V; Secher, N H

    1992-01-01

    Changes in middle cerebral artery flow velocity (Vmean), measured by transcranial Doppler ultrasound, were used to determine whether increases in mean arterial pressure (MAP) or brain activation enhance cerebral perfusion during exercise. We also evaluated the role of "central command......," mechanoreceptors, and/or muscle "metaboreceptors" on cerebral perfusion. Ten healthy subjects performed two levels of dynamic exercise corresponding to a heart rate of 110 (range 89-134) and 148 (129-170) beats/min, respectively, and exhaustive one-legged static knee extension. Measurements were continued during 2......-2.5 min of muscle ischemia. MAP increased similarly during static [114 (102-133) mmHg] and heavy dynamic exercise [121 (104-136) mmHg] and increased during muscle ischemia after dynamic exercise. During heavy dynamic exercise, Vmean increased 24% (10-47%; P less than 0.01) over approximately 3 min despite...

  13. Smooth muscle progenitor cells from peripheral blood promote the neovascularization of endothelial colony-forming cells

    International Nuclear Information System (INIS)

    Highlights: • Two distinct vascular progenitor cells are induced from adult peripheral blood. • ECFCs induce vascular structures in vitro and in vivo. • SMPCs augment the in vitro and in vivo angiogenic potential of ECFCs. • Both cell types have synergistic therapeutic potential in ischemic hindlimb model. - Abstract: Proangiogenic cell therapy using autologous progenitors is a promising strategy for treating ischemic disease. Considering that neovascularization is a harmonized cellular process that involves both endothelial cells and vascular smooth muscle cells, peripheral blood-originating endothelial colony-forming cells (ECFCs) and smooth muscle progenitor cells (SMPCs), which are similar to mature endothelial cells and vascular smooth muscle cells, could be attractive cellular candidates to achieve therapeutic neovascularization. We successfully induced populations of two different vascular progenitor cells (ECFCs and SMPCs) from adult peripheral blood. Both progenitor cell types expressed endothelial-specific or smooth muscle-specific genes and markers, respectively. In a protein array focused on angiogenic cytokines, SMPCs demonstrated significantly higher expression of bFGF, EGF, TIMP2, ENA78, and TIMP1 compared to ECFCs. Conditioned medium from SMPCs and co-culture with SMPCs revealed that SMPCs promoted cell proliferation, migration, and the in vitro angiogenesis of ECFCs. Finally, co-transplantation of ECFCs and SMPCs induced robust in vivo neovascularization, as well as improved blood perfusion and tissue repair, in a mouse ischemic hindlimb model. Taken together, we have provided the first evidence of a cell therapy strategy for therapeutic neovascularization using two different types of autologous progenitors (ECFCs and SMPCs) derived from adult peripheral blood

  14. Smooth muscle progenitor cells from peripheral blood promote the neovascularization of endothelial colony-forming cells

    Energy Technology Data Exchange (ETDEWEB)

    Joo, Hyung Joon; Seo, Ha-Rim [Department of Cardiology, Cardiovascular Center, College of Medicine, Korea University, Seoul (Korea, Republic of); Jeong, Hyo Eun [Department of Mechanical Engineering, Korea University, Seoul (Korea, Republic of); Choi, Seung-Cheol; Park, Jae Hyung; Yu, Cheol Woong; Hong, Soon Jun [Department of Cardiology, Cardiovascular Center, College of Medicine, Korea University, Seoul (Korea, Republic of); Chung, Seok [Department of Mechanical Engineering, Korea University, Seoul (Korea, Republic of); Lim, Do-Sun, E-mail: dslmd@kumc.or.kr [Department of Cardiology, Cardiovascular Center, College of Medicine, Korea University, Seoul (Korea, Republic of)

    2014-07-11

    Highlights: • Two distinct vascular progenitor cells are induced from adult peripheral blood. • ECFCs induce vascular structures in vitro and in vivo. • SMPCs augment the in vitro and in vivo angiogenic potential of ECFCs. • Both cell types have synergistic therapeutic potential in ischemic hindlimb model. - Abstract: Proangiogenic cell therapy using autologous progenitors is a promising strategy for treating ischemic disease. Considering that neovascularization is a harmonized cellular process that involves both endothelial cells and vascular smooth muscle cells, peripheral blood-originating endothelial colony-forming cells (ECFCs) and smooth muscle progenitor cells (SMPCs), which are similar to mature endothelial cells and vascular smooth muscle cells, could be attractive cellular candidates to achieve therapeutic neovascularization. We successfully induced populations of two different vascular progenitor cells (ECFCs and SMPCs) from adult peripheral blood. Both progenitor cell types expressed endothelial-specific or smooth muscle-specific genes and markers, respectively. In a protein array focused on angiogenic cytokines, SMPCs demonstrated significantly higher expression of bFGF, EGF, TIMP2, ENA78, and TIMP1 compared to ECFCs. Conditioned medium from SMPCs and co-culture with SMPCs revealed that SMPCs promoted cell proliferation, migration, and the in vitro angiogenesis of ECFCs. Finally, co-transplantation of ECFCs and SMPCs induced robust in vivo neovascularization, as well as improved blood perfusion and tissue repair, in a mouse ischemic hindlimb model. Taken together, we have provided the first evidence of a cell therapy strategy for therapeutic neovascularization using two different types of autologous progenitors (ECFCs and SMPCs) derived from adult peripheral blood.

  15. The diffusion permeability to water of the rat blood-brain barrier

    DEFF Research Database (Denmark)

    Bolwig, T G; Lassen, N A

    1975-01-01

    The diffusion permeability to water of the rat blood-brain-barrier (BBB) was studied. Preliminary data obtained with the Oldendorf tissue uptake method (Oldendorf 1970) in seizure experiments suggested that the transfer from blood to brain of labelled water is diffusion-limited. More definite...... passage increased from 0.26 to 0.67 when the arterial carbon dioxide tension was changed from 15 to 85 mm Hg, a change increasing the cerebral blood flow about sixfold. This finding suggests that water does not pass the blood-brain barrier as freely as lipophilic gases....

  16. Glucagon-like peptide-1 (GLP-1) raises blood-brain glucose transfer capacity and hexokinase activity in human brain

    DEFF Research Database (Denmark)

    Jensen, Michael Gejl; Lerche, Susanne; Egefjord, Lærke; Brock, Birgitte; Møller, Niels; Vang, Kim; Rodell, Anders B; Bibby, Bo M; Holst, Jens Juul; Rungby, Jørgen; Gjedde, Albert

    2013-01-01

    phosphorylation velocity (V max) in the gray matter regions of cerebral cortex, thalamus, and cerebellum, as well as increased blood-brain glucose transport capacity (T max) in gray matter, white matter, cortex, thalamus, and cerebellum. In hypoglycemia, GLP-1 had no effects on net glucose metabolism, brain......In hyperglycemia, glucagon-like peptide-1 (GLP-1) lowers brain glucose concentration together with increased net blood-brain clearance and brain metabolism, but it is not known whether this effect depends on the prevailing plasma glucose (PG) concentration. In hypoglycemia, glucose depletion...... potentially impairs brain function. Here, we test the hypothesis that GLP-1 exacerbates the effect of hypoglycemia. To test the hypothesis, we determined glucose transport and consumption rates in seven healthy men in a randomized, double-blinded placebo-controlled cross-over experimental design. The acute...

  17. Magnetic Nanoparticles Cross the Blood-Brain Barrier: When Physics Rises to a Challenge

    Directory of Open Access Journals (Sweden)

    Maria Antònia Busquets

    2015-12-01

    Full Text Available The blood-brain barrier is a physical and physiological barrier that protects the brain from toxic substances within the bloodstream and helps maintain brain homeostasis. It also represents the main obstacle in the treatment of many diseases of the central nervous system. Among the different approaches employed to overcome this barrier, the use of nanoparticles as a tool to enhance delivery of therapeutic molecules to the brain is particularly promising. There is special interest in the use of magnetic nanoparticles, as their physical characteristics endow them with additional potentially useful properties. Following systemic administration, a magnetic field applied externally can mediate the capacity of magnetic nanoparticles to permeate the blood-brain barrier. Meanwhile, thermal energy released by magnetic nanoparticles under the influence of radiofrequency radiation can modulate blood-brain barrier integrity, increasing its permeability. In this review, we present the strategies that use magnetic nanoparticles, specifically iron oxide nanoparticles, to enhance drug delivery to the brain.

  18. Computational and in vitro studies of blast-induced blood-brain barrier disruption

    OpenAIRE

    Del Razo, Mauricio J.; MOROFUJI, Yoichi; Meabon, James S.; Huber, B. Russell; Peskind, Elaine R.; Banks, William A; Mourad, Pierre D.; LeVeque, Randall J.; Cook, David G.

    2015-01-01

    There is growing concern that blast-exposed individuals are at risk of developing neurological disorders later in life. Therefore, it is important to understand the dynamic properties of blast forces on brain cells, including the endothelial cells that maintain the blood-brain barrier (BBB), which regulates the passage of nutrients into the brain and protects it from toxins in the blood. To better understand the effect of shock waves on the BBB we have investigated an {\\em in vitro} model in ...

  19. PROGRESS AND PROBLEMS IN THE APPLICATION OF FOCUSED ULTRASOUND FOR BLOOD-BRAIN BARRIER DISRUPTION

    OpenAIRE

    Vykhodtseva, Natalia; McDannold, Nathan; Hynynen, Kullervo

    2008-01-01

    Advances in neuroscience have resulted in the development of new diagnostic and therapeutic agents for potential use in the central nervous system (CNS). However, the ability to deliver the majority of these agents to the brain is limited by the blood–brain barrier (BBB), a specialized structure of the blood vessel wall that hampers transport and diffusion from the blood to the brain. Many CNS disorders could be treated with drugs, enzymes, genes, or large-molecule biotechnological products s...

  20. Blood interference in fluorescence spectrum : Experiment, analysis and comparison with intraoperativemeasurements on brain tumor

    OpenAIRE

    Lowndes, Shannely

    2010-01-01

    The optical touch pointer (OTP), a fluorescence spectroscopy based system, assists brain surgeons during guided brain tumor resection in patients with glioblastoma multiforme (GBM). After recording and analyzing the autofluorescence spectrum of the tissue, it is possible to distinguish malignant from healthy brain tissue. A challenge during the intraoperative measurements is the interference of blood. If it gets in contact with the laser pointer, the blood blocks the light transmission to and...

  1. P03.09PHARMACOLOGICAL MODULATION OF BLOOD-BRAIN BARRIER: FUTURE STRATEGY FOR TREATMENT OF BRAIN TUMORS

    OpenAIRE

    Sardi, I.; Cardellicchio, S.; Iorio, A.L.; da Ros, M.; la Marca, G.; Giunti, L.; Massimino, M.; L. Genitori

    2014-01-01

    A prerequisite for the efficacy of chemotherapy is that it reaches the tumor mass at a therapeutic concentration. In brain tumors this phenomenon is hampered by the presence of the blood brain barrier (BBB) which limits the spread of chemotherapeutic agents within the brain. It is lately emerged as this Multi Drug Resistance (MDR) phenomenon is explained through the cooperation of P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP, ABCG2), two “gatekeeper" transporters th...

  2. Contribution of respiratory muscle blood flow to exercise-induced diaphragmatic fatigue in trained cyclists

    DEFF Research Database (Denmark)

    Vogiatzis, Ioannis; Athanasopoulos, Dimitris; Boushel, Robert Christopher;

    2008-01-01

    exercise tests at inspired O(2) fractions (FIO2) of 0.13, 0.21 and 1.00 in balanced order. Work rates were selected to produce the same tidal volume, breathing frequency and respiratory muscle load at each FIO2 (63 +/- 1, 78 +/- 1 and 87 +/- 1% of normoxic maximal work rate, respectively). Intercostals......We investigated whether the greater degree of exercise-induced diaphragmatic fatigue previously reported in highly trained athletes in hypoxia (compared with normoxia) could have a contribution from limited respiratory muscle blood flow. Seven trained cyclists completed three constant load 5 min......(-1) and 95.1 +/- 7.8 ml (100 ml)(-1) min(-1), respectively). Neither IMBF was different across hypoxia, normoxia and hyperoxia (53.6 +/- 8.5, 49.9 +/- 5.9 and 52.9 +/- 5.9 ml (100 ml)(-1) min(-1), respectively). We conclude that when respiratory muscle energy requirement is not different between...

  3. Smuggling Drugs into the Brain: An Overview of Ligands Targeting Transcytosis for Drug Delivery across the Blood-Brain Barrier

    NARCIS (Netherlands)

    Zuhorn, Inge; Georgieva, Julia V.; Hoekstra, Dick

    2015-01-01

    The blood-brain barrier acts as a physical barrier that prevents free entry of blood-derived substances, including those intended for therapeutic applications. The development of molecular Trojan horses is a promising drug targeting technology that allows for non-invasive delivery of therapeutics in

  4. Alteration of blood-brain barrier integrity by retroviral infection.

    Directory of Open Access Journals (Sweden)

    Philippe V Afonso

    2008-11-01

    Full Text Available The blood-brain barrier (BBB, which forms the interface between the blood and the cerebral parenchyma, has been shown to be disrupted during retroviral-associated neuromyelopathies. Human T Lymphotropic Virus (HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP is a slowly progressive neurodegenerative disease associated with BBB breakdown. The BBB is composed of three cell types: endothelial cells, pericytes and astrocytes. Although astrocytes have been shown to be infected by HTLV-1, until now, little was known about the susceptibility of BBB endothelial cells to HTLV-1 infection and the impact of such an infection on BBB function. We first demonstrated that human cerebral endothelial cells express the receptors for HTLV-1 (GLUT-1, Neuropilin-1 and heparan sulfate proteoglycans, both in vitro, in a human cerebral endothelial cell line, and ex vivo, on spinal cord autopsy sections from HAM/TSP and non-infected control cases. In situ hybridization revealed HTLV-1 transcripts associated with the vasculature in HAM/TSP. We were able to confirm that the endothelial cells could be productively infected in vitro by HTLV-1 and that blocking of either HSPGs, Neuropilin 1 or Glut1 inhibits this process. The expression of the tight-junction proteins within the HTLV-1 infected endothelial cells was altered. These cells were no longer able to form a functional barrier, since BBB permeability and lymphocyte passage through the monolayer of endothelial cells were increased. This work constitutes the first report of susceptibility of human cerebral endothelial cells to HTLV-1 infection, with implications for HTLV-1 passage through the BBB and subsequent deregulation of the central nervous system homeostasis. We propose that the susceptibility of cerebral endothelial cells to retroviral infection and subsequent BBB dysfunction is an important aspect of HAM/TSP pathogenesis and should be considered in the design of future therapeutics strategies.

  5. Distribution of radiolabeled L-glutamate and D-aspartate from blood into peripheral tissues in naive rats: Significance for brain neuroprotection

    Energy Technology Data Exchange (ETDEWEB)

    Klin, Yael [Department of Neurobiology, The Weizmann Institute of Science, Rehovot 76100 (Israel); Zlotnik, Alexander; Boyko, Matthew; Ohayon, Sharon; Shapira, Yoram [The Division of Anesthesiology, Soroka Medical Center and Ben Gurion University of the Negev, Beer-Sheva (Israel); Teichberg, Vivian I., E-mail: Vivian.teichberg@weizmann.ac.il [Department of Neurobiology, The Weizmann Institute of Science, Rehovot 76100 (Israel)

    2010-09-03

    Research highlights: {yields} Blood glutamate has a half-life time of 2-3 min. {yields} Blood glutamate is submitted to rapid decarboxylation. {yields} Blood glutamate and its metabolites are mainly absorbed in skeletal muscle and liver. {yields} The skeletal muscle and liver are now targets for potential drugs affording brain neuroprotection. -- Abstract: Excess L-glutamate (glutamate) levels in brain interstitial and cerebrospinal fluids (ISF and CSF, respectively) are the hallmark of several neurodegenerative conditions such as stroke, traumatic brain injury or amyotrophic lateral sclerosis. Its removal could prevent the glutamate excitotoxicity that causes long-lasting neurological deficits. As in previous studies, we have established the role of blood glutamate levels in brain neuroprotection, we have now investigated the contribution of the peripheral organs to the homeostasis of glutamate in blood. We have administered naive rats with intravenous injections of either L-[1-{sup 14}C] Glutamic acid (L-[1-{sup 14}C] Glu), L-[G-{sup 3}H] Glutamic acid (L-[G-{sup 3}H] Glu) or D-[2,3-{sup 3}H] Aspartic acid (D-[2,3-{sup 3}H] Asp), a non-metabolized analog of glutamate, and have followed their distribution into peripheral organs. We have observed that the decay of the radioactivity associated with L-[1-{sup 14}C] Glu and L-[G-{sup 3}H] Glu was faster than that associated with glutamate non-metabolized analog, D-[2,3-{sup 3}H] Asp. L-[1-{sup 14}C] Glu was subjected in blood to a rapid decarboxylation with the loss of {sup 14}CO{sub 2}. The three major sequestrating organs, serving as depots for the eliminated glutamate and/or its metabolites were skeletal muscle, liver and gut, contributing together 92% or 87% of total L-[U-{sup 14}C] Glu or D-[2,3-{sup 3}H] Asp radioactivity capture. L-[U-{sup 14}C] Glu and D-[2,3-{sup 3}H] Asp showed a different organ sequestration pattern. We conclude that glutamate is rapidly eliminated from the blood into peripheral tissues

  6. Vascular Function and Regulation of Blood Flow in Resting and Contracting Skeletal Muscle

    DEFF Research Database (Denmark)

    Nyberg, Michael Permin

    no single compound can explain exercise hyperemia and indicates that any condition associated with reduced oxygen delivery needs to be investigated independently. Physical activity can attenuate or even counteract the effects of essential hypertension and aging on vascular function and exercise...... importance. The present work provides new insight in to vasodilator interactions important for exercise hyperemia and sheds light on mechanisms important for vascular function and regulation of skeletal muscle blood flow in essential hypertension (high blood pressure) and aging and identifies mechanisms by...... which physical activity affects the function of the vascular network. Conclusion The vasodilators ATP and adenosine stimulate the nitric oxide and prostanoid systems in skeletal muscle. These vasodilator interactions may, at least in part, explain the central role of nitric oxide and prostanoids in the...

  7. Insulin action in muscle and adipose tissue in type 2diabetes: The significance of blood flow

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Under normal metabolic conditions insulin stimulatesmicrovascular perfusion (capillary recruitment) ofskeletal muscle and subcutaneous adipose tissue andthus increases blood flow mainly after meal ingestionor physical exercise. This helps the delivery of insulinitself but also that of substrates and of other signallingmolecules to multiple tissues beds and facilitatesglucose disposal and lipid kinetics. This effect is impairedin insulin resistance and type 2 diabetes early in thedevelopment of metabolic dysregulation and reflectsearly-onset endothelial dysfunction. Failure of insulinto increase muscle and adipose tissue blood flowresults in decreased glucose handling. In fat depots, ablunted postprandial blood flow response will result inan insufficient suppression of lipolysis and an increasedspill over of fatty acids in the circulation, leading toa more pronounced insulin resistant state in skeletalmuscle. This defect in blood flow response is apparenteven in the prediabetic state, implying that it is afacet of insulin resistance and exists long before overthyperglycaemia develops. The following review intendsto summarize the contribution of blood flow impairmentto the development of the atherogenic dysglycemia anddyslipidaemia.

  8. High-frequency brain activity and muscle artifacts in MEG/EEG: a review and recommendations

    OpenAIRE

    Suresh Muthukumaraswamy

    2013-01-01

    In recent years high-frequency brain activity in the gamma-frequency band (30–80 Hz) and above has become the focus of a growing body of work in MEG/EEG research. Unfortunately, high-frequency neural activity overlaps entirely with the spectral bandwidth of muscle activity (~20–300 Hz). It is becoming appreciated that artifacts of muscle activity may contaminate a number of non-invasive reports of high-frequency activity. In this review, the spectral, spatial, and temporal characteristics of ...

  9. Noninvasive monitoring of treatment response in a rabbit cyanide toxicity model reveals differences in brain and muscle metabolism

    Science.gov (United States)

    Kim, Jae G.; Lee, Jangwoen; Mahon, Sari B.; Mukai, David; Patterson, Steven E.; Boss, Gerry R.; Tromberg, Bruce J.; Brenner, Matthew

    2012-10-01

    Noninvasive near infrared spectroscopy measurements were performed to monitor cyanide (CN) poisoning and recovery in the brain region and in foreleg muscle simultaneously, and the effects of a novel CN antidote, sulfanegen sodium, on tissue hemoglobin oxygenation changes were compared using a sub-lethal rabbit model. The results demonstrated that the brain region is more susceptible to CN poisoning and slower in endogenous CN detoxification following exposure than peripheral muscles. However, sulfanegen sodium rapidly reversed CN toxicity, with brain region effects reversing more quickly than muscle. In vivo monitoring of multiple organs may provide important clinical information regarding the extent of CN toxicity and subsequent recovery, and facilitate antidote drug development.

  10. Smuggling Drugs into the Brain: An Overview of Ligands Targeting Transcytosis for Drug Delivery across the Blood-Brain Barrier.

    Science.gov (United States)

    Georgieva, Julia V; Hoekstra, Dick; Zuhorn, Inge S

    2014-01-01

    The blood-brain barrier acts as a physical barrier that prevents free entry of blood-derived substances, including those intended for therapeutic applications. The development of molecular Trojan horses is a promising drug targeting technology that allows for non-invasive delivery of therapeutics into the brain. This concept relies on the application of natural or genetically engineered proteins or small peptides, capable of specifically ferrying a drug-payload that is either directly coupled or encapsulated in an appropriate nanocarrier, across the blood-brain barrier via receptor-mediated transcytosis. Specifically, in this process the nanocarrier-drug system ("Trojan horse complex") is transported transcellularly across the brain endothelium, from the blood to the brain interface, essentially trailed by a native receptor. Naturally, only certain properties would favor a receptor to serve as a transporter for nanocarriers, coated with appropriate ligands. Here we briefly discuss brain microvascular endothelial receptors that have been explored until now, highlighting molecular features that govern the efficiency of nanocarrier-mediated drug delivery into the brain. PMID:25407801

  11. Blood-brain barrier permeability in rats exposed to electromagnetic fields used in wireless communication

    OpenAIRE

    Persson, Bertil R.; Leif G Salford; Brun, Arne

    1997-01-01

    iological effects of radio frequency electromagnetic fields (EMF) on the blood-brain barrier (BBB) have been studied in Fischer 344 rats of both sexes. The rats were not anaesthetised during the exposure. All animals were sacrificed by perfusion–fixation of the brains under chloralhydrate anaesthesia after the exposure. The brains were perfused with saline for 3–4 minutes, and thereafter perfusion fixed with 4% formaldehyde for 5–6 minutes. Whole coronal sections of the brains were d...

  12. Muscle blood flow and muscle metabolism during exercise and heat stress

    DEFF Research Database (Denmark)

    Nielsen, Bodil; Savard, G; Richter, Erik;

    1990-01-01

    The effect of heat stress on blood flow and metabolism in an exercising leg was studied in seven subjects walking uphill (12-17%) at 5 km/h on a treadmill for 90 min or until exhaustion. The first 30 min of exercise were performed in a cool environment (18-21 degrees C); then subjects moved to an...... adjacent room at 40 degrees C and continued to exercise at the same speed and inclination for a further 60 min or to exhaustion, whichever occurred first. The rate of O2 consumption, 2.6 l/min (1.8-3.3) (average from cool and hot conditions), corresponded to 55-77% of their individual maximums. In the cool...

  13. The blood-brain barrier penetration and distribution of PEGylated fluorescein-doped magnetic silica nanoparticles in rat brain

    International Nuclear Information System (INIS)

    PEGylated PAMAM conjugated fluorescein-doped magnetic silica nanoparticles (PEGylated PFMSNs) have been synthesized for evaluating their ability across the blood-brain barrier (BBB) and distribution in rat brain. The obtained nanoparticles were characterized by transmission electron microscopy (TEM), thermal gravimetry analyses (TGA), zeta potential (ζ-potential) titration, and X-ray photoelectron spectroscopy (XPS). The BBB penetration and distribution of PEGylated PFMSNs and FMSNs in rat brain were investigated not only at the cellular level with Confocal laser scanning microscopy (CLSM), but also at the subcellular level with transmission electron microscopy (TEM). The results provide direct evidents that PEGylated PFMSNs could penetrate the BBB and spread into the brain parenchyma.

  14. Blood flow index using near-infrared spectroscopy and indocyanine green as a minimally invasive tool to assess respiratory muscle blood flow in humans

    DEFF Research Database (Denmark)

    Guenette, Jordan A; Henderson, William R; Dominelli, Paolo B; Querido, Jordan S; Brasher, Penelope M; Griesdale, Donald E G; Boushel, Robert Christopher; Sheel, A William

    2011-01-01

    Near-infrared spectroscopy (NIRS) in combination with indocyanine green (ICG) dye has recently been used to measure respiratory muscle blood flow (RMBF) in humans. This method is based on the Fick principle and is determined by measuring ICG in the respiratory muscles using transcutaneous NIRS in...... relationships with the work of breathing and EMG for both respiratory muscles. The coefficients of determination (R(2)) comparing BFI vs. the work of breathing for the intercostal and sternocleidomastoid muscles were 0.887 (P <0.001) and 0.863 (P <0.001), respectively, whereas the R(2) for BFI vs. EMG for the...

  15. Pressure passive cerebral blood flow and breakdown of the blood-brain barrier in experimental fetal asphyxia

    DEFF Research Database (Denmark)

    Lou, H C; Lassen, N A; Tweed, W A;

    1979-01-01

    mean arterial blood pressure in the fetuses by blood withdrawal or infusion in this state, CBF was measured at different perfusion pressures (mean arterial blood pressure (MABP) minus central venous pressure (CVP)). A passive flow/pressure relationship--loss of autoregulation--was found, with hyperemia...... reaching CBF values up to 6 times normal at normal MABP of about 60 to 70 mmHg, and severe ischemia reaching CBF values close to zero in large cortical areas at MABP of 30 mmHg. CVP remained essentially unchanged at 10--15 mmHg. The severe and prolonged asphyxia rendered the blood-brain barrier leaky to...

  16. Blood flow and muscle oxygenation during low, moderate, and maximal sustained isometric contractions.

    Science.gov (United States)

    McNeil, Chris J; Allen, Matti D; Olympico, Eric; Shoemaker, J Kevin; Rice, Charles L

    2015-09-01

    A reduction of blood flow to active muscle will precipitate fatigue, and sustained isometric contractions produce intramuscular and compartmental pressures that can limit flow. The present study explored how blood flow and muscle oxygenation respond to isometric contractions at low, moderate, and maximal intensities. Over two visits, 10 males (26 ± 2 yr; means ± SD) performed 1-min dorsiflexion contractions at 30, 60, and 100% of maximal voluntary contraction (MVC) torque. Doppler ultrasound of the anterior tibial artery was used to record arterial diameter and mean blood velocity and to calculate absolute blood flow. The tissue oxygenation index (TOI) of tibialis anterior was acquired with near-infrared spectroscopy (NIRS). There was a progressive increase in blood flow at 30% MVC (peak of 289 ± 139% resting value), no change from rest until an increase in the final 10 s of exercise at 60% MVC (peak of 197 ± 102% rest), and an initial decrease (59 ± 30% resting value) followed by a progressive increase at 100% MVC (peak of 355 ± 133% rest). Blood flow was greater at 30 and 100% than 60% MVC during the last 30 s of exercise. TOI was ∼63% at rest and, within 30 s of exercise, reached steady-state values of ∼42%, ∼22%, and ∼22% for 30, 60, and 100% MVC, respectively. Even maximal contraction of the dorsiflexors is unable to cause more than a transient decrease of flow in the anterior tibial artery. Unlike dynamic or intermittent isometric exercise, our results indicate blood flow is not linearly graded with intensity or directly coupled with oxygenation during sustained isometric contractions. PMID:26084698

  17. Positron emission tomographic measurement of blood-to-brain and blood-to-tumor transport of 82Rb: the effect of dexamethasone and whole-brain radiation therapy

    International Nuclear Information System (INIS)

    Unidirectional blood-to-brain and blood-to-tumor transport rate constants for rubidium 82 were determined using dynamic positron emission tomography in patients with primary or metastatic brain tumors. Regional influx rate constants (K1) and plasma water volume (Vp) were estimated from the time course of blood and brain radioactivity following a bolus injection of tracer. Eight patients were studied before and 24 to 72 hours after treatment using pharmacological doses of dexamethasone, and 6 additional patients with metastatic brain tumors were studied before and within 60 to 90 minutes after 200- to 600-rad whole-brain radiation therapy. Steroid treatment was associated with a 9 to 48% decrease in tumor K1 and a 21% mean decrease in tumor Vp. No consistent changes in K1 or Vp were observed in control brain regions. Tumor K1 and Vp did not increase in patients undergoing whole-brain radiation therapy, all of whom were taking dexamethasone at the time of study. These data suggest that corticosteroids decrease the permeability of tumor capillaries to small hydrophilic molecules (including those of some chemotherapeutic agents) and that steroid pretreatment prevents acute, and potentially dangerous, increases in tumor capillary permeability following cranial irradiation

  18. Blood flow restriction exercise stimulates mTORC1 signaling and muscle protein synthesis in older men

    OpenAIRE

    Fry, Christopher S.; Glynn, Erin L.; Drummond, Micah J.; Timmerman, Kyle L.; Fujita, Satoshi; Abe, Takashi; Dhanani, Shaheen; Volpi, Elena; Rasmussen, Blake B.

    2010-01-01

    The loss of skeletal muscle mass during aging, sarcopenia, increases the risk for falls and dependence. Resistance exercise (RE) is an effective rehabilitation technique that can improve muscle mass and strength; however, older individuals are resistant to the stimulation of muscle protein synthesis (MPS) with traditional high-intensity RE. Recently, a novel rehabilitation exercise method, low-intensity RE, combined with blood flow restriction (BFR), has been shown to stimulate mammalian targ...

  19. Influence of differential expression of acetylcholinesterase in brain and muscle on respiration

    OpenAIRE

    Boudinot, Eliane; Bernard, Véronique; Camp, Shelley; Taylor, Palmer; Champagnat, Jean; Krejci, Eric; Foutz, Arthur S.

    2008-01-01

    A mouse strain with a deleted acetylcholinesterase (AChE) gene (AChE knockout) shows a decreased inspiration time and increased tidal volume and ventilation. To investigate the respective roles of AChE in brain and muscle, we recorded respiration by means of whole-body plethysmography in knockout mice with tissue selective deletions in AChE expression. A mouse strain with the anchoring domains of AChE deleted (del E5+6 knockout mice) has very low activity in the brain and neuromuscular juncti...

  20. Cerebral Blood Flow and Autoregulation after Pediatric Traumatic Brain Injury

    OpenAIRE

    Udomphorn, Yuthana; Armstead, William M.; Vavilala, Monica S.

    2008-01-01

    Traumatic brain injury is a global health concern and is the leading cause of traumatic morbidity and mortality in children. Despite a lower overall mortality than in adult traumatic brain injury, the cost to society from the sequelae of pediatric traumatic brain injury is very high. Predictors of poor outcome after traumatic brain injury include altered systemic and cerebral physiology, including altered cerebral hemodynamics. Cerebral autoregulation is often impaired following traumatic bra...

  1. Measurement of human blood brain barrier integrity using 11C-inulin and positron emission tomography

    International Nuclear Information System (INIS)

    Positron emission tomography (PET) using 11C-inulin was demonstrated to be applicable to the clinical measurement of blood brain barrier permeability and cerebral interstitial fluid volume. Kinetic data were analyzed by application of a two compartment model, in which blood plasma and interstitial fluid spaces constitute the compartments. The blood activity contribution was subtracted from the PET count with the aid of the 11CO inhalation technique. The values we estimated in a human brain were in agreement with the reported values obtained for animal brains by the use of 14C-inulin. (orig.)

  2. Increases in muscle sympathetic nerve activity, heart rate, respiration and skin blood flow during passive viewing of exercise

    OpenAIRE

    RachaelBrown; VaughanGMacefield

    2013-01-01

    The cardiovascular and respiratory effects of exercise have been widely studied, as have the autonomic effects of imagined and observed exercise. However, the effects of observed exercise in the first person have not been documented, nor have direct recordings of muscle sympathetic nerve activity (MSNA) been obtained during observed or imagined exercise. The aim of the current study was to measure blood pressure, heart rate, respiration, skin blood flow, sweat release and muscle sympathetic ...

  3. The fibrinolytic system facilitates tumor cell migration across the blood-brain barrier in experimental melanoma brain metastasis

    International Nuclear Information System (INIS)

    Patients with metastatic tumors to the brain have a very poor prognosis. Increased metastatic potential has been associated with the fibrinolytic system. We investigated the role of the fibrinolytic enzyme plasmin in tumor cell migration across brain endothelial cells and growth of brain metastases in an experimental metastatic melanoma model. Metastatic tumors to the brain were established by direct injection into the striatum or by intracarotid injection of B16F10 mouse melanoma cells in C57Bl mice. The role of plasminogen in the ability of human melanoma cells to cross a human blood-brain barrier model was studied on a transwell system. Wild type mice treated with the plasmin inhibitor epsilon-aminocaproic acid (EACA) and plg-/- mice developed smaller tumors and survived longer than untreated wild type mice. Tumors metastasized to the brain of wild type mice treated with EACA and plg-/- less efficiently than in untreated wild type mice. No difference was observed in the tumor growth in any of the three groups of mice. Human melanoma cells were able to cross the human blood-brain barrier model in a plasmin dependent manner. Plasmin facilitates the development of tumor metastasis to the brain. Inhibition of the fibrinolytic system could be considered as means to prevent tumor metastasis to the brain

  4. The Trojan Horse Liposome Technology for Nonviral Gene Transfer across the Blood-Brain Barrier

    OpenAIRE

    Boado, Ruben J; Pardridge, William M

    2011-01-01

    The application of blood-borne gene therapy protocols to the brain is limited by the presence of the blood-brain barrier (BBB). Viruses have been extensively used as gene delivery systems. However, their efficacy in brain is limited by the lack of transport across the BBB following intravenous (IV) administration. Recent progress in the “Trojan Horse Liposome” (THL) technology applied to transvascular non-viral gene therapy of the brain presents a promising solution to the trans-vascular brai...

  5. Hyperammonemia,brain edema and blood-brain barrier alterations in prehepatic portal hypertensive rats and paravrtamol intoxication

    Institute of Scientific and Technical Information of China (English)

    Camila Scorticati; Juan P. Prestifilippo; Francisco X. Eizayaga; José L. Castro; Salvador Romay; Maria A. Fernández; Abraham Lemberg; Juan C. Perazzo

    2004-01-01

    AIM: To study the blood-brain barrier integrity, brain edema,animal behavior and ammonia plasma levels in prehepatic portal hypertensive rats with and without acute liver intoxication.METHODS: Adults male Wistar rats were divided into four groups. Group Ⅰ: sham operation; Ⅱ: Prehepatic portal hypertension, produced by partial portal vein ligation; Ⅲ:Acetaminophen intoxication and Ⅳ: Prehepatic portal hypertension plus acetaminophen. Acetaminophen was administered to produce acute hepatic injury. Portal pressure, liver serum enzymes and ammonia plasma levels were determined. Brain cortex water content was registered and trypan blue was utilized to study blood brain barrier integrity. Reflexes and behavioral tests were recorded.RESULTS: Portal hypertension was significantly elevated in groups Ⅱ and Ⅳ. Liver enzymes and ammonia plasma levels were increased in groups Ⅱ, Ⅳ and Ⅳ. Prehepatic portal hypertension (group Ⅱ), acetaminophen intoxication (group Ⅲ) and both (group Ⅳ) had changes in the blood brain-barrier integrity (trypan blue) and hyperammonemia. Cortical edema was present in rats with acute hepatic injury in groups Ⅲ and Ⅳ. Behavioral test (rota rod) was altered in group Ⅳ.CONCLUSION: These results suggest the possibility of another pathway for cortical edema production because blood brain barrier was altered (vasogenic) and hyperammonemia was registered (cytotoxic). Group Ⅳ, with behavioral altered test, can be considered as a model for study at an early stage of portal-systemic encephalopathy.

  6. Regional differences of [18F]-FDG uptake within the brain during fatiguing muscle contractions

    OpenAIRE

    Kindred, John H.; Kalliokoski, Kari K.; Bojsen-Møller, Jens; Rudroff, Thorsten

    2015-01-01

    Background and Purpose Many studies have shown that a position task is more difficult than a force task although both are performed at a similar net muscle force. Thus, the time to task failure is consistently shown to be briefer during the position task. The contributions of the central nervous system to these two types of fatiguing contractions are not completely understood. The purpose of this pilot study was to examine differences in regional brain activity between force and position task...

  7. Regional differences of [18F]-FDG uptake within the brain during fatiguing muscle contractions.

    OpenAIRE

    Kindred, John H.; Kalliokoski, Kari K.; Bojsen-Møller, Jens; Rudroff, Thorsten

    2015-01-01

    Background and Purpose: Many studies have shown that a position task is more difficult than a force task although both are performed at a similar net muscle force. Thus, the time to task failure is consistently shown to be briefer during the position task. The contributions of the central nervous system to these two types of fatiguing contractions are not completely understood. The purpose of this pilot study was to examine differences in regional brain activity between force and position tas...

  8. Restoration of grasp following paralysis through brain-controlled stimulation of muscles

    OpenAIRE

    Ethier, C.; Oby, E.R.; Bauman, M.J.; Miller, L.E.

    2012-01-01

    Patients with spinal cord injury lack the connections between brain and spinal cord circuits essential for voluntary movement. Clinical systems that achieve muscle contraction through functional electrical stimulation (FES) have proven to be effective in allowing patients with tetraplegia to regain control of hand movement and to achieve a greater measure of independence in activities of daily living 1,2 . In typical systems, the patient uses residual proximal limb movements to trigger pre-pr...

  9. Antioxidant activity of carnosine, homocarnosine, and anserine present in muscle and brain.

    OpenAIRE

    Kohen, R; Yamamoto, Y.; Cundy, K C; Ames, B N

    1988-01-01

    Carnosine, homocarnosine, and anserine are present in high concentrations in the muscle and brain of many animals and humans. However, their exact function is not clear. The antioxidant activity of these compounds has been examined by testing their peroxyl radical-trapping ability at physiological concentrations. Carnosine, homocarnosine, anserine, and other histidine derivatives all showed antioxidant activity. All of these compounds showing peroxyl radical-trapping activity were also electr...

  10. Demonstration of blood brain barrier injury by computed tomography

    International Nuclear Information System (INIS)

    Blood brain barrier (BBB) injury was evoked by the injection of hypertonic solution, 50% glucose or 80% sodium iothalamate, through the catheter placed in the common carotid artery of the adult mongrel dogs. Plain CT and then contrast CT were performed at 30 minutes intervals until 3 hours to determine the relationship between the degrees of contrast enhancement (CE) and the amount of injected hypertonic solution, and to examine the diminishing rates of CE according to time elapsed after the intravenous contrast injection. Another four groups of dogs received contrast CT immediately, at 1, 2 and 3 hours after the injection of hypertonic solution to examine the degree of repair of BBB injury. Contrast media, which was leaked through BBB injured by the injection of hypertonic solution, was recognized by CT, and the area of CE coincided exactly with the dyed area by Evans blue, injected intravenously after induction of BBB injury. Degrees of CE were found to correlate linearly to the amount of hypertonic solution within a certain range. These results indicate that CT can demonstrate BBB injury qualitatively and quantitatively. In sequential CT after the artificial injury of BBB, degree of CE diminished linearly with a half life of about 3 hours. Hydrocortisone accelerated this washout of leaked contrast media. Repair of BBB itself, determined by contrast CT which were performed at 1, 2 and 3 hours after the induction of BBB injury, has been accomplished until 3 hours, and not affected by the administration of hydrocortisone. These experimental results suggest that CT is the most promising method to detect quantitatively and non-invasively the degree and the extent of BBB injury in clinical cases. (J.P.N.)

  11. Signals Analysis and Clinical Validation of Blood and Oxygen Data in Human Brain

    Institute of Scientific and Technical Information of China (English)

    LI Kai-yang; LIU Li-jun; WANG Xiang; QIN Zhao; XIE Ze-ping

    2005-01-01

    With a self-made near-infrared analytical instrument to blood and oxygen parameters in human brain, 80 cases in which 20 are healthy persons and 30are anaesthetised cases and others are patients with heart function lack is taken to examine, and the data of blood and oxygen in brain tissue were collected and analyzed by the method of power spectrum and correlation function. The results indicate that: (1) The average brain oxygen saturation of healthy persons and anaesthetised cases is about 80%, in accord with normal parameter of physiology. Contrastively, the average brain oxygen saturation of patients with heart function lack is 72. 8%, which is obviously less than that of healthy persons and anaesthetised cases. The probability of medical statistics is less than 0. 01. (2) The shapes of wave of brain blood and oxygen for the healthy person and the anaesthetised case reveal small periodical fluctuations with stable shape and base line, and the trend of increase or decrease of blood and oxygen parameters in brain tissue is synchronous and a phase reversal, but for the patient with heart function lack in a brain oxygen lack state, the shapes of wave are irregular. This is a hint that near infrared light passing through tissue can reflect the intuitionistic change of brain blood and oxygen parameters. (3) The power spectra of brain blood and oxygen for the healthy person and the anaesthetised case has a clear main peak, narrow bandwidth and perfect superposition each other, but the power spectra for the patient with heart function lack in a brain oxygen lack state is on the contrary. (4) The average cross correlation coefficient of brain blood and oxygen for healthy persons and anaesthetised cases is -0. 9825±0. 1027 close to -1. But the average cross correlation coefficient for patients with heart function lack in a brain oxygen lack state is merely -0. 8923± 0. 1035 which is obviously greater than -1 and the probability of medical statistics is less than 0. 01

  12. Brain blood flow studies with single photon emission computed tomography in patients with plateau waves

    International Nuclear Information System (INIS)

    The authors studied brain blood flow with single photon emission computed tomography (SPECT) in two patients with plateau waves. The intracranial pressure and blood pressure were also monitored continuously in these patients. They included one patient with brain-tumor (rt. sphenoid ridge meningioma) and another with hydrocephalus after subarachnoid hemorrhage due to rupture of lt. internal carotid aneurysm. The intracranial pressure was monitored through an indwelling ventricular catheter attached to a pressure transducer. The blood pressure was recorded through an intraarterial catheter placed in the dorsalis pedis artery. Brain blood flow was studied with Headtome SET-011 (manufactured by Shimazu Co., Ltd.). For this flow measurement study, an intravenous injection of Xenon-133 of about 30 mCi was given via an antecubital vein. The position of the slice for the SPECT was selected so as to obtain information not only from the cerebral hemisphere but also from the brain stem : a cross section 25 deg over the orbito-meatal line, passing through the inferior aspect of the frontal horn, the basal ganglia, the lower recessus of the third ventricle and the brain stem. The results indicated that, in the cerebral hemisphere, plateau waves were accompanied by a decrease in blood flow, whereas, in the brain stem, the blood flow showed little change during plateau waves as compared with the interval phase between two plateau waves. These observations may explain why there is no rise in the blood pressure and why patients are often alert during plateau waves. (author)

  13. Smooth-muscle BMAL1 participates in blood pressure circadian rhythm regulation.

    Science.gov (United States)

    Xie, Zhongwen; Su, Wen; Liu, Shu; Zhao, Guogang; Esser, Karyn; Schroder, Elizabeth A; Lefta, Mellani; Stauss, Harald M; Guo, Zhenheng; Gong, Ming Cui

    2015-01-01

    As the central pacemaker, the suprachiasmatic nucleus (SCN) has long been considered the primary regulator of blood pressure circadian rhythm; however, this dogma has been challenged by the discovery that each of the clock genes present in the SCN is also expressed and functions in peripheral tissues. The involvement and contribution of these peripheral clock genes in the circadian rhythm of blood pressure remains uncertain. Here, we demonstrate that selective deletion of the circadian clock transcriptional activator aryl hydrocarbon receptor nuclear translocator-like (Bmal1) from smooth muscle, but not from cardiomyocytes, compromised blood pressure circadian rhythm and decreased blood pressure without affecting SCN-controlled locomotor activity in murine models. In mesenteric arteries, BMAL1 bound to the promoter of and activated the transcription of Rho-kinase 2 (Rock2), and Bmal1 deletion abolished the time-of-day variations in response to agonist-induced vasoconstriction, myosin phosphorylation, and ROCK2 activation. Together, these data indicate that peripheral inputs contribute to the daily control of vasoconstriction and blood pressure and suggest that clock gene expression outside of the SCN should be further evaluated to elucidate pathogenic mechanisms of diseases involving blood pressure circadian rhythm disruption. PMID:25485682

  14. Influence of erythrocyte oxygenation and intravascular ATP on resting and exercising skeletal muscle blood flow in humans with mitochondrial myopathy

    DEFF Research Database (Denmark)

    Jeppesen, Tina D; Vissing, John; González-Alonso, José

    2012-01-01

    Oxygen (O(2)) extraction is impaired in exercising skeletal muscle of humans with mutations of mitochondrial DNA (mtDNA), but the muscle hemodynamic response to exercise has never been directly investigated. This study sought to examine the extent to which human skeletal muscle perfusion can...... healthy control subjects: 1) at rest during normoxia, hypoxia, hyperoxia and intra-femoral artery ATP infusion, and 2) during passive and dynamic one-legged knee-extensor exercises. At rest, blood flow (LBF), femoral arterial and venous blood oxygenation and plasma ATP were similar in the two groups...

  15. Permeability of the blood-brain barrier predicts conversion from optic neuritis to multiple sclerosis

    DEFF Research Database (Denmark)

    Cramer, Stig P; Modvig, Signe; Simonsen, Helle Juhl;

    2015-01-01

    permeability of the blood-brain barrier in normal-appearing white matter of patients with multiple sclerosis and here, for the first time, we present a study on the capability of blood-brain barrier permeability in predicting conversion from optic neuritis to multiple sclerosis and a direct comparison with...... cerebrospinal fluid markers of inflammation, cellular trafficking and blood-brain barrier breakdown. To this end, we applied dynamic contrast-enhanced magnetic resonance imaging at 3 T to measure blood-brain barrier permeability in 39 patients with monosymptomatic optic neuritis, all referred for imaging as...... part of the diagnostic work-up at time of diagnosis. Eighteen healthy controls were included for comparison. Patients had magnetic resonance imaging and lumbar puncture performed within 4 weeks of onset of optic neuritis. Information on multiple sclerosis conversion was acquired from hospital records 2...

  16. Molecular biology of the blood-brain and the blood-cerebrospinal fluid barriers: similarities and differences

    Directory of Open Access Journals (Sweden)

    Redzic Zoran

    2011-01-01

    Full Text Available Abstract Efficient processing of information by the central nervous system (CNS represents an important evolutionary advantage. Thus, homeostatic mechanisms have developed that provide appropriate circumstances for neuronal signaling, including a highly controlled and stable microenvironment. To provide such a milieu for neurons, extracellular fluids of the CNS are separated from the changeable environment of blood at three major interfaces: at the brain capillaries by the blood-brain barrier (BBB, which is localized at the level of the endothelial cells and separates brain interstitial fluid (ISF from blood; at the epithelial layer of four choroid plexuses, the blood-cerebrospinal fluid (CSF barrier (BCSFB, which separates CSF from the CP ISF, and at the arachnoid barrier. The two barriers that represent the largest interface between blood and brain extracellular fluids, the BBB and the BCSFB, prevent the free paracellular diffusion of polar molecules by complex morphological features, including tight junctions (TJs that interconnect the endothelial and epithelial cells, respectively. The first part of this review focuses on the molecular biology of TJs and adherens junctions in the brain capillary endothelial cells and in the CP epithelial cells. However, normal function of the CNS depends on a constant supply of essential molecules, like glucose and amino acids from the blood, exchange of electrolytes between brain extracellular fluids and blood, as well as on efficient removal of metabolic waste products and excess neurotransmitters from the brain ISF. Therefore, a number of specific transport proteins are expressed in brain capillary endothelial cells and CP epithelial cells that provide transport of nutrients and ions into the CNS and removal of waste products and ions from the CSF. The second part of this review concentrates on the molecular biology of various solute carrier (SLC transport proteins at those two barriers and underlines

  17. Assessing the quality of angiographic display of brain blood vessels aneurysms compared to intraoperative state

    OpenAIRE

    Nikolić Igor M.; Tasić Goran M.; Jovanović Vladimir T.; Repac Nikola R.; Janićijević Aleksandar M.; Šćepanović Vuk D.; Nestorović Branislav D.

    2013-01-01

    Background/Aim. Aneurysms in brain blood vessels are expanding bags composed of a neck, body and fundus. Clear visibility of the neck, the position of the aneurysm and surrounding structures are necessary for a proper choice of methods for excluding the aneurysm from the circulation. The aim of this study was to evaluate the reliability of spatial reconstruction of blood vessels of the brain based on the original software for 3D reconstruction of the equipment manufacturer and a persona...

  18. Restraint Stress-Induced Morphological Changes at the Blood-Brain Barrier in Adult Rats

    OpenAIRE

    Petra eSántha; Szilvia eVeszelka; Zsófia eHoyk; Mária eMészáros; Walter, Fruzsina R.; Andrea E Tóth; Lóránd eKiss; András eKincses; Zita eOláh; György eSeprényi; Gabor eRakhely; András eDér; Magdolna ePákáski; Janos eKalman; Ágnes eKittel

    2016-01-01

    Stress is well-known to contribute to the development of both neurological and psychiatric diseases. While the role of the blood-brain barrier is increasingly recognized in the development of neurodegenerative disorders, such as Alzheimer's disease, dysfunction of the blood-brain barrier has been linked to stress-related psychiatric diseases only recently. In the present study the effects of restraint stress with different duration (1, 3, and 21 days) were investigated on the morphology of th...

  19. What is the correct value for the brain: blood partition coefficient for water

    Energy Technology Data Exchange (ETDEWEB)

    Herscovitch, P.; Raichle, M.E.

    1984-01-01

    A knowledge of the brain: blood partition coefficient (lambda) for water is usually required for the measurement of cerebral blood flow (CBF) with positron emission tomography (PET) and 0-15 labelled water. The correct calculation of this important parameter from the ratio of brain and blood water contents is reviewed, and the effect of physiological variations in these water contents on lambda is demonstrated. The currently accepted value for whole brain lambda is 0.95-0.96 ml/g, calculated from brain and blood water contents of 77g/100g and 80.5g/100g, respectively. However, this value for lambda is incorrect, because in the calculation the blood water content value was not adjusted for the density of blood. The correct value is 0.91 ml/g. Variations in brain or blood water content affect lambda. Over an hematocrit range of 25% to 55%, lambda varies from 0.86 to 0.93 ml/g, due to a decrease in blood water content. lambda changes with age, and varies regionally in the brain, as brain water content is inversely related to lipid and myelin content. The lambda of the human newborn brain, 1.10 ml/g, is considerably higher than in the adult. Differences in lambda between gray and white matter are well known. However, because of variations in water content, the lambda's of thalamus (0.88 ml/g) and caudate nucleus (0.96 ml/g) are less than that of cerebral cortex (0.99 ml/g), while the lambda of corpus callosum (0.89 ml/g) is greater than that of centrum semiovale (0.83 ml/g). These regional variations in lambda will assume more importance as PET resolution improves. The impact of using an incorrect lambda will depend upon the sensitivity of the particular CBF measurement technique to errors in lambda.

  20. Understanding the rules of the road: proteomic approaches to interrogate the blood brain barrier

    OpenAIRE

    Torbett, Bruce E.; Baird, Andrew; Eliceiri, Brian P

    2015-01-01

    The blood brain barrier (BBB) is often regarded as a passive barrier that protects brain parenchyma from toxic substances, circulating leukocytes, while allowing the passage of selected molecules. Recently, a combination of molecular profiling techniques have characterized the constituents of the BBB based on in vitro models using isolated endothelial cells and ex vivo models analyzing isolated blood vessels. Characterization of gene expression profiles that are specific to the endothelium of...

  1. Blood-Brain Barrier Effects of the Fusarium Mycotoxins Deoxynivalenol, 3 Acetyldeoxynivalenol, and Moniliformin and Their Transfer to the Brain

    Science.gov (United States)

    Behrens, Matthias; Hüwel, Sabine; Galla, Hans-Joachim; Humpf, Hans-Ulrich

    2015-01-01

    Background Secondary metabolites produced by Fusarium fungi frequently contaminate food and feed and have adverse effects on human and animal health. Fusarium mycotoxins exhibit a wide structural and biosynthetic diversity leading to different toxicokinetics and toxicodynamics. Several studies investigated the toxicity of mycotoxins, focusing on very specific targets, like the brain. However, it still remains unclear how fast mycotoxins reach the brain and if they impair the integrity of the blood-brain barrier. This study investigated and compared the effects of the Fusarium mycotoxins deoxynivalenol, 3-acetyldeoxynivalenol and moniliformin on the blood-brain barrier. Furthermore, the transfer properties to the brain were analyzed, which are required for risk assessment, including potential neurotoxic effects. Methods Primary porcine brain capillary endothelial cells were cultivated to study the effects of the examined mycotoxins on the blood-brain barrier in vitro. The barrier integrity was monitored by cellular impedance spectroscopy and 14C radiolabeled sucrose permeability measurements. The distribution of the applied toxins between blood and brain compartments of the cell monolayer was analyzed by high performance liquid chromatography-mass spectrometry to calculate transfer rates and permeability coefficients. Results Deoxynivalenol reduced the barrier integrity and caused cytotoxic effects at 10 μM concentrations. Slight alterations of the barrier integrity were also detected for 3-acetyldeoxynivalenol. The latter was transferred very quickly across the barrier and additionally cleaved to deoxynivalenol. The transfer of deoxynivalenol and moniliformin was slower, but clearly exceeded the permeability of the negative control. None of the compounds was enriched in one of the compartments, indicating that no efflux transport protein is involved in their transport. PMID:26600019

  2. Blood-Brain Barrier Effects of the Fusarium Mycotoxins Deoxynivalenol, 3 Acetyldeoxynivalenol, and Moniliformin and Their Transfer to the Brain.

    Directory of Open Access Journals (Sweden)

    Matthias Behrens

    Full Text Available Secondary metabolites produced by Fusarium fungi frequently contaminate food and feed and have adverse effects on human and animal health. Fusarium mycotoxins exhibit a wide structural and biosynthetic diversity leading to different toxicokinetics and toxicodynamics. Several studies investigated the toxicity of mycotoxins, focusing on very specific targets, like the brain. However, it still remains unclear how fast mycotoxins reach the brain and if they impair the integrity of the blood-brain barrier. This study investigated and compared the effects of the Fusarium mycotoxins deoxynivalenol, 3-acetyldeoxynivalenol and moniliformin on the blood-brain barrier. Furthermore, the transfer properties to the brain were analyzed, which are required for risk assessment, including potential neurotoxic effects.Primary porcine brain capillary endothelial cells were cultivated to study the effects of the examined mycotoxins on the blood-brain barrier in vitro. The barrier integrity was monitored by cellular impedance spectroscopy and 14C radiolabeled sucrose permeability measurements. The distribution of the applied toxins between blood and brain compartments of the cell monolayer was analyzed by high performance liquid chromatography-mass spectrometry to calculate transfer rates and permeability coefficients.Deoxynivalenol reduced the barrier integrity and caused cytotoxic effects at 10 μM concentrations. Slight alterations of the barrier integrity were also detected for 3-acetyldeoxynivalenol. The latter was transferred very quickly across the barrier and additionally cleaved to deoxynivalenol. The transfer of deoxynivalenol and moniliformin was slower, but clearly exceeded the permeability of the negative control. None of the compounds was enriched in one of the compartments, indicating that no efflux transport protein is involved in their transport.

  3. Biomarkers of traumatic injury are transported from brain to blood via the glymphatic system.

    Science.gov (United States)

    Plog, Benjamin A; Dashnaw, Matthew L; Hitomi, Emi; Peng, Weiguo; Liao, Yonghong; Lou, Nanhong; Deane, Rashid; Nedergaard, Maiken

    2015-01-14

    The nonspecific and variable presentation of traumatic brain injury (TBI) has motivated an intense search for blood-based biomarkers that can objectively predict the severity of injury. However, it is not known how cytosolic proteins released from traumatized brain tissue reach the peripheral blood. Here we show in a murine TBI model that CSF movement through the recently characterized glymphatic pathway transports biomarkers to blood via the cervical lymphatics. Clinically relevant manipulation of glymphatic activity, including sleep deprivation and cisternotomy, suppressed or eliminated TBI-induced increases in serum S100β, GFAP, and neuron specific enolase. We conclude that routine TBI patient management may limit the clinical utility of blood-based biomarkers because their brain-to-blood transport depends on glymphatic activity. PMID:25589747

  4. Comparison study of ferrofluid and powder iron oxide nanoparticle permeability across the blood-brain barrier.

    Science.gov (United States)

    Hoff, Dan; Sheikh, Lubna; Bhattacharya, Soumya; Nayar, Suprabha; Webster, Thomas J

    2013-01-01

    In the present study, the permeability of 11 different iron oxide nanoparticle (IONP) samples (eight fluids and three powders) was determined using an in vitro blood-brain barrier model. Importantly, the results showed that the ferrofluid formulations were statistically more permeable than the IONP powder formulations at the blood-brain barrier, suggesting a role for the presently studied in situ synthesized ferrofluid formulations using poly(vinyl) alcohol, bovine serum albumin, collagen, glutamic acid, graphene, and their combinations as materials which can cross the blood-brain barrier to deliver drugs or have other neurological therapeutic efficacy. Conversely, the results showed the least permeability across the blood-brain barrier for the IONP with collagen formulation, suggesting a role as a magnetic resonance imaging contrast agent but limiting IONP passage across the blood-brain barrier. Further analysis of the data yielded several trends of note, with little correlation between permeability and fluid zeta potential, but a larger correlation between permeability and fluid particle size (with the smaller particle sizes having larger permeability). Such results lay the foundation for simple modification of iron oxide nanoparticle formulations to either promote or inhibit passage across the blood-brain barrier, and deserve further investigation for a wide range of applications. PMID:23426527

  5. What role does the blood brain barrier play in acute mountain sickness?

    Science.gov (United States)

    Baneke, Alex

    2010-07-01

    As high altitude travel increases, acute mountain sickness (AMS) and life threatening high altitude cerebral oedema (HACE) are becoming more prevalent. Acute mountain sickness occurs in 45% of lowlanders above 4250 m. Predisposing factors are still unknown and its development is more complex than the original "tight fit" hypothesis. This review examines evidence relating to a possible role of the blood brain barrier in AMS as suggested by MRI studies. Underlying mechanisms may involve vascular endothelial growth factor and free radicals in addition to increases in hydrostatic pressure. An increased understanding is important in advising patients planning high altitude adventures. Current studies have linked increased blood brain barrier permeability to high altitude cerebral oedema, but the role of the blood brain barrier in acute mountain sickness is less clear; varied symptoms include headache. MRI shows vasogenic oedema occurs in high altitude cerebral oedema, suggesting blood brain barrier permeability increases, and acute mountain sickness typically precedes high altitude cerebral oedema. Hypoxia leads to increased hydrostatic pressure, and blood brain barrier permeability has been shown to increase in stroke patients. Vascular endothelial growth factor is upregulated in hypoxia, and may increase blood brain barrier permeability. PMID:20952272

  6. Next generation of non-mammalian blood-brain barrier models to study parasitic infections of the central nervous system

    OpenAIRE

    Siddiqui, Ruqaiyyah; Edwards-Smallbone, James; Flynn, Robin; Khan, Naveed Ahmed

    2012-01-01

    Transmigration of neuropathogens across the blood-brain barrier is a key step in the development of central nervous system infections, making it a prime target for drug development. The ability of neuropathogens to traverse the blood-brain barrier continues to inspire researchers to understand the specific strategies and molecular mechanisms that allow them to enter the brain. The availability of models of the blood-brain barrier that closely mimic the situation in vivo offers unprecedented o...

  7. Defense at the border : the blood-brain barrier versus bacterial foreigners

    NARCIS (Netherlands)

    van Sorge, Nina M.; Doran, Kelly S.

    2012-01-01

    Bacterial meningitis is among the top ten causes of infectious disease-related deaths worldwide, with up to half of the survivors left with permanent neurological sequelae. The blood-brain barrier (BBB), composed mainly of specialized brain microvascular endothelial cells, maintains biochemical home

  8. St. John's Wort constituents modulate P-glycoprotein transport activity at the blood-brain barrier.

    NARCIS (Netherlands)

    Ott, M.; Huls, M.; Cornelius, M.G.; Fricker, G.

    2010-01-01

    PURPOSE: The purpose of this study was to investigate the short-term signaling effects of St. John's Wort (SJW) extract and selected SJW constituents on the blood-brain barrier transporter P-glycoprotein and to describe the role of PKC in the signaling. METHODS: Cultured porcine brain capillary endo

  9. The model of the decay of a radioactive tracer introduced to the muscle involving considerable variation of the muscle blood flow

    International Nuclear Information System (INIS)

    The paper describes an electronic analogous model simulating the activity decay curve of a radioactive sample of 133Xe injected to the muscle and washed out by the blood flow. The model experiments aimed at estimating the accuracy of the isotope method of determining the speed of blood flow in the heart muscle involving considerable flow variations. From the results and experimental data it was found that the periodical changes in the blood flow resulting from the heart action do not effect significantly the activity decay curve. The changes in the blood flow caused by other factors such as changes in the heart rate and perfusion pressure can be determined from the changes in the shape of the curve provided they are big enough. (author)

  10. Evaluation of low level laser therapy irradiation parameters on rat muscle inflammation through systemic blood cytokines

    Science.gov (United States)

    Mantineo, Matias; Pinheiro, João. P.; Morgado, António M.

    2014-02-01

    Low level laser therapy (LLLT) has been used for inflammation treatment. Here, we evaluate the effect of different doses, using continuous (830 and 980 nm) and pulsed illumination (830 nm), in the treatment of inflammation induced in the gastrocnemius muscle of Wistar rats, through cytokines concentration in systemic blood and histological analysis of muscle tissue. Animals were randomly divided into five groups per wavelength (5 animals per group: 10, 20, 30, 40 and 50 mW) plus a control group. LLLT was applied during five days, with constant exposure time and irradiated area (3 minutes; 0.5026 cm2). Blood was collected on days 0, 3 and 6. TNF-α, IL-1β, IL-2 and IL-6 cytokines were quantified by ELISA. Rats were killed on day 6. Muscle inflammatory cells were counted using optical microscopy. Treatment effects occurred for all applied doses (largest effect at 40 mW: 7.2 J, 14 J/cm2 per irradiation), with reduction of proinflammatory TNF-α, IL-1β and IL-6 cytokines and lower number of inflammatory cells. Results were better for 830 nm. Identical methodology was used with pulsed illumination. Average power (40 mW) and duty cycle were kept constant (80%) at five frequencies (5, 25, 50, 100 and 200 Hz). Treatment effects were observed at higher frequencies, with no significant differences between them. However, the treatment effect was lower than for continuous illumination. LLLT effect on inflammation treatment can be monitored by measuring systemic blood cytokines. A larger treatment effect was observed with continuous illumination, where results seem to be compatible with a biphasic dose response.

  11. Changes in extracellular muscle volume affect heart rate and blood pressure responses to static exercise

    Science.gov (United States)

    Baum, K.; Essfeld, D.; Stegemann, J.

    To investigate the effect of μg-induced peripheral extracellular fluid reductions on heart rate and blood pressure during isometric exercise, six healthy male subjects performed three calf ergometer test with different extracellular volumes of working muscles. In all tests, body positions during exercise were identical (supine with the knee joint flexed to 900). After a pre-exercise period of 25 min, during which calf volumes were manipulated, subjects had to counteract an external force of 180 N for 5 min. During the pre-exercise period three different protocols were applied. Test A: Subjects rested in the exercise position; test B: Body position was the same as in A but calf volume was increased by venous congestion (cuffs inflated to 80 mm Hg); test C: Calf volumes were decreased by a negative hydrostatic pressure (calves about 40 cm above heart level with the subjects supine). To clamp the changed calf volumes in tests B and C, cuffs were inflated to 300 mm Hg 5 min before the onset of exercise. This occlusion was maintained until termination of exercise. Compared to tests A and B, the reduced volume of test C led to significant increases in heart rate and blood pressure during exercise. Oxygen uptake did not exceed resting levels in B and C until cuffs were deflated, indicating that exclusively calf muscles contributed to the neurogenic peripheral drive. It is concluded that changes in extracellular muscle volume have to be taken into account when comparing heart rate and blood pressure during lg- and μg- exercise.

  12. Blood-Brain Barrier Active Efflux Transporters: ATP-Binding Cassette Gene Family

    OpenAIRE

    Löscher, Wolfgang; Potschka, Heidrun

    2005-01-01

    Summary: The blood-brain barrier (BBB) contributes to brain homeostasis by protecting the brain from potentially harmful endogenous and exogenous substances. BBB active drug efflux transporters of the ATP-binding cassette (ABC) gene family are increasingly recognized as important determinants of drug distribution to, and elimination from, the CNS. The ABC efflux transporter P-glycoprotein (Pgp) has been demonstrated as a key element of the BBB that can actively transport a huge variety of lip...

  13. Selective permeabilization of the blood-brain barrier at sites of metastasis

    OpenAIRE

    Sibson, NR; Vallis, KA; Hamilton, A.; Seymour, L.; Anthony, DC; Connell, JJ; Chatain, G

    2013-01-01

    BACKGROUND: Effective chemotherapeutics for primary systemic tumors have limited access to brain metastases because of the blood-brain barrier (BBB). The aim of this study was to develop a strategy for specifically permeabilizing the BBB at sites of cerebral metastases. METHODS: BALB/c mice were injected intracardially to induce brain metastases. After metastasis induction, either tumor necrosis factor (TNF) or lymphotoxin (LT) was administered intravenously, and 2 to 24 hours later gadoliniu...

  14. Muscle activation, blood lactate, and perceived exertion responses to changing resistance training programming variables.

    Science.gov (United States)

    Hiscock, Daniel J; Dawson, Brian; Donnelly, Cyril J; Peeling, Peter

    2016-08-01

    Ratings of perceived exertion (RPE: 0-10) during resistance training with varying programming demands were examined. Blood lactate (BLa) and muscle activation (using surface electromyography: EMG) were measured as potential mediators of RPE responses. Participants performed three sets of single arm (preferred side) bicep curls at 70% of 1 repetition maximum over 4 trials: Trial (A) 3 sets × 8 repetitions × 120 s recovery between sets; (B) 3 sets × 8 repetitions × 240 s recovery; (C) 3 sets × maximum number of repetitions (MNR) × 120 s recovery; (D) 3 sets × MNR × 240 s recovery. Overall body (RPE-O) and active muscle (RPE-AM) perceptual responses were assessed following each set in each trial. Biceps brachii and brachioradialis muscle EMG was measured during each set for each trial. RPE-O and RPE-AM were not different between Trial A (3.5 ± 1 and 6 ± 1, respectively) and Trial B (3.5 ± 1 and 5.5 ± 1, respectively) (p < .05). However, RPE-AM was significantly greater in Trial C (7.5 ± 1.5) and Trial D (7.5 ± 1.5) than in Trial B (p < .05). There were no significant differences in muscle activation or BLa between trials; however, work rate (tonnage/min) was greater in Trials C and D compared to Trial B. In conclusion, BLa and muscle activation were not related to RPE, but resistance training variables, such as work rate, may impact on RPE when intensity (%1RM) and the number of sets completed remain constant. PMID:26267339

  15. Endoscopic-assisted minimally invasive resection of a papillary muscle blood cyst in an adult patient.

    Science.gov (United States)

    Okamoto, Kazuma; Kudo, Mikihiko; Hayashi, Kanako; Shimizu, Hideyuki

    2016-02-01

    We describe endoscopic-assisted minimally invasive resection of a blood cyst originating from the papillary muscle that caused severe mitral regurgitation and necessitated mitral valve replacement in an active adult woman, as well as a review of the relevant literature. An endoscopic view increases the visibility of the surgical target and facilitates a precise observation of the tumour and dissection at the appropriate layer. The On-X mechanical valve was chosen for mitral valve repair to minimize thromboembolic risk. This patient additionally benefited from endoscopic-assisted right minithoracotomy in terms of both cosmetic and functional aspects. PMID:26586675

  16. Bryostatin-1 Restores Blood Brain Barrier Integrity following Blast-Induced Traumatic Brain Injury.

    Science.gov (United States)

    Lucke-Wold, Brandon P; Logsdon, Aric F; Smith, Kelly E; Turner, Ryan C; Alkon, Daniel L; Tan, Zhenjun; Naser, Zachary J; Knotts, Chelsea M; Huber, Jason D; Rosen, Charles L

    2015-12-01

    Recent wars in Iraq and Afghanistan have accounted for an estimated 270,000 blast exposures among military personnel. Blast traumatic brain injury (TBI) is the 'signature injury' of modern warfare. Blood brain barrier (BBB) disruption following blast TBI can lead to long-term and diffuse neuroinflammation. In this study, we investigate for the first time the role of bryostatin-1, a specific protein kinase C (PKC) modulator, in ameliorating BBB breakdown. Thirty seven Sprague-Dawley rats were used for this study. We utilized a clinically relevant and validated blast model to expose animals to moderate blast exposure. Groups included: control, single blast exposure, and single blast exposure + bryostatin-1. Bryostatin-1 was administered i.p. 2.5 mg/kg after blast exposure. Evan's blue, immunohistochemistry, and western blot analysis were performed to assess injury. Evan's blue binds to albumin and is a marker for BBB disruption. The single blast exposure caused an increase in permeability compared to control (t = 4.808, p < 0.05), and a reduction back toward control levels when bryostatin-1 was administered (t = 5.113, p < 0.01). Three important PKC isozymes, PKCα, PKCδ, and PKCε, were co-localized primarily with endothelial cells but not astrocytes. Bryostatin-1 administration reduced toxic PKCα levels back toward control levels (t = 4.559, p < 0.01) and increased the neuroprotective isozyme PKCε (t = 6.102, p < 0.01). Bryostatin-1 caused a significant increase in the tight junction proteins VE-cadherin, ZO-1, and occludin through modulation of PKC activity. Bryostatin-1 ultimately decreased BBB breakdown potentially due to modulation of PKC isozymes. Future work will examine the role of bryostatin-1 in preventing chronic neurodegeneration following repetitive neurotrauma. PMID:25301233

  17. Spatial mapping of blood flow and oxygen consumption in the human calf muscle using near-infrared spectroscopy

    Science.gov (United States)

    Fantini, Sergio; Hoimes, Matthew L.; Casavola, Claudia; Franceschini, Maria-Angela

    2001-05-01

    We have designed a new optical probe to perform spatially resolved measurements of blood flow and oxygen consumption over an area of about 4 x 4 cm2 of the lateral gastrocnemius muscle (calf muscle) of human subjects. The blood flow and the oxygen consumption were measured non- invasively with frequency-domain, near-infrared spectroscopy from the maximum rate of increase of the oxy- and deoxy- hemoglobin concentrations in the muscle during venous occlusion. In a preliminary test on one subject, involving measurements at rest and after exercise, we have found that the spatial variability of the measured blood flow and oxygen consumption is significantly greater than the variability of repeated measurements at a given tissue location. We have also observed a strong spatial dependence of the exercise-induced increase in blood flow and oxygen consumption.

  18. Mitochondrial energetic defects in muscle and brain of a Hmbs-/- mouse model of acute intermittent porphyria.

    Science.gov (United States)

    Homedan, Chadi; Schmitt, Caroline; Laafi, Jihane; Gueguen, Naïg; Desquiret-Dumas, Valérie; Lenglet, Hugo; Karim, Zoubida; Gouya, Laurent; Deybach, Jean-Charles; Simard, Gilles; Puy, Hervé; Malthièry, Yves; Reynier, Pascal

    2015-09-01

    Acute intermittent porphyria (AIP), an autosomal dominant metabolic disease (MIM #176000), is due to a deficiency of hydroxymethylbilane synthase (HMBS), which catalyzes the third step of the heme biosynthetic pathway. The clinical expression of the disease is mainly neurological, involving the autonomous, central and peripheral nervous systems. We explored mitochondrial oxidative phosphorylation (OXPHOS) in the brain and skeletal muscle of the Hmbs(-/-) mouse model first in the basal state (BS), and then after induction of the disease with phenobarbital and treatment with heme arginate (HA). The modification of the respiratory parameters, determined in mice in the BS, reflected a spontaneous metabolic energetic adaptation to HMBS deficiency. Phenobarbital induced a sharp alteration of the oxidative metabolism with a significant decrease of ATP production in skeletal muscle that was restored by treatment with HA. This OXPHOS defect was due to deficiencies in complexes I and II in the skeletal muscle whereas all four respiratory chain complexes were affected in the brain. To date, the pathogenesis of AIP has been mainly attributed to the neurotoxicity of aminolevulinic acid and heme deficiency. Our results show that mitochondrial energetic failure also plays an important role in the expression of the disease. PMID:26071363

  19. Differential effects of angiopoietin-like 4 in brain and muscle on regulation of lipoprotein lipase activity

    DEFF Research Database (Denmark)

    Vienberg, Sara Gry; Kleinridders, André; Suzuki, Ryo; Kahn, C Ronald

    2014-01-01

    2 (ob/ob) diabetic mice, there is a ~2-fold increase of Angptl4 in the hypothalamus and skeletal muscle. Intracerebroventricular insulin injection into STZ mice at levels which have no effect on plasma glucose restores Angptl4 expression in hypothalamus. Isolation of cells from the brain reveals...... activity in skeletal muscle is increased 3-fold, and this is further increased by STZ-induced diabetes. By contrast, Angptl4-/- mice show no significant difference in LPL activity in hypothalamus or brain independent of diabetic and nutritional status. Conclusion: Thus, Angptl4 in brain is produced in glia...

  20. Blood-brain barrier transport kinetics of the cyclic depsipeptide mycotoxins beauvericin and enniatins.

    Science.gov (United States)

    Taevernier, Lien; Bracke, Nathalie; Veryser, Lieselotte; Wynendaele, Evelien; Gevaert, Bert; Peremans, Kathelijne; De Spiegeleer, Bart

    2016-09-01

    The cyclic depsipeptide mycotoxins beauvericin and enniatins are capable of reaching the systemic circulation through various routes of exposure and are hence capable of exerting central nervous system (CNS) effects, if they are able to pass the blood-brain barrier (BBB), which was the main objective of this study. Quantification of the mycotoxins was performed using an in-house developed and validated bio-analytical UHPLC-MS/MS method. Prior to the BBB experiments, the metabolic stability of the mycotoxins was evaluated in vitro in mouse serum and brain homogenate. The BBB permeation kinetics of beauvericin and enniatins were studied using an in vivo mice model, applying multiple time regression for studying the blood-to-brain influx. Additionally, capillary depletion was applied to obtain the fraction of the peptides really entering the brain parenchyma and the fraction loosely adhered to the brain capillary wall. Finally, also the brain-to-blood efflux transport kinetics was studied. Metabolic stability data indicated that the investigated mycotoxins were stable during the duration of the in vivo study. The brain influx study showed that beauvericin and enniatins are able to cross the blood-brain barrier in mice: using the Gjedde-Patlak biphasic model, it was shown that all investigated mycotoxins exert a high initial influx rate into the brain (K1 ranging from 11 to 53μL/(g×min)), rapidly reaching a plateau. After penetration, the mycotoxins reached the brain parenchyma (95%) with only a limited amount residing in the capillaries (5%). Negligible efflux (<0.005min(-1)) from the brain was observed in the 15min post-intracerebroventricular injection. PMID:27349679

  1. Simulation of Local Blood Flow in Human Brain under Altered Gravity

    Science.gov (United States)

    Kim, Chang Sung; Kiris, Cetin; Kwak, Dochan

    2003-01-01

    In addition to the altered gravitational forces, specific shapes and connections of arteries in the brain vary in the human population (Cebral et al., 2000; Ferrandez et al., 2002). Considering the geometric variations, pulsatile unsteadiness, and moving walls, computational approach in analyzing altered blood circulation will offer an economical alternative to experiments. This paper presents a computational approach for modeling the local blood flow through the human brain under altered gravity. This computational approach has been verified through steady and unsteady experimental measurements and then applied to the unsteady blood flows through a carotid bifurcation model and an idealized Circle of Willis (COW) configuration under altered gravity conditions.

  2. Effects of Yishendaluo decoction on blood-brain barrier integrity in mice with experimental autoimmune encephalomyelitis

    Institute of Scientific and Technical Information of China (English)

    Yanqing Wu; Ying Gao; Lingqun Zhu; Yonghong Gao; Dongmei Zhang; Lixia Lou; Yanfang Yan

    2011-01-01

    This study investigated the effects of Yishendaluo decoction on the loss of blood-brain barrier integrity in mice exhibiting experimental autoimmune encephalomyelitis.To this end,we used real-time fluorescent quantitative PCR to measure the levels of mRNAs specific to the T cell markers CD4 and CD8,and the monocyte marker CD11b.In addition,we used Evans blue dye extravasation in the spinal cord and brain tissues to assess blood-brain barrier permeability.The results indicated that an increase in blood-brain barrier permeability was associated with an increase in CD4,CD8 and CD11b mRNA expression in experimental autoimmune encephalomyelitis mice.Yishendaluo decoction administration significantly reversed inflammatory cell accumulation in cerebral tissues of experimental autoimmune encephalomyelitis mice.

  3. The Trojan Horse Liposome Technology for Nonviral Gene Transfer across the Blood-Brain Barrier

    Directory of Open Access Journals (Sweden)

    Ruben J. Boado

    2011-01-01

    Full Text Available The application of blood-borne gene therapy protocols to the brain is limited by the presence of the blood-brain barrier (BBB. Viruses have been extensively used as gene delivery systems. However, their efficacy in brain is limited by the lack of transport across the BBB following intravenous (IV administration. Recent progress in the “Trojan Horse Liposome” (THL technology applied to transvascular non-viral gene therapy of the brain presents a promising solution to the trans-vascular brain gene delivery problem. THLs are comprised of immunoliposomes carrying nonviral gene expression plasmids. The tissue target specificity of the THL is provided by peptidomimetic monoclonal antibody (MAb component of the THL, which binds to specific endogenous receptors located on both the BBB and on brain cellular membranes, for example, insulin receptor and transferrin receptor. These MAbs mediate (a receptor-mediated transcytosis of the THL complex through the BBB, (b endocytosis into brain cells and (c transport to the brain cell nuclear compartment. The expression of the transgene in brain may be restricted using tissue/cell specific gene promoters. This manuscript presents an overview on the THL transport technology applied to brain disorders, including lysosomal storage disorders and Parkinson's disease.

  4. Lactography as an approach to monitor glucose metabolism on-line in brain and muscle.

    Science.gov (United States)

    Korf, J; de Boer, J

    1990-01-01

    1. Thus far metabolic processes in the intact animal (or man) have been studied either by the analysis of body fluids, of biopsies, of tissue obtained post mortem or by techniques, requiring dedicated and expensive equipment (such as positron emission tomography or magnetic resonance spectroscopy). 2. Here we describe a relatively simple and inexpensive technique, that can be applied in vivo to study metabolism in brain regions and muscle in the freely moving rat and in human peripheral tissue. 3. The method is based on microdialysis allowing continuous sampling from the extracellular space, the enzymatic conversion of lactate and the on-line detection of fluorescent NADH. 4. Examples of the application of our technique include the monitoring of lactate efflux from various brain regions of behaving animals under a variety of stress exposures, during ischemia or hypoxia and drug treatments. 5. The results indicate that in brain lactate is not exclusively formed under hypoxia and that neuronal activation leads also to lactate formation, possibly due to the compartmentation of both the involved enzymes and the energy metabolism. 6. The increase of lactate formation in contracting or ischemic muscle or during exercise could also be followed on-line in the rat, suggesting that our approach allows the continuous monitoring of anaerobic metabolism in man e.g. during traumatic or arteriosclerotic limb ischemia or lactic acidosis in shock states. 7. The principle of our approach can easily be adapted to other metabolites, thus enabling to monitor other metabolic pathways in vivo as well. PMID:2276411

  5. Creatine supplementation in the aging population: effects on skeletal muscle, bone and brain.

    Science.gov (United States)

    Gualano, Bruno; Rawson, Eric S; Candow, Darren G; Chilibeck, Philip D

    2016-08-01

    This narrative review aims to summarize the recent findings on the adjuvant application of creatine supplementation in the management of age-related deficits in skeletal muscle, bone and brain metabolism in older individuals. Most studies suggest that creatine supplementation can improve lean mass and muscle function in older populations. Importantly, creatine in conjunction with resistance training can result in greater adaptations in skeletal muscle than training alone. The beneficial effect of creatine upon lean mass and muscle function appears to be applicable to older individuals regardless of sex, fitness or health status, although studies with very old (>90 years old) and severely frail individuals remain scarce. Furthermore, there is evidence that creatine may affect the bone remodeling process; however, the effects of creatine on bone accretion are inconsistent. Additional human clinical trials are needed using larger sample sizes, longer durations of resistance training (>52 weeks), and further evaluation of bone mineral, bone geometry and microarchitecture properties. Finally, a number of studies suggest that creatine supplementation improves cognitive processing under resting and various stressed conditions. However, few data are available on older adults, and the findings are discordant. Future studies should focus on older adults and possibly frail elders or those who have already experienced an age-associated cognitive decline. PMID:27108136

  6. Mercury correlations among blood, muscle, and hair of northern elephant seals during the breeding and molting fasts.

    Science.gov (United States)

    Peterson, Sarah H; Ackerman, Joshua T; Costa, Daniel P

    2016-08-01

    Mercury (Hg) biomonitoring and toxicological risk assessments for marine mammals commonly sample different tissues, making comparisons with toxicity benchmarks and among species and regions difficult. Few studies have examined how life-history events, such as fasting, influence the relationship between total Hg (THg) concentrations in different tissues. The authors evaluated the relationships between THg concentrations in blood, muscle, and hair of female and male northern elephant seals (Mirounga angustirostris) at the start and end of the breeding and molting fasts. The relationships between tissues varied among tissue pairs and differed by sampling period and sex. Blood and muscle were generally related at all time periods; however, hair, an inert tissue, did not strongly represent the metabolically active tissues (blood and muscle) at all times of year. The strongest relationships between THg concentrations in hair and those in blood or muscle were observed during periods of active hair growth (end of the molting period) or during time periods when internal body conditions were similar to those when the hair was grown (end of the breeding fast). The results indicate that THg concentrations in blood or muscle can be translated to the other tissue type using the equations developed but that THg concentrations in hair were generally a poor index of internal THg concentrations except during the end of fasting periods. Environ Toxicol Chem 2016;35:2103-2110. © 2016 SETAC. PMID:26757244

  7. Mercury correlations among blood, muscle, and hair of northern elephant seals during the breeding and molting fasts

    Science.gov (United States)

    Peterson, Sarah; Ackerman, Josh; Costa, Daniel P.

    2016-01-01

    Mercury (Hg) biomonitoring and toxicological risk assessments for marine mammals commonly sample different tissues, making comparisons to toxicity benchmarks and among species and regions difficult. Few studies have examined how life history events, such as fasting, influence the relationship between total Hg (THg) concentrations in different tissues. We evaluated the relationships between THg concentrations in blood, muscle, and hair of female and male northern elephant seals (Mirounga angustirostris) at the start and end of the breeding and molting fasts. The relationships between tissues varied among tissue pairs and differed by sampling period and sex. Blood and muscle were generally related at all time periods; however, hair, an inert tissue, did not strongly represent the metabolically active tissues (blood and muscle) at all times of year. The strongest relationships between THg concentrations in hair and those in blood or muscle were observed during periods of active hair growth (end of the molting period) or during time periods when internal body conditions were similar to those when the hair was grown (end of the breeding fast). Our results indicate that THg concentrations in blood or muscle can be translated to the other tissue type using the equations we developed, but that THg concentrations in hair were generally a poor index of internal THg concentrations except during the end of fasting periods.

  8. A model for investigating the control of muscle blood flow: the masseteric artery in conscious rabbits

    International Nuclear Information System (INIS)

    The complex interplay of neural, metabolic, myogenic and mechanical mechanisms that regulate blood flow in skeletal muscle (MBF) is still incompletely understood. For the first time, a method is presented for high time-resolution recording of MBF from a purely muscular artery in physiological conditions. Ultrasound perivascular flow probes were implanted (n = 15) mono- or bilaterally around the masseteric branch of the facial artery in nine rabbits and tested up to 16 days after implant. Reliable and stable recordings were achieved in 50% of implants. Blood flow was observed to increase from a resting level of 0.2–0.3 ml min−1 up to 4.0–6.0 ml min−1 during spontaneous masticatory activity. In addition, within single masticatory cycles marked back flow transients could be observed (peak flow = −10 ml min−1) during powerful masticatory strokes but not during mild mastication. The possibility of (1) surgically removing the sympathetic supply to the relevant vascular bed and of (2) bilaterally monitoring the perfusion of masseter muscles thus allowing to use one side as control side for different types of interventions makes this model a useful tool for disentangling the different mechanisms involved in the control of MBF. (note)

  9. Exceptional evolutionary divergence of human muscle and brain metabolomes parallels human cognitive and physical uniqueness.

    Directory of Open Access Journals (Sweden)

    Katarzyna Bozek

    2014-05-01

    Full Text Available Metabolite concentrations reflect the physiological states of tissues and cells. However, the role of metabolic changes in species evolution is currently unknown. Here, we present a study of metabolome evolution conducted in three brain regions and two non-neural tissues from humans, chimpanzees, macaque monkeys, and mice based on over 10,000 hydrophilic compounds. While chimpanzee, macaque, and mouse metabolomes diverge following the genetic distances among species, we detect remarkable acceleration of metabolome evolution in human prefrontal cortex and skeletal muscle affecting neural and energy metabolism pathways. These metabolic changes could not be attributed to environmental conditions and were confirmed against the expression of their corresponding enzymes. We further conducted muscle strength tests in humans, chimpanzees, and macaques. The results suggest that, while humans are characterized by superior cognition, their muscular performance might be markedly inferior to that of chimpanzees and macaque monkeys.

  10. In vivo two-photon imaging measuring the blood-brain barrier permeability during early postnatal brain development in rodent

    Science.gov (United States)

    Shi, Lingyan; Rodríguez-Contreras, Adrián.

    2016-03-01

    The blood-brain barrier (BBB) is a unique structure between the cerebral blood circulation and the delicate neural environment that is important in regulating the movement of molecules and ions involved in brain development and function. However, little is known about the physiological permeability of molecules and ions across the BBB during brain development. In this study we applied an innovative approach to examine the development of BBB properties quantitatively. Two-photon microscopy was employed to measure BBB permeability in real time in vivo. Vascular growth and specific interactions between astrocyte end feet and microvessels were studied by using a combination of IB4 histochemistry, immunohistochemistry, confocal microscopy and 3D analysis.

  11. In vitro screening of nanomedicines through the blood brain barrier: A critical review.

    Science.gov (United States)

    Aparicio-Blanco, Juan; Martín-Sabroso, Cristina; Torres-Suárez, Ana-Isabel

    2016-10-01

    The blood-brain barrier accounts for the high attrition rate of the treatments of most brain disorders, which therefore remain one of the greatest health-care challenges of the twenty first century. Against this background of hindrance to brain delivery, nanomedicine takes advantage of the assembly at the nanoscale of available biomaterials to provide a delivery platform with potential to raising brain levels of either imaging or therapeutic agents. Nevertheless, to prevent later failure due to ineffective drug levels at the target site, researchers have been endeavoring to develop a battery of in vitro screening procedures that can predict earlier in the drug discovery process the ability of these cutting-edge drug delivery platforms to cross the blood-brain barrier for biomedical purposes. This review provides an in-depth analysis of the currently available in vitro blood-brain barrier models (both cell-based and non-cell-based) with the focus on their suitability for understanding the biological brain distribution of forthcoming nanomedicines. The relationship between experimental factors and underlying physiological assumptions that would ultimately lead to a more predictive capacity of their in vivo performance, and those methods already assayed for the evaluation of the brain distribution of nanomedicines are comprehensively discussed. PMID:27392291

  12. Regional cerebral blood flow in psychiatry: The resting and activated brains of schizophrenic patients

    International Nuclear Information System (INIS)

    The investigation of regional brain functioning in schizophrenia has been based on behavioral techniques. Although results are sometimes inconsistent, the behavioral observations suggest left hemispheric dysfunction and left hemispheric overreaction. Recent developments in neuroimaging technology make possible major refinements in assessing regional brain function. Both anatomical and physiological information now be used to study regional brain development in psychiatric disorders. This chapter describes the application of one method - the xenon-133 technique for measuring regional cerebral blood flow (rCBF) - in studying the resting and activated brains of schizoprenic patients

  13. Trafficking of Endogenous Immunoglobulins by Endothelial Cells at the Blood-Brain Barrier

    OpenAIRE

    Villaseñor, Roberto; Ozmen, Laurence; Messaddeq, Nadia; Grüninger, Fiona; Loetscher, Hansruedi; Keller, Annika; Betsholtz, Christer; Freskgård, Per-Ola; Collin, Ludovic

    2016-01-01

    The Blood-Brain Barrier (BBB) restricts access of large molecules to the brain. The low endocytic activity of brain endothelial cells (BECs) is believed to limit delivery of immunoglobulins (IgG) to the brain parenchyma. Here, we report that endogenous mouse IgG are localized within intracellular vesicles at steady state in BECs in vivo. Using high-resolution quantitative microscopy, we found a fraction of endocytosed IgG in lysosomes. We observed that loss of pericytes (key components of the...

  14. Electroconvulsive therapy, hypertensive surge, blood-brain barrier breach, and amnesia

    DEFF Research Database (Denmark)

    Andrade, Chittaranjan; Bolwig, Tom G

    2014-01-01

    Preclinical and clinical evidence show that electroconvulsive therapy (ECT)-induced intraictal surge in blood pressure may result in a small, transient breach in the blood-brain barrier, leading to mild cerebral edema and a possible leach of noxious substances from blood into brain tissues. These...... changes may impair neuronal functioning and contribute to the mechanisms underlying ECT-induced cognitive deficits. Some but not all clinical data on the subject suggest that blood pressure changes during ECT correlate with indices of cognitive impairment. In animal models, pharmacological manipulations...... of blood pressure during electroconvulsive shocks attenuate electroconvulsive shock-induced amnestic changes; however, the evidence suggests that antihypertensive mechanisms may not necessarily be involved. Clinical studies involving pre-ECT administration of antihypertensive medications do not...

  15. Cerebral blood volume measured using near-infrared spectroscopy and radiolabels in the immature lamb brain.

    Science.gov (United States)

    Barfield, C P; Yu, V Y; Noma, O; Kukita, J; Cussen, L J; Oates, A; Walker, A M

    1999-07-01

    Near-infrared spectroscopy (NIRS) is a technique that is increasingly being used for the noninvasive measurement of cerebral blood volume (CBV) in newborn infants, but it has not been fully validated against established methods. These experiments in immature lambs (gestation 92+/-1 d, mean+/-SEM) compared CBV measured using NIRS-derived estimates of oxygenated Hb (n = 5) with CBV estimated with radiolabeled indicators (125I-labeled serum albumin and 51Cr-labeled red blood cells, n = 10). Total brain CBV (mL/100 g tissue) measured using NIRS was 2.5+/-0.2 compared with 2.5+/-0.2 using radiolabels (NS). Regional tissue plasma, red blood cells, and whole blood volumes from radiolabels varied significantly (p cerebellum > cortex > brain stem = midbrain > white matter. Regional plasma and red blood cell distributions were similar to whole blood, being highest in choroid plexus (13.0+/-1.6 and 3.2+/-0.9, respectively), and least in white matter (0.8+/-0.1 and 0, respectively). These data from the immature lamb brain indicate that total CBV measured with NIRS is essentially identical with the volumes obtained using intravascular radiolabels. Among cerebral regions, white matter contributes little to the global blood volume measured with NIRS because its red blood cell content is very low. PMID:10400134

  16. One-year high fat diet affects muscle-but not brain mitochondria

    DEFF Research Database (Denmark)

    Joergensen, Tenna; Grunnet, Niels; Quistorff, Bjørn

    2015-01-01

    It is well known that few weeks of high fat (HF) diet may induce metabolic disturbances and mitochondrial dysfunction in skeletalmuscle. However, little is known about the effects of long-term HF exposure and effects on brain mitochondria are unknown. Wistarrats were fed either chow (13E% fat) or...... HF diet (60E% fat) for 1 year. The HF animals developed obesity, dyslipidemia, insulinresistance, and dysfunction of isolated skeletal muscle mitochondria: state 3 and state 4 were 30% to 50% increased (P < 0.058)with palmitoyl carnitine (PC), while there was no effect with pyruvate as substrate....... Adding also succinate in state 3 resulted in ahigher substrate control ratio (SCR) with PC, but a lower SCR with pyruvate (P < 0.05). The P/O2 ratio was lower with PC (P < 0.004).However, similar tests on isolated brain mitochondria from the same animal showed no changes with the substrates relevant...

  17. Prompt gamma-ray spectrometry for measurement of B-10 concentration in brain tissue and blood

    International Nuclear Information System (INIS)

    Boron-10 (B-10) concentration in the brain tissue and blood was measured continuously for 24 hours after injection of the B-10 compound in live rabbits using prompt gamma-ray spectrometry. Following injection of B-10 compound (Na2B12H11SH, 50mg/kg) dissolved in physiological saline, B-10 concentration was continuously measured in the brain tissue. Intermittently the concentration of B-10 in blood and cerebro-spinal fluid (CSF) was also measured. In 10 minutes after the injection of B-10 compound, the level of B-10 concentration reached the peak of 400-500 ppm in blood and 20-30 ppm in the normal brain tissue. In 60 minutes the level of B-10 concentration rapidly decreased and then a gradual decline was observed. The value was 15-30 ppm at 3 hours after injection, 5-10 ppm at 6 hours and 2-5 ppm at 24 hours in the blood. The concentration in the brain tissue was 3-8 ppm at 3 hours, 2-5 ppm at 6 hours and below 1.5 ppm at 24 hours. B-10 concentration in cerebro-spinal fluid was below 1 ppm. B-10 concentration was also measured in the brain tumor and blood in the human cases at boron neutron capture therapy (BNCT). These data studied by prompt gamma-ray spectrometry are very important and useful to decide the irradiation time. (author)

  18. Regional cerebral blood flow and brain atrophy in senile dementia of Alzheimer type (SDAT)

    International Nuclear Information System (INIS)

    To investigate the relationship between the reduction of cerebal blood flow and brain atrophy in SDAT, these were measured in 13 cases of senile dementia of Alzheimer type, and compared to 15 cases of multi-infarct Dementia, 39 cases of lacunar infarction without dementia (non-demented CVD group) and 69 cases of aged normal control. Brain atrophy was evaluated by two-dimensional method on CT film by digitizer and regional cerebral blood flow (rCBF) was measured by 133Xe inhalation method. The degree of brain atrophy in SDAT was almost similar of that of MID. But it was more severe than that of non-demented group. MID showed the lowest rCBF among these groups. SDAT showed significantly lower rCBF than that of aged control, but rCBF in SDAT was equal to that of lacunar stroke without dementia. Focal reduction of cerebral blood flow in bilateral fronto-parietal and left occipital regions were observed in SDAT. Verbal intelligence score (Hasegawa's score) correlated with rCBF and brain atrophy index in MID, and a tendency of correlation between rCBF and brain atrophy in MID was also observed. However, there was no correlation among those indices in SDAT. These findings suggest that the loss of brain substance dose not correspond to the reduction of rCBF in SDAT and simultaneous measurement of rCBF and brain atrophy was useful to differ SDAT from MID. (author)

  19. Increased blood-brain transfer in a rabbit model of acute liver failure

    International Nuclear Information System (INIS)

    The blood-to-brain transfer of [14C]alpha-aminoisobutyric acid was investigated by quantitative autoradiography in normal rabbits and rabbits with acute liver failure induced by the selective hepatotoxin galactosamine. The blood-to-brain transfer of alpha-aminoisobutyric acid was similar in control animals and animals 2 and 7 h after galactosamine injections, but was increased five- to tenfold in certain gray-matter areas of the brain in animals 11 and 18 h after galactosamine treatment. No detectable differences in white-matter uptake of [14C]alpha-aminoisobutyric acid were found between the control and treated groups. The increase in alpha-aminoisobutyric acid transfer within the gray-matter areas suggested that a general or nonspecific increase in brain capillary permeability occurred in these areas. No clinical signs of early hepatic encephalopathy were observed in the treated rabbits, except for 1 animal from the 18-h postgalactosamine group. Thus, enhanced blood-brain transfer of alpha-aminoisobutyric acid preceded the development of overt hepatic encephalopathy. The distribution of radioactivity after the intravenous administration of [14C]galactosamine showed that virtually none of the hepatotoxin localized in the brain, suggesting that the drug itself does not have a direct effect upon the blood-brain barrier or the brain. The increased uptake of alpha-aminoisobutyric acid at 11 and 18 h implies that the transfer of other solutes would also be enhanced, that central nervous system homeostasis would be compromised, and that the resulting changes in brain fluid composition could contribute to or cause hepatic encephalopathy

  20. Disruption in the Blood-Brain Barrier: The Missing Link between Brain and Body Inflammation in Bipolar Disorder?

    Directory of Open Access Journals (Sweden)

    Jay P. Patel

    2015-01-01

    Full Text Available The blood-brain barrier (BBB regulates the transport of micro- and macromolecules between the peripheral blood and the central nervous system (CNS in order to maintain optimal levels of essential nutrients and neurotransmitters in the brain. In addition, the BBB plays a critical role protecting the CNS against neurotoxins. There has been growing evidence that BBB disruption is associated with brain inflammatory conditions such as Alzheimer’s disease and multiple sclerosis. Considering the increasing role of inflammation and oxidative stress in the pathophysiology of bipolar disorder (BD, here we propose a novel model wherein transient or persistent disruption of BBB integrity is associated with decreased CNS protection and increased permeability of proinflammatory (e.g., cytokines, reactive oxygen species substances from the peripheral blood into the brain. These events would trigger the activation of microglial cells and promote localized damage to oligodendrocytes and the myelin sheath, ultimately compromising myelination and the integrity of neural circuits. The potential implications for research in this area and directions for future studies are discussed.

  1. Glucagon-like peptide-1 inhibits blood-brain glucose transfer in humans

    DEFF Research Database (Denmark)

    Lerche, Susanne; Brock, Birgitte; Rungby, Jørgen;

    2008-01-01

    demonstrated that a hormone involved in postprandial glucose regulation also limits glucose delivery to brain tissue and hence provides a possible regulatory mechanism for the link between plasma glucose and brain glucose. Because GLP-1 reduces glucose uptake across the intact blood-brain barrier at normal...... glycemia, GLP-1 may also protect the brain by limiting intracerebral glucose fluctuation when plasma glucose is increased.......OBJECTIVE: Glucagon-like peptide-1 (GLP-1) has many effects on glucose homeostasis, and GLP-1 receptors are broadly represented in many tissues including the brain. Recent research in rodents suggests a protective effect of GLP-1 on brain tissue. The mechanism is unknown. We therefore tested...

  2. Blood lactate is an important energy source for the human brain

    DEFF Research Database (Denmark)

    G., van Hall; Stromstad, M.; Rasmussen, P.; Jans, O.; Zaar, M.; Gam, Christiane Marie Bourgin; Quistorff, B.; Secher, Niels H.; Nielsen, H.B.

    2009-01-01

    Lactate is a potential energy source for the brain. The aim of this study was to establish whether systemic lactate is a brain energy source. We measured in vivo cerebral lactate kinetics and oxidation rates in 6 healthy individuals at rest with and without 90 mins of intravenous lactate infusion...... is taken up and oxidized by the human brain and is an important substrate for the brain both under basal and hyperlactatemic conditions.Journal of Cerebral Blood Flow & Metabolism advance online publication, 1 April 2009; doi:10.1038/jcbfm.2009.35.......Lactate is a potential energy source for the brain. The aim of this study was to establish whether systemic lactate is a brain energy source. We measured in vivo cerebral lactate kinetics and oxidation rates in 6 healthy individuals at rest with and without 90 mins of intravenous lactate infusion...

  3. Functional photoacoustic tomography for non-invasive imaging of cerebral blood oxygenation and blood volume in rat brain in vivo

    Science.gov (United States)

    Wang, Xueding; Xie, Xueyi; Ku, Geng; Stoica, George; Wang, Lihong V.

    2005-04-01

    Based on the multi-wavelength laser-based photoacoustic tomography, non-invasive in vivo imaging of functional parameters, including the hemoglobin oxygen saturation and the total concentration of hemoglobin, in small-animal brains was realized. The high sensitivity of this technique is based on the spectroscopic differences between oxy- and deoxy-hemoglobin while its spatial resolution is bandwidth-limited by the photoacoustic signals rather than by the optical diffusion as in optical imaging. The point-by-point distributions of blood oxygenation and blood volume in the cerebral cortical venous vessels, altered by systemic physiological modulations including hyperoxia, normoxia and hypoxia, were visualized successfully through the intact skin and skull. This technique, with its prominent intrinsic advantages, can potentially accelerate the progress in neuroscience and provide important new insights into cerebrovascular physiology and brain function that are of great significance to the neuroscience community.

  4. Restraint stress-induced morphological changes at the blood-brain barrier in adult rats

    Directory of Open Access Journals (Sweden)

    Petra eSántha

    2016-01-01

    Full Text Available Stress is well known to contribute to the development of both neurological and psychiatric diseases. While the role of the blood-brain barrier is increasingly recognised in the development of neurodegenerative disorders, such as Alzheimer’s disease, dysfunction of the blood-brain barrier has been linked to stress-related psychiatric diseases only recently. In the present study the effects of restraint stress with different duration (1, 3 and 21 days were investigated on the morphology of the blood-brain barrier in male adult Wistar rats. Frontal cortex and hippocampus sections were immunostained for markers of brain endothelial cells (claudin-5, occludin and glucose transporter-1 and astroglia (GFAP. Staining pattern and intensity were visualized by confocal microscopy and evaluated by several types of image analysis. The ultrastructure of brain capillaries was investigated by electron microscopy. Morphological changes and intensity alterations in brain endothelial tight junction proteins claudin-5 and occludin were induced by stress. Following restraint stress significant increases in the fluorescence intensity of glucose transporter-1 were detected in brain endothelial cells in the frontal cortex and hippocampus. Significant reductions in GFAP fluorescence intensity were observed in the frontal cortex in all stress groups. As observed by electron microscopy, one-day acute stress induced morphological changes indicating damage in capillary endothelial cells in both brain regions. After 21 days of stress thicker and irregular capillary basal membranes in the hippocampus and edema in astrocytes in both regions were seen. These findings indicate that stress exerts time-dependent changes in the staining pattern of tight junction proteins occludin, claudin-5 and glucose transporter-1 at the level of brain capillaries and in the ultrastructure of brain endothelial cells and astroglial endfeet, which may contribute to neurodegenerative processes

  5. Effects of Flight on Gene Expression and Aging in the Honey Bee Brain and Flight Muscle

    Directory of Open Access Journals (Sweden)

    Michelle M. Elekonich

    2012-12-01

    Full Text Available Honey bees move through a series of in-hive tasks (e.g., “nursing” to outside tasks (e.g., “foraging” that are coincident with physiological changes and higher levels of metabolic activity. Social context can cause worker bees to speed up or slow down this process, and foragers may revert back to their earlier in-hive tasks accompanied by reversion to earlier physiological states. To investigate the effects of flight, behavioral state and age on gene expression, we used whole-genome microarrays and real-time PCR. Brain tissue and flight muscle exhibited different patterns of expression during behavioral transitions, with expression patterns in the brain reflecting both age and behavior, and expression patterns in flight muscle being primarily determined by age. Our data suggest that the transition from behaviors requiring little to no flight (nursing to those requiring prolonged flight bouts (foraging, rather than the amount of previous flight per se, has a major effect on gene expression. Following behavioral reversion there was a partial reversion in gene expression but some aspects of forager expression patterns, such as those for genes involved in immune function, remained. Combined with our real-time PCR data, these data suggest an epigenetic control and energy balance role in honey bee functional senescence.

  6. Determination of endogenous corticosterone in rodent's blood, brain and hair with LC-APCI-MS/MS.

    Science.gov (United States)

    Yu, Tian; Xu, Hang; Wang, Weiwen; Li, Shifei; Chen, Zheng; Deng, Huihua

    2015-10-01

    Endogenous corticosterone in rodent's hair would be a potential biomarker to assess the response of the hypothalamus-pituitary-adrenal axis to chronic stress. However, currently unknown is whether hair corticosterone is associated with endogenous corticosterone in blood and brain. The present study aimed to develop an enhanced assay for determination of endogenous corticosterone in blood, brain and hair, and to examine associations of hair corticosterone with blood and brain corticosterone under basal condition and association with blood corticosterone under chronic stressful condition. Hair at the back and blood samples were collected from non-stressed and stressed rodents, and prefrontal lobe and thalamus from non-stressed rodents. Chronic stress exerted on mice was 30-day repeated social defeat. The analyses were done using high performance liquid chromatography tandem mass spectrometry with atmospheric pressure chemical ionization in positive mode. Limits of detection and quantification were 0.2 and 0.5ng/ml for rat's blood, and 0.5 and 1.0pg/mg for rat's hair and brain, and 1.25 and 2.50ng/ml (or pg/mg) for mouse's blood (or hair). Recovery ranged from 84.2 to 108.0%. The intra- and inter-day coefficients of variation were less than 10%. Additionally, correlation of hair corticosterone with blood corticosterone was significant in both mice and rats, but correlations with corticosterone in prefrontal lobe and thalamus were not significant in rats. Both hair and blood corticosterone were significantly higher in stressed mice compared with controls. PMID:26343018

  7. Review of lithium effects on brain and blood.

    Science.gov (United States)

    Young, Wise

    2009-01-01

    Clinicians have long used lithium to treat manic depression. They have also observed that lithium causes granulocytosis and lymphopenia while it enhances immunological activities of monocytes and lymphocytes. In fact, clinicians have long used lithium to treat granulocytopenia resulting from radiation and chemotherapy, to boost immunoglobulins after vaccination, and to enhance natural killer activity. Recent studies revealed a mechanism that ties together these disparate effects of lithium. Lithium acts through multiple pathways to inhibit glycogen synthetase kinase-3beta (GSK3 beta). This enzyme phosphorylates and inhibits nuclear factors that turn on cell growth and protection programs, including the nuclear factor of activated T cells (NFAT) and WNT/beta-catenin. In animals, lithium upregulates neurotrophins, including brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3 (NT3), as well as receptors to these growth factors in brain. Lithium also stimulates proliferation of stem cells, including bone marrow and neural stem cells in the subventricular zone, striatum, and forebrain. The stimulation of endogenous neural stem cells may explain why lithium increases brain cell density and volume in patients with bipolar disorders. Lithium also increases brain concentrations of the neuronal markers n-acetyl-aspartate and myoinositol. Lithium also remarkably protects neurons against glutamate, seizures, and apoptosis due to a wide variety of neurotoxins. The effective dose range for lithium is 0.6-1.0 mM in serum and >1.5 mM may be toxic. Serum lithium levels of 1.5-2.0 mM may have mild and reversible toxic effects on kidney, liver, heart, and glands. Serum levels of >2 mM may be associated with neurological symptoms, including cerebellar dysfunction. Prolonged lithium intoxication >2 mM can cause permanent brain damage. Lithium has low mutagenic and carcinogenic risk. Lithium is still the most effective therapy for depression. It "cures" a third

  8. A brain-machine-muscle interface for restoring hindlimb locomotion after complete spinal transection in rats.

    Directory of Open Access Journals (Sweden)

    Monzurul Alam

    Full Text Available A brain-machine interface (BMI is a neuroprosthetic device that can restore motor function of individuals with paralysis. Although the feasibility of BMI control of upper-limb neuroprostheses has been demonstrated, a BMI for the restoration of lower-limb motor functions has not yet been developed. The objective of this study was to determine if gait-related information can be captured from neural activity recorded from the primary motor cortex of rats, and if this neural information can be used to stimulate paralysed hindlimb muscles after complete spinal cord transection. Neural activity was recorded from the hindlimb area of the primary motor cortex of six female Sprague Dawley rats during treadmill locomotion before and after mid-thoracic transection. Before spinal transection there was a strong association between neural activity and the step cycle. This association decreased after spinal transection. However, the locomotive state (standing vs. walking could still be successfully decoded from neural recordings made after spinal transection. A novel BMI device was developed that processed this neural information in real-time and used it to control electrical stimulation of paralysed hindlimb muscles. This system was able to elicit hindlimb muscle contractions that mimicked forelimb stepping. We propose this lower-limb BMI as a future neuroprosthesis for human paraplegics.

  9. A functional requirement for astroglia in promoting blood vessel development in the early postnatal brain.

    Directory of Open Access Journals (Sweden)

    Shang Ma

    Full Text Available Astroglia are a major cell type in the brain and play a key role in many aspects of brain development and function. In the adult brain, astrocytes are known to intimately ensheath blood vessels and actively coordinate local neural activity and blood flow. During development of the neural retina, blood vessel growth follows a meshwork of astrocytic processes. Several genes have also been implicated in retinal astrocytes for regulating vessel development. This suggests a role of astrocytes in promoting angiogenesis throughout the central nervous system. To determine the roles that astrocytes may play during brain angiogenesis, we employ genetic approaches to inhibit astrogliogenesis during perinatal corticogenesis and examine its effects on brain vessel development. We find that conditional deletion from glial progenitors of orc3, a gene required for DNA replication, dramatically reduces glial progenitor cell number in the subventricular zone and astrocytes in the early postnatal cerebral cortex. This, in turn, results in severe reductions in both the density and branching frequency of cortical blood vessels. Consistent with a delayed growth but not regression of vessels, we find neither significant net decreases in vessel density between different stages after normalizing for cortical expansion nor obvious apoptosis of endothelial cells in these mutants. Furthermore, concomitant with loss of astroglial interactions, we find increased endothelial cell proliferation, enlarged vessel luminal size as well as enhanced cytoskeletal gene expression in pericytes, which suggests compensatory changes in vascular cells. Lastly, we find that blood vessel morphology in mutant cortices recovers substantially at later stages, following astrogliosis. These results thus implicate a functional requirement for astroglia in promoting blood vessel growth during brain development.

  10. Could Cord Blood Cell Therapy Reduce Preterm Brain Injury?

    OpenAIRE

    Li, Jingang; McDonald, Courtney A.; Fahey, Michael C.; Jenkin, Graham; Miller, Suzanne L.

    2014-01-01

    Major advances in neonatal care have led to significant improvements in survival rates for preterm infants, but this occurs at a cost, with a strong causal link between preterm birth and neurological deficits, including cerebral palsy (CP). Indeed, in high-income countries, up to 50% of children with CP were born preterm. The pathways that link preterm birth and brain injury are complex and multifactorial, but it is clear that preterm birth is strongly associated with damage to the white matt...

  11. Enhanced blood-brain barrier transmigration using a novel Transferrin-embedded fluorescent magnetoliposome nanoformulation

    OpenAIRE

    Ding, Hong; Sagar, Vidya; Agudelo, Marisela; Pilakka-Kanthikeel, Sudheesh; Atluri, Venkata Subba Rao; Raymond, Andrea; Thangavel, Samikkannu; Nair, Madhavan P.

    2014-01-01

    Blood-brain barrier (BBB) is considered as the primary impediment barrier for most of drugs. Delivering therapeutic agents to brain is still a big challenge by now. In our study, a dual mechanism, receptor mediation combining with external non-invasive magnetic force, was incorporated together into ferrous magnet-based liposome for BBB transmigration enhancement. The homogenous magnetic nanoparticles (MNPs) with size of ~ 10 nm were synthesized and confirmed by TEM and XRD respectively. The c...

  12. Influence of BNCT radiations on the blood-brain barrier in terms of boron-10 uptake

    International Nuclear Information System (INIS)

    A key issue is to determine whether fractionated BNCT is a feasible proposition. This issue has been reviewed by Dorn et al, who call for further experimental investigation of BNCT induced changes in the blood brain barrier and investigated by Hatanaka et al. In order to investigate the effect on BNCT, the authors measured 10B concentration and water content in the normal brain which has been subjected to BNCT regimen

  13. Matrix Metalloproteinases and Blood-Brain Barrier Disruption in Acute Ischemic Stroke

    OpenAIRE

    Lakhan, Shaheen E.; Kirchgessner, Annette; Tepper, Deborah; Leonard, Aidan

    2013-01-01

    Ischemic stroke continues to be one of the most challenging diseases in translational neurology. Tissue plasminogen activator (tPA) remains the only approved treatment for acute ischemic stroke, but its use is limited to the first hours after stroke onset due to an increased risk of hemorrhagic transformation over time resulting in enhanced brain injury. In this review we discuss the role of matrix metalloproteinases (MMPs) in blood-brain barrier (BBB) disruption as a consequence of ischemic ...

  14. TCP-FA4: A DERIVATIVE OF TRANYLCYPROMINE SHOWING IMPROVED BLOOD-BRAIN PERMEABILITY

    OpenAIRE

    Desino, Kelly E.; Pignatello, Rosario; Guccione, Salvatore; Basile, Livia; Ansar, Sabah; Michaelis, Mary Lou; Ramsay, Rona R.; Audus, Kenneth L.

    2009-01-01

    Abstract A variety of approaches have been taken to improve the brain penetration of pharmaceutical agents. The amphipathic character of a compound can improve its interaction with the lipid bilayer within cell membranes, and as a result improve permeability. Fatty acid chains or lipoamino acids of various lengths were attached to tranylcypromine (TCP), in an attempt to improve the blood-brain barrier (BBB) permeability by increasing the lipophilicity as well as the amphiphatic cha...

  15. Traversal of Candida albicans across Human Blood-Brain Barrier In Vitro

    OpenAIRE

    Jong, Ambrose Y.; Stins, Monique F.; Huang, Sheng-He; Chen, Steven H. M.; Kim, Kwang Sik

    2001-01-01

    Candida albicans is an opportunistic pathogen, which primarily affects neonates and immunocompromised individuals. The pathogen can invade the central nervous system, resulting in meningitis. At present, the pathogenesis of C. albicans meningitis is unclear. We used an in vitro model of the human blood-brain barrier to investigate the interaction(s) of C. albicans with human brain microvascular endothelial cells (BMEC). Binding of C. albicans to human BMEC was time and inoculum dependent. Inv...

  16. A statistical model describing combined irreversible electroporation and electroporation-induced blood-brain barrier disruption

    Directory of Open Access Journals (Sweden)

    Sharabi Shirley

    2016-03-01

    Full Text Available Electroporation-based therapies such as electrochemotherapy (ECT and irreversible electroporation (IRE are emerging as promising tools for treatment of tumors. When applied to the brain, electroporation can also induce transient blood-brain-barrier (BBB disruption in volumes extending beyond IRE, thus enabling efficient drug penetration. The main objective of this study was to develop a statistical model predicting cell death and BBB disruption induced by electroporation. This model can be used for individual treatment planning.

  17. A statistical model describing combined irreversible electroporation and electroporation-induced blood-brain barrier disruption

    OpenAIRE

    Sharabi Shirley; Kos Bor; Last David; Guez David; Daniels Dianne; Harnof Sagi; Mardor Yael; Miklavcic Damijan

    2016-01-01

    Background Electroporation-based therapies such as electrochemotherapy (ECT) and irreversible electroporation (IRE) are emerging as promising tools for treatment of tumors. When applied to the brain, electroporation can also induce transient blood-brain-barrier (BBB) disruption in volumes extending beyond IRE, thus enabling efficient drug penetration. The main objective of this study was to develop a statistical model predicting cell death and BBB disruption induced by electroporation. This m...

  18. Computational Prediction of Blood-Brain Barrier Permeability Using Decision Tree Induction

    OpenAIRE

    Jörg Huwyler; Felix Hammann; Claudia Suenderhauf

    2012-01-01

    Predicting blood-brain barrier (BBB) permeability is essential to drug development, as a molecule cannot exhibit pharmacological activity within the brain parenchyma without first transiting this barrier. Understanding the process of permeation, however, is complicated by a combination of both limited passive diffusion and active transport. Our aim here was to establish predictive models for BBB drug permeation that include both active and passive transport. A database of 153 compounds was co...

  19. A Mixed Approach for Modeling Blood Flow in Brain Microcirculation

    Science.gov (United States)

    Lorthois, Sylvie; Peyrounette, Myriam; Davit, Yohan; Quintard, Michel; Groupe d'Etude sur les Milieux Poreux Team

    2015-11-01

    Consistent with its distribution and exchange functions, the vascular system of the human brain cortex is a superposition of two components. At small-scale, a homogeneous and space-filling mesh-like capillary network. At large scale, quasi-fractal branched veins and arteries. From a modeling perspective, this is the superposition of: (a) a continuum model resulting from the homogenization of slow transport in the small-scale capillary network; and (b) a discrete network approach describing fast transport in the arteries and veins, which cannot be homogenized because of their fractal nature. This problematic is analogous to fast conducting wells embedded in a reservoir rock in petroleum engineering. An efficient method to reduce the computational cost is to use relatively large grid blocks for the continuum model. This makes it difficult to accurately couple both components. We solve this issue by adapting the ``well model'' concept used in petroleum engineering to brain specific 3D situations. We obtain a unique linear system describing the discrete network, the continuum and the well model. Results are presented for realistic arterial and venous geometries. The mixed approach is compared with full network models including various idealized capillary networks of known permeability. ERC BrainMicroFlow GA615102.

  20. Chromatographic Behaviour Predicts the Ability of Potential Nootropics to Permeate the Blood-Brain Barrier

    OpenAIRE

    Farsa, Oldřich

    2012-01-01

    The log BB parameter is the logarithm of the ratio of a compound’s equilibrium concentrations in the brain tissue versus the blood plasma. This parameter is a useful descriptor in assessing the ability of a compound to permeate the blood-brain barrier. The aim of this study was to develop a Hansch-type linear regression QSAR model that correlates the parameter log BB and the retention time of drugs and other organic compounds on a reversed-phase HPLC containing an embedded amide moiety. The r...

  1. Evaluation of blood-brain barrier-stealth nanocomposites for in situ glioblastoma theranostics applications

    Science.gov (United States)

    Su, Chia-Hao; Tsai, Ching-Yi; Tomanek, Boguslaw; Chen, Wei-Yu; Cheng, Fong-Yu

    2016-04-01

    The blood-brain barrier (BBB) is a physiological structure of the blood vessels in the brain. The BBB efficiently traps most therapeutic drugs in the blood vessels and stops them from entering the brain tissue, resulting in a decreased therapeutic efficiency. In this study, we developed BBB-stealth nanocomposites composed of iron oxide (Fe3O4) nanoparticles (NPs) as a safe nanocarrier for glioblastoma therapy. We showed the antitumor activity of Dox/alg-Fe3O4 NPs using in vitro and in vivo tests. We demonstrated that G23-alg-Fe3O4 NPs crossed the BBB and entered the brain. In situ glioblastoma tumor-bearing mice were used to successfully evaluate the antitumor activity of G23-Dox/alg-Fe3O4 NPs. Magnetic resonance imaging (MRI) and bioluminescence imaging (BLI) confirmed the BBB crossing. The BBB-stealth nanocomposites show great potential for a proof-of-concept clinical trial as a theranostics platform for human brain tumor therapy.The blood-brain barrier (BBB) is a physiological structure of the blood vessels in the brain. The BBB efficiently traps most therapeutic drugs in the blood vessels and stops them from entering the brain tissue, resulting in a decreased therapeutic efficiency. In this study, we developed BBB-stealth nanocomposites composed of iron oxide (Fe3O4) nanoparticles (NPs) as a safe nanocarrier for glioblastoma therapy. We showed the antitumor activity of Dox/alg-Fe3O4 NPs using in vitro and in vivo tests. We demonstrated that G23-alg-Fe3O4 NPs crossed the BBB and entered the brain. In situ glioblastoma tumor-bearing mice were used to successfully evaluate the antitumor activity of G23-Dox/alg-Fe3O4 NPs. Magnetic resonance imaging (MRI) and bioluminescence imaging (BLI) confirmed the BBB crossing. The BBB-stealth nanocomposites show great potential for a proof-of-concept clinical trial as a theranostics platform for human brain tumor therapy. Electronic supplementary information (ESI) available: Experimental details. See DOI: 10.1039/c6nr00280c

  2. The Role of P-Glycoprotein in Transport of Danshensu across the Blood-Brain Barrier

    Directory of Open Access Journals (Sweden)

    Peng-Fei Yu

    2011-01-01

    Full Text Available Danshensu (3-(3, 4-dihydroxyphenyl lactic acid, a water-soluble active component isolated from the root of Salvia miltiorrhiza Bunge, is widely used for the treatment of cerebrovascular diseases. The present study aims to investigate the role of P-glycoprotein in transport of Danshensu across the blood-brain barrier. Sprague-Dawley rats were pretreated with verapamil at a dose of 20 mg kg−1 (verapamil group or the same volume of normal saline (control group. Ninety minutes later, the animals were administrated with Danshensu (15 mg kg−1 by intravenous injection. At 15 min, 30 min, and 60 min after Danshensu administration, the levels of Danshensu in the blood and brain were detected by high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS. The results showed that Danshensu concentrations in the brain of the rats pretreated with verapamil were significantly increased. In addition, the brain-plasma ratios of the group pretreated with verapamil were much higher than that of the control group. There was no difference in Danshensu level in plasma between the verapamil group and control group. The findings indicated that Danshensu can pass the blood-brain barrier, and P-glycoprotein plays an important role in Danshensu transportation in brain.

  3. Minocycline ameliorates prenatal valproic acid induced autistic behaviour, biochemistry and blood brain barrier impairments in rats.

    Science.gov (United States)

    Kumar, Hariom; Sharma, Bhupesh

    2016-01-01

    Autism is a neurodevelopment disorder. One percent worldwide population suffers with autism and males suffer more than females. Microglia plays an important role in neurodevelopment, neuropsychiatric and neurodegenerative disorders. The present study has been designed to investigate the role of minocycline in prenatal valproic acid induced autism in rats. Animals with prenatal valproic acid have reduced social interaction (three chamber social behaviour apparatus), spontaneous alteration (Y-Maze), exploratory activity (Hole board test), intestinal motility, serotonin levels (both in prefrontal cortex and ileum) and prefrontal cortex mitochondrial complex activity (complexes I, II, IV). Furthermore, prenatal valproic acid treated animals have shown an increase in locomotion (actophotometer), anxiety (elevated plus maze), brain oxidative stress (thiobarbituric acid reactive species, glutathione, catalase), nitrosative stress (nitrite/nitrate), inflammation (both in brain and ileum myeloperoxidase activity), calcium and blood brain barrier permeability. Treatment with minocycline significantly attenuated prenatal valproic acid induced reduction in social interaction, spontaneous alteration, exploratory activity intestinal motility, serotonin levels and prefrontal cortex mitochondrial complex activity. Furthermore, minocycline has also attenuated prenatal valproic acid induced increase in locomotion, anxiety, brain oxidative and nitrosative stress, inflammation, calcium and blood brain barrier permeability. Thus, it may be concluded that prenatal valproic acid has induced autistic behaviour, biochemistry and blood brain barrier impairment in animals, which were significantly attenuated by minocycline. Minocycline should be explored further for its therapeutic benefits in autism. PMID:26551768

  4. Increases in muscle sympathetic nerve activity, heart rate, respiration, and skin blood flow during passive viewing of exercise

    OpenAIRE

    Brown, Rachael; Kemp, Ursula; Macefield, Vaughan

    2013-01-01

    The cardiovascular and respiratory effects of exercise have been widely studied, as have the autonomic effects of imagined and observed exercise. However, the effects of observed exercise in the first person have not been documented, nor have direct recordings of muscle sympathetic nerve activity (MSNA) been obtained during observed or imagined exercise. The aim of the current study was to measure blood pressure, heart rate, respiration, skin blood flow, sweat release, and MSNA (via microelec...

  5. Sodium butyrate exerts neuroprotective effects by restoring the blood-brain barrier in traumatic brain injury mice.

    Science.gov (United States)

    Li, Haixiao; Sun, Jing; Wang, Fangyan; Ding, Guoqiang; Chen, Wenqian; Fang, Renchi; Yao, Ye; Pang, Mengqi; Lu, Zhong-Qiu; Liu, Jiaming

    2016-07-01

    Sodium butyrate (SB) has been widely used to treat cerebral diseases. The aim of the present study is to examine the neuroprotective effects of SB on early TBI in mice and to explore the underlying mechanisms of these effects. TBI was induced using a modified weight-drop method. Neurological deficits were evaluated according to the neurological severity score (NSS), brain oedema was measured by brain water content, and blood-brain barrier (BBB) permeability was evaluated by Evans blue (EB) dye extravasation. Neuronal injury was assessed by hematoxylin and eosin (H&E) staining and Fluoro-Jade C staining. The expression of tight junction-associated proteins, such as occludin and zonula occludens-1 (ZO-1), was analysed by western blotting and immunofluorescence. Our results showed that mice subjected to TBI exhibited worsened NSS, brain oedema, neuronal damage and BBB permeability. However, these were all attenuated by SB. Moreover, SB reversed the decrease in occludin and ZO-1 expression induced by TBI. These findings suggest that SB might attenuate neurological deficits, brain oedema, neuronal change and BBB damage, as well as increase occludin and ZO-1 expression in the brain to protect against TBI. The protective effect of SB may be correlated with restoring the BBB following its impairment. PMID:27017959

  6. Subarachnoid blood converts neurally evoked vasodilation to vasoconstriction in rat brain cortex

    OpenAIRE

    Koide, Masayo; Bonev, Adrian D.; Nelson, Mark T.; Wellman, George C.

    2013-01-01

    The matching of blood flow to regional brain function, called functional hyperemia or neurovascular coupling, involves the coordinated activity of neurons, astrocytes and parenchymal arterioles. Under physiological conditions, localized neuronal activation leads to elevated astrocyte endfoot Ca2+ and vasodilation, resulting in an increase in cerebral blood flow. In this study, we examined the impact of subarachnoid hemorrhage (SAH) on neurovascular coupling. SAH model rats received two inject...

  7. Core modular blood and brain biomarkers in social defeat mouse model for post traumatic stress disorder

    OpenAIRE

    Yang, Ruoting; Daigle Jr, Bernie J; Muhie, Seid Y; Hammamieh, Rasha; Jett, Marti; Petzold, Linda; Francis J Doyle

    2013-01-01

    Abstract Background Post-traumatic stress disorder (PTSD) is a severe anxiety disorder that affects a substantial portion of combat veterans and poses serious consequences to long-term health. Consequently, the identification of diagnostic and prognostic blood biomarkers for PTSD is of great interest. Previously, we assessed genome-wide gene expression of seven brain regions and whole blood in a social defeat mouse model subjected to various stress co...

  8. Repair of astrocytes, blood vessels, and myelin in the injured brain: possible roles of blood monocytes

    OpenAIRE

    Jeong, Hey-Kyeong; Ji, Kyung-min; Kim, Jun; Jou, Ilo; Joe, Eun-hye

    2013-01-01

    Inflammation in injured tissue has both repair functions and cytotoxic consequences. However, the issue of whether brain inflammation has a repair function has received little attention. Previously, we demonstrated monocyte infiltration and death of neurons and resident microglia in LPS-injected brains (Glia. 2007. 55:1577; Glia. 2008. 56:1039). Here, we found that astrocytes, oligodendrocytes, myelin, and endothelial cells disappeared in the damage core within 1–3 d and then re-appeared at 7...

  9. Reduced blood flow to contracting skeletal muscle in ageing humans: is it all an effect of sand through the hourglass?

    Science.gov (United States)

    Nyberg, Michael; Hellsten, Ylva

    2016-04-15

    The ability to sustain a given absolute submaximal workload declines with advancing age, likely to be due to a lower level of blood flow and O2 delivery to the exercising muscles. Given that physical inactivity mimics many of the physiological changes associated with ageing, separating the physiological consequences of ageing and physical inactivity can be challenging; yet, observations from cross-sectional and longitudinal studies on the effects of physical activity have provided some insight. Physical activity has the potential to offset the age-related decline in blood flow to contracting skeletal muscle during exercise where systemic blood flow is not limited by cardiac output, thereby improving O2 delivery and allowing for an enhanced energy production from oxidative metabolism. The mechanisms underlying the increase in blood flow with regular physical activity include improved endothelial function and the ability for functional sympatholysis - an attenuation of the vasoconstrictor effect of sympathetic nervous activity. These vascular adaptations with physical activity are likely to be an effect of improved nitric oxide and ATP signalling. Collectively, precise matching of blood flow and O2 delivery to meet the O2 demand of the active skeletal muscle of aged individuals during conditions where systemic blood flow is not limited by cardiac output seems to a large extent to be related to the level of physical activity. PMID:26095873

  10. An ex Vivo Model for Evaluating Blood-Brain Barrier Permeability, Efflux, and Drug Metabolism.

    Science.gov (United States)

    Hellman, Karin; Aadal Nielsen, Peter; Ek, Fredrik; Olsson, Roger

    2016-05-18

    The metabolism of drugs in the brain is difficult to study in most species because of enzymatic instability in vitro and interference from peripheral metabolism in vivo. A locust ex vivo model that combines brain barrier penetration, efflux, metabolism, and analysis of the unbound fraction in intact brains was evaluated using known drugs. Clozapine was analyzed, and its major metabolites, clozapine N-oxide (CNO) and N-desmethylclozapine (NDMC), were identified and quantified. The back-transformation of CNO into clozapine observed in humans was also observed in locusts. In addition, risperidone, citalopram, fluoxetine, and haloperidol were studied, and one preselected metabolite for each drug was analyzed, identified, and quantified. Metabolite identification studies of clozapine and midazolam showed that the locust brain was highly metabolically active, and 18 and 14 metabolites, respectively, were identified. The unbound drug fraction of clozapine, NDMC, carbamazepine, and risperidone was analyzed. In addition, coadministration of drugs with verapamil or fluvoxamine was performed to evaluate drug-drug interactions in all setups. All findings correlated well with the data in the literature for mammals except for the stated fact that CNO is a highly blood-brain barrier permeant compound. Overall, the experiments indicated that invertebrates might be useful for screening of blood-brain barrier permeation, efflux, metabolism, and analysis of the unbound fraction of drugs in the brain in early drug discovery. PMID:26930271

  11. Drug Delivery Systems, CNS Protection, and the Blood Brain Barrier

    Directory of Open Access Journals (Sweden)

    Ravi Kant Upadhyay

    2014-01-01

    Full Text Available Present review highlights various drug delivery systems used for delivery of pharmaceutical agents mainly antibiotics, antineoplastic agents, neuropeptides, and other therapeutic substances through the endothelial capillaries (BBB for CNS therapeutics. In addition, the use of ultrasound in delivery of therapeutic agents/biomolecules such as proline rich peptides, prodrugs, radiopharmaceuticals, proteins, immunoglobulins, and chimeric peptides to the target sites in deep tissue locations inside tumor sites of brain has been explained. In addition, therapeutic applications of various types of nanoparticles such as chitosan based nanomers, dendrimers, carbon nanotubes, niosomes, beta cyclodextrin carriers, cholesterol mediated cationic solid lipid nanoparticles, colloidal drug carriers, liposomes, and micelles have been discussed with their recent advancements. Emphasis has been given on the need of physiological and therapeutic optimization of existing drug delivery methods and their carriers to deliver therapeutic amount of drug into the brain for treatment of various neurological diseases and disorders. Further, strong recommendations are being made to develop nanosized drug carriers/vehicles and noninvasive therapeutic alternatives of conventional methods for better therapeutics of CNS related diseases. Hence, there is an urgent need to design nontoxic biocompatible drugs and develop noninvasive delivery methods to check posttreatment clinical fatalities in neuropatients which occur due to existing highly toxic invasive drugs and treatment methods.

  12. NON-INVASIVE ESTIMATION OF METABOLIC FLUX AND BLOOD FLOW IN WORKING MUSCLE: EFFECT OF BLOOD-TISSUE DISTRIBUTION

    OpenAIRE

    Lai, Nicola; Saidel, Gerald M.; Iorio, Matthew; Cabrera, Marco E.

    2009-01-01

    Muscle oxygenation measurements by near infrared spectroscopy (NIRS) are frequently obtained in humans to make inferences about mechanisms of metabolic control of respiration in working skeletal muscle. However, these measurements have technical limitations that can mislead the evaluation of tissue processes. In particular, NIRS measurements of working muscle represent oxygenation of a mix of fibers with heterogeneous activation, perfusion and architecture. Specifically, the relative volume d...

  13. In vitro model of the blood-brain barrier established by co-culture of primary cerebral microvascular endothelial and astrocyte cells

    OpenAIRE

    Yan Wang; Ning Wang; Biao Cai; Guang-yun Wang; Jing Li; Xing-xing Piao

    2015-01-01

    Drugs for the treatment and prevention of nervous system diseases must permeate the blood-brain barrier to take effect. In vitro models of the blood-brain barrier are therefore important in the investigation of drug permeation mechanisms. However, to date, no unified method has been described for establishing a blood-brain barrier model. Here, we modified an in vitro model of the blood-brain barrier by seeding brain microvascular endothelial cells and astrocytes from newborn rats on a polyest...

  14. Calmodulin Methyltransferase Is Required for Growth, Muscle Strength, Somatosensory Development and Brain Function.

    Directory of Open Access Journals (Sweden)

    Sitvanit Haziza

    2015-08-01

    Full Text Available Calmodulin lysine methyl transferase (CaM KMT is ubiquitously expressed and highly conserved from plants to vertebrates. CaM is frequently trimethylated at Lys-115, however, the role of CaM methylation in vertebrates has not been studied. CaM KMT was found to be homozygously deleted in the 2P21 deletion syndrome that includes 4 genes. These patients present with cystinuria, severe intellectual disabilities, hypotonia, mitochondrial disease and facial dysmorphism. Two siblings with deletion of three of the genes included in the 2P21 deletion syndrome presented with cystinuria, hypotonia, a mild/moderate mental retardation and a respiratory chain complex IV deficiency. To be able to attribute the functional significance of the methylation of CaM in the mouse and the contribution of CaM KMT to the clinical presentation of the 2p21deletion patients, we produced a mouse model lacking only CaM KMT with deletion borders as in the human 2p21deletion syndrome. No compensatory activity for CaM methylation was found. Impairment of complexes I and IV, and less significantly III, of the mitochondrial respiratory chain was more pronounced in the brain than in muscle. CaM KMT is essential for normal body growth and somatosensory development, as well as for the proper functioning of the adult mouse brain. Developmental delay was demonstrated for somatosensory function and for complex behavior, which involved both basal motor function and motivation. The mutant mice also had deficits in motor learning, complex coordination and learning of aversive stimuli. The mouse model contributes to the evaluation of the role of methylated CaM. CaM methylation appears to have a role in growth, muscle strength, somatosensory development and brain function. The current study has clinical implications for human patients. Patients presenting slow growth and muscle weakness that could result from a mitochondrial impairment and mental retardation should be considered for sequence

  15. Calmodulin Methyltransferase Is Required for Growth, Muscle Strength, Somatosensory Development and Brain Function.

    Science.gov (United States)

    Haziza, Sitvanit; Magnani, Roberta; Lan, Dima; Keinan, Omer; Saada, Ann; Hershkovitz, Eli; Yanay, Nurit; Cohen, Yoram; Nevo, Yoram; Houtz, Robert L; Sheffield, Val C; Golan, Hava; Parvari, Ruti

    2015-08-01

    Calmodulin lysine methyl transferase (CaM KMT) is ubiquitously expressed and highly conserved from plants to vertebrates. CaM is frequently trimethylated at Lys-115, however, the role of CaM methylation in vertebrates has not been studied. CaM KMT was found to be homozygously deleted in the 2P21 deletion syndrome that includes 4 genes. These patients present with cystinuria, severe intellectual disabilities, hypotonia, mitochondrial disease and facial dysmorphism. Two siblings with deletion of three of the genes included in the 2P21 deletion syndrome presented with cystinuria, hypotonia, a mild/moderate mental retardation and a respiratory chain complex IV deficiency. To be able to attribute the functional significance of the methylation of CaM in the mouse and the contribution of CaM KMT to the clinical presentation of the 2p21deletion patients, we produced a mouse model lacking only CaM KMT with deletion borders as in the human 2p21deletion syndrome. No compensatory activity for CaM methylation was found. Impairment of complexes I and IV, and less significantly III, of the mitochondrial respiratory chain was more pronounced in the brain than in muscle. CaM KMT is essential for normal body growth and somatosensory development, as well as for the proper functioning of the adult mouse brain. Developmental delay was demonstrated for somatosensory function and for complex behavior, which involved both basal motor function and motivation. The mutant mice also had deficits in motor learning, complex coordination and learning of aversive stimuli. The mouse model contributes to the evaluation of the role of methylated CaM. CaM methylation appears to have a role in growth, muscle strength, somatosensory development and brain function. The current study has clinical implications for human patients. Patients presenting slow growth and muscle weakness that could result from a mitochondrial impairment and mental retardation should be considered for sequence analysis of the Ca

  16. Activation of ATP/UTP-selective receptors increases blood flow and blunts sympathetic vasoconstriction in human skeletal muscle

    DEFF Research Database (Denmark)

    Yegutkin, G.G.; Gonzalez-Alonso, J.; Rosenmeier, Jaya Birgitte

    2008-01-01

    Sympathetic vasoconstriction is blunted in the vascular beds of contracting skeletal muscle in humans, presumably due to the action of vasoactive metabolites (functional sympatholysis). Recently, we demonstrated that infusion of ATP into the arterial circulation of the resting human leg increases...... hyperaemia in conditions of increased sympathetic nerve drive such as exercise or hypoxia Udgivelsesdato: 2008/10/15...... blood flow and concomitantly blunts alpha-adrenergic vasoconstriction in a similar manner to that during moderate exercise. Here we tested the hypothesis that ATP, rather than its dephosphorylated metabolites, induces vasodilatation and sympatholysis in resting skeletal muscle via activation of ATP...... vasodilatory and sympatholytic effects of exogenous ATP in the skeletal muscle vasculature are largely mediated via ATP itself rather than its dephosphorylated metabolites, most likely via binding to endothelial ATP/UTP-selective P2Y(2) receptors. These data are consistent with a role of ATP in skeletal muscle...

  17. Immunological changes in human blood and skeletal muscle in response to physical exercise

    OpenAIRE

    Malm, Christer

    2001-01-01

    Pysical exercise is essential for maintaining normal function of skeletal muscle. Muscle tissue also has a remarkable capacity for adaptation to changes in physical demand. In fact, without stimulation from physical activity, muscle tissue will atrophy. The mechanisms responsible for increases or decreases in muscle function are to a large extent not known. According to current opinions, one consequence of physical exercise can be muscle cell damage and inflammation. The inf...

  18. Toward Eradicating HIV Reservoirs in the Brain: Inhibiting P-glycoprotein at the Blood-Brain Barrier with Prodrug Abacavir Dimers

    OpenAIRE

    Namanja, Hilda A.; Emmert, Dana; Davis, David A.; Campos, Christopher; Miller, David S.; Hrycyna, Christine A.; Chmielewski, Jean

    2011-01-01

    Eradication of HIV reservoirs in the brain necessitates penetration of antiviral agents across the blood-brain barrier (BBB), a process limited by drug efflux proteins such as P-glycoprotein (P-gp) at the membrane of brain capillary endothelial cells. We present an innovative chemical strategy toward the goal of therapeutic brain penetration of the P-gp substrate and anti-viral agent abacavir, in conjunction with a traceless tether. Dimeric prodrugs of abacavir were designed to have two funct...

  19. On ultrasound-induced microbubble oscillation in a capillary blood vessel and its implications for the blood-brain barrier

    Science.gov (United States)

    Wiedemair, W.; Tuković, Ž.; Jasak, H.; Poulikakos, D.; Kurtcuoglu, V.

    2012-02-01

    The complex interaction between an ultrasound-driven microbubble and an enclosing capillary microvessel is investigated by means of a coupled, multi-domain numerical model using the finite volume formulation. This system is of interest in the study of transient blood-brain barrier disruption (BBBD) for drug delivery applications. The compliant vessel structure is incorporated explicitly as a distinct domain described by a dedicated physical model. Red blood cells (RBCs) are taken into account as elastic solids in the blood plasma. We report the temporal and spatial development of transmural pressure (Ptm) and wall shear stress (WSS) at the luminal endothelial interface, both of which are candidates for the yet unknown mediator of BBBD. The explicit introduction of RBCs shapes the Ptm and WSS distributions and their derivatives markedly. While the peak values of these mechanical wall parameters are not affected considerably by the presence of RBCs, a pronounced increase in their spatial gradients is observed compared to a configuration with blood plasma alone. The novelty of our work lies in the explicit treatment of the vessel wall, and in the modelling of blood as a composite fluid, which we show to be relevant for the mechanical processes at the endothelium.

  20. Blood-brain barrier P-glycoprotein function is not impaired in early Parkinson's disease

    NARCIS (Netherlands)

    Bartels, A. L.; van Berckel, B. N. M.; Lubberink, M.; Luurtsema, G.; Lammertsma, A. A.; Leenders, K. L.

    2008-01-01

    The cause of Parkinson's disease (PD) is unknown. Genetic susceptibility and exposure to environmental toxins contribute to specific neuronal loss in PD. Decreased blood-brain barrier (BBB) P-glycoprotein (P-gp) efflux function has been proposed as a possible causative link between toxin exposure an

  1. Making Ends Meet: Myeloid Cells Catalyze Blood Vessel Repair in the Brain.

    Science.gov (United States)

    Deczkowska, Aleksandra; Schwartz, Michal

    2016-05-17

    Hemorrhagic stroke, primarily caused by rupture of blood vessels in the brain, is a leading cause of death and disability in adults. In this issue of Immunity, Liu et al. (2016) demonstrate that repair of cerebrovascular ruptures can be directly mediated by myeloid cells. PMID:27192572

  2. Blood-brain barrier leakage after status epilepticus in rapamycin-treated rats II: Potential mechanisms

    NARCIS (Netherlands)

    E.A. van Vliet; W.M. Otte; W.J. Wadman; E. Aronica; G. Kooij; H.E. de Vries; R.M. Dijkhuizen; J.A. Gorter

    2016-01-01

    OBJECTIVE: Blood-brain barrier (BBB) leakage may play a pro-epileptogenic role after status epilepticus. In the accompanying contrast-enhanced magnetic resonance imaging (CE-MRI) study we showed that the mammalian target of rapamycin (mTOR) inhibitor rapamycin reduced BBB leakage and seizure activit

  3. Blood-brain barrier leakage after status epilepticus in rapamycin-treated rats II : Potential mechanisms

    NARCIS (Netherlands)

    van Vliet, Erwin A; Otte, Wim M; Wadman, Wytse J; Aronica, Eleonora; Kooij, Gijs; de Vries, Helga E; Dijkhuizen, Rick M; Gorter, Jan A

    2016-01-01

    OBJECTIVE: Blood-brain barrier (BBB) leakage may play a pro-epileptogenic role after status epilepticus. In the accompanying contrast-enhanced magnetic resonance imaging (CE-MRI) study we showed that the mammalian target of rapamycin (mTOR) inhibitor rapamycin reduced BBB leakage and seizure activit

  4. Average blood flow and oxygen uptake in the human brain during resting wakefulness

    DEFF Research Database (Denmark)

    Madsen, P L; Holm, S; Herning, M; Lassen, N A

    1993-01-01

    tracer between the brain and its venous blood is not reached. As a consequence, normal values for CBF and CMRO2 of 54 ml 100 g-1 min-1 and 3.5 ml 100 g-1 min-1 obtained with the Kety-Schmidt technique are an overestimation of the true values. Using the Kety-Schmidt technique we have performed 57...

  5. Reproductive hormones regulate the selective permeability of the blood-brain barrier

    OpenAIRE

    Wilson, Andrea C.; Clemente, Luca; Liu, Tianbing; Bowen, Richard L.; Meethal, Sivan Vadakkadath; Atwood, Craig S.

    2008-01-01

    Reproductive hormones regulate the selective permeability of the blood-brain barrier : Current address: Department of Biochemistry, Colorado State University, CO, USA. (Clemente, Luca) correspondence: Corresponding author. University of Wisconsin-Madison Medical School, Wm S. Middleton Memorial VA (GRECC 11G), 2500 Overlook Terrace, Madison, WI 53705, USA. Tel.: +1 608 256 1901x11664; fax: +1 608 280 7291. (Atw...

  6. Effects of anesthetic agents on brain blood oxygenation level revealed with ultra-high field MRI.

    Directory of Open Access Journals (Sweden)

    Luisa Ciobanu

    Full Text Available During general anesthesia it is crucial to control systemic hemodynamics and oxygenation levels. However, anesthetic agents can affect cerebral hemodynamics and metabolism in a drug-dependent manner, while systemic hemodynamics is stable. Brain-wide monitoring of this effect remains highly challenging. Because T(2*-weighted imaging at ultra-high magnetic field strengths benefits from a dramatic increase in contrast to noise ratio, we hypothesized that it could monitor anesthesia effects on brain blood oxygenation. We scanned rat brains at 7T and 17.2T under general anesthesia using different anesthetics (isoflurane, ketamine-xylazine, medetomidine. We showed that the brain/vessels contrast in T(2*-weighted images at 17.2T varied directly according to the applied pharmacological anesthetic agent, a phenomenon that was visible, but to a much smaller extent at 7T. This variation is in agreement with the mechanism of action of these agents. These data demonstrate that preclinical ultra-high field MRI can monitor the effects of a given drug on brain blood oxygenation level in the absence of systemic blood oxygenation changes and of any neural stimulation.

  7. Sensitivity analysis aimed at blood vessels detection using interstitial optical tomography during brain needle biopsy procedures.

    Science.gov (United States)

    Pichette, Julien; Goyette, Andréanne; Picot, Fabien; Tremblay, Marie-Andrée; Soulez, Gilles; Wilson, Brian C; Leblond, Frédéric

    2015-11-01

    A brain needle biopsy procedure is performed for suspected brain lesions in order to sample tissue that is subsequently analysed using standard histopathology techniques. A common complication resulting from this procedure is brain hemorrhaging from blood vessels clipped off during tissue extraction. Interstitial optical tomography (iOT) has recently been introduced by our group as a mean to assess the presence of blood vessels in the vicinity of the needle. The clinical need to improve safety requires the detection of blood vessels within 2 mm from the outer surface of the needle, since this distance is representative of the volume of tissue that is aspirated durirng tissue extraction. Here, a sensitivity analysis is presented to establish the intrinsic detection limits of iOT based on simulations and experiments using brain tissue phantoms. It is demonstrated that absorbers can be detected with diameters >300 μm located up to >2 mm from the biopsy needle core for bulk optical properties consistent with brain tissue. PMID:26600990

  8. AMYLOID BETA ACCUMULATION IN HIV-1-INFECTED BRAIN: THE ROLE OF THE BLOOD BRAIN BARRIER

    OpenAIRE

    András, Ibolya E.; Toborek, Michal

    2012-01-01

    In recent years we face an increase in the aging of the HIV-1-infected population, which is not only due to effective antiretroviral therapy but also to new infections among older people. Even with the use of the antiretroviral therapy, HIV-associated neurocognitive disorders represent an increasing problem as the HIV-1-infected population ages. Increased amyloid beta (Aβ) deposition is characteristic of HIV-1-infected brains, and it has been hypothesized that brain vascular dysfunction contr...

  9. P-glycoprotein activity in the blood-brain barrier is affected by virus-induced neuroinflammation and antipsychotic treatment

    NARCIS (Netherlands)

    Doorduin, Janine; de Vries, Erik F. J.; Dierckx, Rudi A.; Klein, Hans C.

    2014-01-01

    A large percentage of schizophrenic patients respond poorly to antipsychotic treatment. This could be explained by inefficient drug transport across the blood-brain barrier due to P-glycoprotein mediated efflux. P-glycoprotein activity and expression in the blood-brain barrier can be affected by inf

  10. Blood pH and brain uptake of 14C-morphine

    International Nuclear Information System (INIS)

    14C-Morphine was injected iv in control awake rats or in rats subjected to metabolic alkalosis or acidosis. Ten minutes later, radioactivity was determined within each of seven brain regions, after correction was made for intravascular tracer. In each region, parenchymal radioactivity was correlated positively and significantly (P less than 0.05) with arterial blood pH. Brain radioactivity was twofold to threefold greater in alkalotic rats (mean pH . 7.62) than in acidotic rats (mean pH . 7.16). The results are consistent with the pH-partition hypothesis for drug entry into the brain and indicate that morphine uptake can be increased by elevating the fraction of lipid-soluble uncharged morphine base in blood, by means of alkalosis. The observations may account for an exaggerated morphine-induced analgesia in alkalotic patients

  11. Blood pH and brain uptake of /sup 14/C-morphine

    Energy Technology Data Exchange (ETDEWEB)

    Schulman, D.S.; Kaufman, J.J.; Eisenstein, M.M.; Rapoport, S.I.

    1984-11-01

    /sup 14/C-Morphine was injected iv in control awake rats or in rats subjected to metabolic alkalosis or acidosis. Ten minutes later, radioactivity was determined within each of seven brain regions, after correction was made for intravascular tracer. In each region, parenchymal radioactivity was correlated positively and significantly (P less than 0.05) with arterial blood pH. Brain radioactivity was twofold to threefold greater in alkalotic rats (mean pH . 7.62) than in acidotic rats (mean pH . 7.16). The results are consistent with the pH-partition hypothesis for drug entry into the brain and indicate that morphine uptake can be increased by elevating the fraction of lipid-soluble uncharged morphine base in blood, by means of alkalosis. The observations may account for an exaggerated morphine-induced analgesia in alkalotic patients.

  12. The in vitro blood-brain barrier model under OGD condition

    DEFF Research Database (Denmark)

    Tornabene, Erica; Helms, Hans Christian Cederberg; Berndt, Philipp;

    Introduction - The blood-brain barrier (BBB) is a physical, transport and metabolic barrier which plays a key role in preventing uncontrolled exchanges between blood and brain, ensuring an optimal environment for neurons activity. This extent interface is created by the endothelial cells forming...... decreasing the oxygen level to 1% in a hypoxia workbench. To mimic the reperfusion phase, the aglycemic medium was replaced by glucose-supplemented medium and cells were further transferred in a normoxia incubator for 48h. TEER was monitored with an EVOHM and expression levels of relevant proteins were...... therapies to treat this devastating disease. Materials and Methods - Primary cultures of endothelial cells from bovine brain microvessels were cocultured with rat astrocytes in transwell inserts. At day 11, cells were treated with 4h of OGD by changing the culture medium with glucose-free medium and...

  13. Signaled drug delivery and transport across the blood-brain barrier.

    Science.gov (United States)

    Hinow, Peter; Radunskaya, Ami; Mackay, Sean M; Reynolds, John N J; Schroeder, Morgan; Tan, Eng Wui; Tucker, Ian G

    2016-09-01

    We use a mathematical model to describe the delivery of a drug to a specific region of the brain. The drug is carried by liposomes that can release their cargo by application of focused ultrasound (US). Thereupon, the drug is absorbed through the endothelial cells that line the brain capillaries and form the physiologically important blood-brain barrier (BBB). We present a compartmental model of a capillary that is able to capture the complex binding and transport processes the drug undergoes in the blood plasma and at the BBB. We apply this model to the delivery of levodopa (L-dopa, used to treat Parkinson's disease) and doxorubicin (an anticancer agent). The goal is to optimize the delivery of drug while at the same time minimizing possible side effects of the US. PMID:26572864

  14. A portable wireless near-infrared spatially resolved spectroscopy system for use on brain and muscle.

    Science.gov (United States)

    Everdell, N L; Airantzis, D; Kolvya, C; Suzuki, T; Elwell, C E

    2013-11-01

    We have designed, built and successfully tested a prototype portable and wireless near-infrared spectroscopy system. It takes forward the well-established series of NIRO spectroscopy instruments made by Hamamatsu Photonics (Hamamatsu City, Japan). It uses an identical optical probe, and has a data acquisition rate of 10 Hz. It illuminates the tissue with laser diode sources at 3 wavelengths of 775, 810 and 850 nm, and detects the reflected light with 2 silicon photodiode detectors at 2 different separations, enabling spatially resolved spectroscopy to be performed. We have tested it with both in vitro and in vivo experiments to establish its basic functionality for use in studies of both brain and muscle. PMID:23706504

  15. Next generation of non-mammalian blood-brain barrier models to study parasitic infections of the central nervous system

    Science.gov (United States)

    Siddiqui, Ruqaiyyah; Edwards-Smallbone, James; Flynn, Robin; Khan, Naveed Ahmed

    2012-01-01

    Transmigration of neuropathogens across the blood-brain barrier is a key step in the development of central nervous system infections, making it a prime target for drug development. The ability of neuropathogens to traverse the blood-brain barrier continues to inspire researchers to understand the specific strategies and molecular mechanisms that allow them to enter the brain. The availability of models of the blood-brain barrier that closely mimic the situation in vivo offers unprecedented opportunities for the development of novel therapeutics. PMID:21921682

  16. The brain response to peripheral insulin declines with age: a contribution of the blood-brain barrier?

    Directory of Open Access Journals (Sweden)

    Tina Sartorius

    Full Text Available It is a matter of debate whether impaired insulin action originates from a defect at the neural level or impaired transport of the hormone into the brain. In this study, we aimed to investigate the effect of aging on insulin concentrations in the periphery and the central nervous system as well as its impact on insulin-dependent brain activity.Insulin, glucose and albumin concentrations were determined in 160 paired human serum and cerebrospinal fluid (CSF samples. Additionally, insulin was applied in young and aged mice by subcutaneous injection or intracerebroventricularly to circumvent the blood-brain barrier. Insulin action and cortical activity were assessed by Western blotting and electrocorticography radiotelemetric measurements.In humans, CSF glucose and insulin concentrations were tightly correlated with the respective serum/plasma concentrations. The CSF/serum ratio for insulin was reduced in older subjects while the CSF/serum ratio for albumin increased with age like for most other proteins. Western blot analysis in murine whole brain lysates revealed impaired phosphorylation of AKT (P-AKT in aged mice following peripheral insulin stimulation whereas P-AKT was comparable to levels in young mice after intracerebroventricular insulin application. As readout for insulin action in the brain, insulin-mediated cortical brain activity instantly increased in young mice subcutaneously injected with insulin but was significantly reduced and delayed in aged mice during the treatment period. When insulin was applied intracerebroventricularly into aged animals, brain activity was readily improved.This study discloses age-dependent changes in insulin CSF/serum ratios in humans. In the elderly, cerebral insulin resistance might be partially attributed to an impaired transport of insulin into the central nervous system.

  17. Statistical distribution of blood serotonin as a predictor of early autistic brain abnormalities

    Directory of Open Access Journals (Sweden)

    Janušonis Skirmantas

    2005-07-01

    Full Text Available Abstract Background A wide range of abnormalities has been reported in autistic brains, but these abnormalities may be the result of an earlier underlying developmental alteration that may no longer be evident by the time autism is diagnosed. The most consistent biological finding in autistic individuals has been their statistically elevated levels of 5-hydroxytryptamine (5-HT, serotonin in blood platelets (platelet hyperserotonemia. The early developmental alteration of the autistic brain and the autistic platelet hyperserotonemia may be caused by the same biological factor expressed in the brain and outside the brain, respectively. Unlike the brain, blood platelets are short-lived and continue to be produced throughout the life span, suggesting that this factor may continue to operate outside the brain years after the brain is formed. The statistical distributions of the platelet 5-HT levels in normal and autistic groups have characteristic features and may contain information about the nature of this yet unidentified factor. Results The identity of this factor was studied by using a novel, quantitative approach that was applied to published distributions of the platelet 5-HT levels in normal and autistic groups. It was shown that the published data are consistent with the hypothesis that a factor that interferes with brain development in autism may also regulate the release of 5-HT from gut enterochromaffin cells. Numerical analysis revealed that this factor may be non-functional in autistic individuals. Conclusion At least some biological factors, the abnormal function of which leads to the development of the autistic brain, may regulate the release of 5-HT from the gut years after birth. If the present model is correct, it will allow future efforts to be focused on a limited number of gene candidates, some of which have not been suspected to be involved in autism (such as the 5-HT4 receptor gene based on currently available clinical and

  18. Peculiarities of Brain's Blood Flow : Role of Carbon Dioxide

    CERN Document Server

    Gersten, Alexander

    2011-01-01

    Among the major factors controlling the cerebral blood flow (CBF), the effect of PaCO2 is peculiar in that it violates autoregulatory CBF mechanisms and allows to explore the full range of the CBF. This research resulted in a simple physical model, with a four parameter formula, relating the CBF to PaCO2. The parameters can be extracted in an easy manner, directly from the experimental data. With this model earlier experimental data sets of Rhesus monkeys and rats were well fitted. Human data were also fitted with this model. Exact formulae were found, which can be used to transform the fits of one animal to the fits of another one. The merit of this transformation is that it enable us the use of rats data as monkeys data simply by rescaling the PaCO2 values and the CBF data. This transformation makes possible the use of experimental animal data instead of human ones.

  19. The blood-brain barrier in migraine treatment

    DEFF Research Database (Denmark)

    Edvinsson, L; Tfelt-Hansen, P

    2008-01-01

    Salient aspects of the anatomy and function of the blood-barrier barrier (BBB) are reviewed in relation to migraine pathophysiology and treatment. The main function of the BBB is to limit the access of circulating substances to the neuropile. Smaller lipophilic substances have some access to the...... central nervous system by diffusion, whereas other substances can cross the BBB by carrier-mediated influx transport, receptor-mediated transcytosis and absorptive-mediated transcytosis. Studies of drugs relevant to migraine pathophysiology and treatment have been examined with the pressurized...... other vascular beds also. We discuss how this can be related to genuine migraine attacks. Our view is that there exists no clear proof of breakdown or leakage of the BBB during migraine attacks, and that antimigraine drugs need to pass the BBB for efficacy....

  20. The blood-brain barrier in migraine treatment

    DEFF Research Database (Denmark)

    Edvinsson, L.; Tfelt-Hansen, P.

    2008-01-01

    Salient aspects of the anatomy and function of the blood-barrier barrier (BBB) are reviewed in relation to migraine pathophysiology and treatment. The main function of the BBB is to limit the access of circulating substances to the neuropile. Smaller lipophilic substances have some access to the...... central nervous system by diffusion, whereas other substances can cross the BBB by carrier-mediated influx transport, receptor-mediated transcytosis and absorptive-mediated transcytosis. Studies of drugs relevant to migraine pathophysiology and treatment have been examined with the pressurized...... other vascular beds also. We discuss how this can be related to genuine migraine attacks. Our view is that there exists no clear proof of breakdown or leakage of the BBB during migraine attacks, and that antimigraine drugs need to pass the BBB for efficacy Udgivelsesdato: 2008/12...

  1. Oxygenation and Blood Volume Periodic Waveforms in the Brain

    CERN Document Server

    Gersten, Alexander; Raz, Amir

    2011-01-01

    Results of an experiment are presented whose aim is to explore the relationship between respiration and cerebral oxygenation. Measurements of end tidal CO2 (EtCO2) were taken simultaneously with cerebral oxygen saturation (rSO2) using the INVOS Cerebral Oximeter of Somanetics. Due to the device limitations we could explore only subjects who could perform with a breathing rate of around 2/min or less. Six subjects were used who were experienced in yoga breathing techniques. They performed an identical periodic breathing exercise including periodicity of about 2/min. The results of all six subjects clearly show a periodic change of cerebral oxygenation with the same period as the breathing exercises. Similar periodic changes in blood volume index were observed as well.

  2. Reliability of the Modified Ashworth Scale in the Assessment of Plantarflexor Muscle Spasticity in Patients with Traumatic Brain Injury.

    Science.gov (United States)

    Allison, S. C.; And Others

    1996-01-01

    This attempt to determine the reliability of the Modified Ashworth Scale for assessing the severity of muscle spasticity for ankle plantarflexors in 30 patients with traumatic brain injury concluded that the reliability was minimally adequate to support the scale's continued use. Interrater reliability was less than that previously reported for…

  3. Bypassing the blood-brain barrier: delivery of therapeutic agents by macrophages

    Science.gov (United States)

    Hirschberg, Henry; Baek, Seung-Kuk; Kwon, Young Jik; Sun, Chung-Ho; Madsen, Steen J.

    2010-02-01

    Introduction: Failure to eradicate infiltrating glioma cells using conventional treatment regimens results in tumor recurrence and is responsible for the dismal prognosis of patients with glioblastoma multiforme (GBM). This is due to the fact that these migratory cells are protected by the blood-brain barrier (BBB) and the blood brain tumor barrier (BBTB) which prevents the delivery of most anti-cancer agents. We have evaluated the ability of monocytes/macrophages (Mo/Ma) to cross the BBB in rats. This will permit access of anti-cancer agents such as nanoparticles to effectively target the infiltrating tumor cells, and potentially improve the treatment effectiveness for malignant gliomas. Materials and Methods: The infiltration of Mo/Ma into brain tumor spheroids in vitro was determined using fluorescent stained Mo/Ma. Tumors were also established in the brains of inbred rats and ALA-PDT was given 18 days following tumor induction. The degredation of the BBTB and quantification of the number of infiltrating Mo/Ma was examined on histological sections from removed brains. Results & Conclusion: PDT was highly effective in locally opening the BBTB and inducing macrophage migration into the irradiated portions of brain tumors.

  4. Facilitated transport of glucose from blood to brain in man and the effect of moderate hypoglycaemia on cerebral glucose utilization

    International Nuclear Information System (INIS)

    The effect of steady-state moderate hypoglycaemia on human brain homeostasis has been studied with positron emission tomography using D-glucose 11C(ul) as tracer. To rule out any effects of insulin, the plasma insulin concentration was maintained at the same level under normo- and hypoglycaemic conditions. Reduction of blood glucose by 55% increased the glucose clearance through the blood-brain barrier by 50% and reduced brain glucose consumption by 40%. Blood flow was not affected. The results are consistent with facilitated transport of glucose from blood to brain in humans. The maximal transport rate of glucose from blood to brain was found to be 62±19 (mean±SEM) μmol hg-1 min-1, and the half-saturation constant was found to be 4.1±3.2 mM. (orig.)

  5. Transcriptional profiling of human brain endothelial cells reveals key properties crucial for predictive in vitro blood-brain barrier models.

    Directory of Open Access Journals (Sweden)

    Eduard Urich

    Full Text Available Brain microvascular endothelial cells (BEC constitute the blood-brain barrier (BBB which forms a dynamic interface between the blood and the central nervous system (CNS. This highly specialized interface restricts paracellular diffusion of fluids and solutes including chemicals, toxins and drugs from entering the brain. In this study we compared the transcriptome profiles of the human immortalized brain endothelial cell line hCMEC/D3 and human primary BEC. We identified transcriptional differences in immune response genes which are directly related to the immortalization procedure of the hCMEC/D3 cells. Interestingly, astrocytic co-culturing reduced cell adhesion and migration molecules in both BECs, which possibly could be related to regulation of immune surveillance of the CNS controlled by astrocytic cells within the neurovascular unit. By matching the transcriptome data from these two cell lines with published transcriptional data from freshly isolated mouse BECs, we discovered striking differences that could explain some of the limitations of using cultured BECs to study BBB properties. Key protein classes such as tight junction proteins, transporters and cell surface receptors show differing expression profiles. For example, the claudin-5, occludin and JAM2 expression is dramatically reduced in the two human BEC lines, which likely explains their low transcellular electric resistance and paracellular leakiness. In addition, the human BEC lines express low levels of unique brain endothelial transporters such as Glut1 and Pgp. Cell surface receptors such as LRP1, RAGE and the insulin receptor that are involved in receptor-mediated transport are also expressed at very low levels. Taken together, these data illustrate that BECs lose their unique protein expression pattern outside of their native environment and display a more generic endothelial cell phenotype. A collection of key genes that seems to be highly regulated by the local

  6. Alterations in blood-brain barrier ICAM-1 expression and brain microglial activation after λ-carrageenan-induced inflammatory pain

    Science.gov (United States)

    Huber, J. D.; Campos, C. R.; Mark, K. S.; Davis, T. P.

    2014-01-01

    Previous studies showed that peripheral inflammatory pain increased blood-brain barrier (BBB) permeability and altered tight junction protein expression and the delivery of opioid analgesics to the brain. What remains unknown is which pathways and mediators during peripheral inflammation affect BBB function and structure. The current study investigated effects of λ-carrageenan-induced inflammatory pain (CIP) on BBB expression of ICAM-1. We also examined the systemic contribution of a number of proinflammatory cytokines and microglial activation in the brain to elucidate pathways involved in BBB disruption during CIP. We investigated ICAM-1 RNA and protein expression levels in isolated rat brain microvessels after CIP using RT-PCR and Western blot analyses, screened inflammatory cytokines during the time course of inflammation, assessed white blood cell counts, and probed for BBB and central nervous system stimulation and leukocyte transmigration using immunohistochemistry and flow cytometry. Results showed an early increase in ICAM-1 RNA and protein expression after CIP with no change in circulating levels of several proinflammatory cytokines. Changes in ICAM-1 protein expression were noted at 48 h. Immunohistochemistry showed that the induction of ICAM-1 was region specific with increased expression noted in the thalamus and frontal and parietal cortices, which directly correlated with increased expression of activated microglia. The findings of the present study were that CIP induces increased ICAM-1 mRNA and protein expression at the BBB and that systemic proinflammatory mediators play no apparent role in the early response (1–6 h); however, brain region-specific increases in micro-glial activation suggest a potential for a central-mediated response. PMID:16199477

  7. Acute arginine supplementation fails to improve muscle endurance or affect blood pressure responses to resistance training.

    Science.gov (United States)

    Greer, Beau K; Jones, Brett T

    2011-07-01

    Dietary supplement companies claim that arginine supplements acutely enhance skeletal muscular endurance. The purpose of this study was to determine whether acute arginine α-ketoglutarate supplementation (AAKG) will affect local muscle endurance of the arm and shoulder girdle or the blood pressure (BP) response to anaerobic exercise. Twelve trained college-aged men (22.6 ± 3.8 years) performed 2 trials of exercise separated by at least 1 week. At 4 hours before, and 30 minutes before exercise, a serving of an AAKG supplement (3,700 mg arginine alpha-ketoglutarate per serving) or placebo was administered. Resting BP was assessed pre-exercise after 16 minutes of seated rest, and 5 and 10 minutes postexercise. Three sets each of chin-ups, reverse chin-ups, and push-ups were performed to exhaustion with 3 minutes of rest between each set. Data were analyzed using repeated-measures analysis of variance and paired t-tests. The AAKG supplementation did not improve muscle endurance or significantly affect the BP response to anaerobic work. Subjects performed fewer total chin-ups (23.75 ± 6.38 vs. 25.58 ± 7.18) and total trial repetitions (137.92 ± 28.18 vs. 141.08 ± 28.57) in the supplement trial (p ≤ 0.05). Subjects executed fewer reverse chin-ups (5.83 ± 1.85 vs. 6.75 ± 2.09) during set 2 after receiving the supplement as compared to the placebo (p AAKG supplementation may hinder muscular endurance, the use of these supplements before resistance training should be questioned. PMID:21399536

  8. Deoxycholic Acid as a Modifier of the Permeation of Gliclazide through the Blood Brain Barrier of a Rat

    OpenAIRE

    Mladena Lalić-Popović; Velibor Vasović; Boris Milijašević; Svetlana Goločorbin-Kon; Hani Al-Salami; Momir Mikov

    2013-01-01

    Major problem for diabetic patients represents damage of blood vessels and the oxidative stress of the brain cells due to increased concentration of free radicals and poor nutrition of brain cells. Gliclazide has antioxidative properties and poor blood brain barrier (BBB) penetration. Bile acids are known for their hypoglycemic effect and as promoters of drug penetration across biological membranes. Accordingly, the aim of this study is to investigate whether the bile acid (deoxycholic acid) ...

  9. Blood-borne donor mast cell precursors migrate to mast cell-rich brain regions in the adult mouse

    OpenAIRE

    Nautiyal, Katherine M.; Liu, Charles; Dong, Xin; Silver, Rae

    2011-01-01

    Mast cells are hematopoietic immune cells located throughout the body, including within the brain. Reconstitution of mast cell deficient KitW-sh/W-sh mice has proven valuable in determining peripheral mast cell function. Here we study the brain mast cell population using a novel method of blood transfusion for reconstitution. We show that blood transfusion results in mast cells of donor origin in the WT mouse, including in the brain and are restricted to regions bearing host mast cells. In co...

  10. High muscle blood flow in man: is maximal O2 extraction compromised?

    Science.gov (United States)

    Richardson, R S; Poole, D C; Knight, D R; Kurdak, S S; Hogan, M C; Grassi, B; Johnson, E C; Kendrick, K F; Erickson, B K; Wagner, P D

    1993-10-01

    During conventional cycle ergometry, as work rate (WR) is increased toward maximum, O2 extraction increases hyperbolically, typically achieving values of 80-90% at peak O2 uptake (VO2). In contrast, studies using isolated knee-extensor exercise report much higher mass-specific blood flows (Q) and lower maximal O2 extractions (approximately 70%), which have been interpreted as transit time limitation to O2 movement out of the muscle capillary. However, maximal achievable WR levels during conventional cycle ergometry are generally reached (over 10-15 min) after rapid increases in WR, whereas the reported knee-extensor studies have used only more lengthy protocols (45 min). The duration of these protocols may have prevented the attainment of high WR levels and thus high O2 extraction ratios. Accordingly, this investigation examined leg Q and O2 extraction responses during single-leg knee-extensor exercise incremented rapidly (steps of 15-25 W per 2- to 3-min interval), which produced fatigue in 13-15 min. Q and muscle VO2 increased linearly with WR to fatigue with Q-WR and VO2-WR slopes similar to those reported in previous knee-extensor studies. However, with the use of this protocol, very high maximal achievable WR [99 +/- 6 (SE) W] and muscle Q (385 +/- 26 ml.min-1 x 100 g-1) levels were attained, some 80% greater than previously reported. An O2 extraction of 84.6 +/- 2.1% was reached, giving a maximal VO2 of 60.2 +/- 5.8 ml.min-1 x 100 g-1. We conclude that, even under the high Q conditions of single-leg knee-extensor exercise, O2 extraction does not reach a plateau on the basis of short transit times and that previous conclusions to the contrary reflect failure to attain sufficiently high WR levels. Maximal VO2, Q, and O2 extraction in this model have yet to be defined. PMID:8282650

  11. A unique carrier for delivery of therapeutic compounds beyond the blood-brain barrier.

    Directory of Open Access Journals (Sweden)

    Delara Karkan

    Full Text Available BACKGROUND: Therapeutic intervention in many neurological diseases is thwarted by the physical obstacle formed by the blood-brain barrier (BBB that excludes most drugs from entering the brain from the blood. Thus, identifying efficacious modes of drug delivery to the brain remains a "holy grail" in molecular medicine and nanobiotechnology. Brain capillaries, that comprise the BBB, possess an endogenous receptor that ferries an iron-transport protein, termed p97 (melanotransferrin, across the BBB. Here, we explored the hypothesis that therapeutic drugs "piggybacked" as conjugates of p97 can be shuttled across the BBB for treatment of otherwise inoperable brain tumors. APPROACH: Human p97 was covalently linked with the chemotherapeutic agents paclitaxel (PTAX or adriamycin (ADR and following intravenous injection, measured their penetration into brain tissue and other organs using radiolabeled and fluorescent derivatives of the drugs. In order to establish efficacy of the conjugates, we used nude mouse models to assess p97-drug conjugate activity towards glioma and mammary tumors growing subcutaneously compared to those growing intracranially. PRINCIPAL FINDINGS: Bolus-injected p97-drug conjugates and unconjugated p97 traversed brain capillary endothelium within a few minutes and accumulated to 1-2% of the injected by 24 hours. Brain delivery with p97-drug conjugates was quantitatively 10 fold higher than with free drug controls. Furthermore, both free-ADR and p97-ADR conjugates equally inhibited the subcutaneous growth of gliomas growing outside the brain. Evocatively, only p97-ADR conjugates significantly prolonged the survival of animals bearing intracranial gliomas or mammary tumors when compared to similar cumulated doses of free-ADR. SIGNIFICANCE: This study provides the initial proof of concept for p97 as a carrier capable of shuttling therapeutic levels of drugs from the blood to the brain for the treatment of neurological disorders

  12. [Advances in Biomarkers of Mild Traumatic Brain Injury in Cerebrospinal Fluid and Blood].

    Science.gov (United States)

    Huang, Wen; Li, Shang-xun; Li, Xue-jian; Xu, Hong-yun

    2015-12-01

    Mild traumatic brain injury (MTBI) is defined as a mild brain trauma resulting in a short loss of consciousness and alteration of mental status. It may also occasionally develop persistent and progressive symptoms. It has been confirmed that MTBI causes changes of anatomic structures in central nervous system and biomarkers in the body fluid. However, there is no sufficient research on relevance among threshold for the brain injury, individual vulnerability and duration of disturbance of consciousness. Furthermore, there are no reliable diagnostic methods to establish whether a blow to the head is sufficient to cause the brain injury. This review provides references for biomarkers in cerebrospinal fluid and blood associated with TBI. It also provides application status and potential prospects for further assessment and diagnosis of MTBI. PMID:27141807

  13. Effect of methyl parathion on the muscle and brain acetylcholinesterase activity of matrinxã (Brycon cephalus

    Directory of Open Access Journals (Sweden)

    Almeida Luciana Cristina de

    2005-01-01

    Full Text Available Farming of the freshwater fish is emerging in Brazil and many species from the wild are promising. The teleost matrinxã (Brycon cephalus holds several characteristics such as fast growth rate, high commercial value and adaptability to artificial raring conditions, which make it a promising species for commerce. The use of pesticides in aquatic environment is frequent in Brazil, and methyl parathion is very common in aquaculture. We have determined the enzymatic activity of acetyl cholinesterase in white muscle and brain of matrinxã exposed to 2ppm of environmental methyl parathion for 24 hours. There was 64% and 69% of acetyl cholinesterase inhibition in muscle and brain respectively. These activities were not recovered after 8 days from exposure to this pesticide. It can be concluded that acetyl cholinesterase from those tissues was inhibited by small amounts of methyl parathion, and the main effect was observed in the brain.

  14. Kinetics of creatine in blood and brain after intraperitoneal injection in the rat.

    Science.gov (United States)

    Perasso, Luisa; Cupello, Aroldo; Lunardi, Gian Luigi; Principato, Cristina; Gandolfo, Carlo; Balestrino, Maurizio

    2003-06-01

    Creatine has in recent years raised the interest of the neurologist, because it has been used in children with hereditary disorders of creatine metabolism and because experimental data suggest that it may exert a protective effect against various neurological diseases including stroke. Moreover, it is widely used as a nutritional supplement. It is well known that creatine crosses the blood-brain barrier with difficulty, however its accumulation into the brain after systemic administration is still not completely known. In the present experiments we studied its accumulation into rat brain tissue after intraperitoneal (i.p.) single or repeated injections. After a single injection of 160 mg/kg, radioactively labelled creatine (14C-creatine) entered the brain to a limited extent. It reached a plateau value of around 70 microM above baseline, that remained stable for at least 9 h. This amount of exogenous creatine obviously added to the endogenous creatine store. This increase is a minor one, since endogenous creatine has a brain concentration of about 10 mM. In accordance with this conclusion, when single or repeated injections of unlabelled ('cold') creatine were administered to rats, no sizable increase could be measured with high-performance liquid chromatography in the brain levels of either this compound or its phosphorylated derivative, phosphocreatine. Although our data clearly show some passage of serum creatine into the brain, other strategies are needed to improve passage of creatine across the blood-brain barrier in a way that it may be suitable to treat acute conditions like stroke. PMID:12742622

  15. Muscle size and arterial stiffness after blood flow-restricted low-intensity resistance training in older adults.

    Science.gov (United States)

    Yasuda, T; Fukumura, K; Fukuda, T; Uchida, Y; Iida, H; Meguro, M; Sato, Y; Yamasoba, T; Nakajima, T

    2014-10-01

    Previous studies have shown that blood flow-restricted low-intensity resistance training (BFR-RT) causes muscle hypertrophy while maintaining arterial function in young adults. We examined the effects of BFR-RT on muscle size and arterial stiffness in older adults. Healthy subjects (ages 61-84 years) were divided into BFR-RT (n = 9) or non-training control (CON; n = 10) groups. The BFR-RT group performed 20% and 30%, respectively, of one-repetition maximal (1-RM) knee extension and leg press exercises, 2 days/wk for 12 weeks. The BFR-RT group wore elastic cuffs (120-270 mmHg) on both legs during training. Magnetic resonance imaging-measured muscle cross-sectional area (CSA), 1-RM strength, chair stand (CS) test, and cardio-ankle vascular index testing (CAVI), an index of arterial stiffness, were measured before and 3-5 days after the final training session. Muscle CSA of the quadriceps (8.0%), adductors (6.5%), and gluteus maximus (4.4%), leg extension and leg press 1-RM strength (26.1% and 33.4%), and CS performance (18.3%) improved (P testing, there were no changes in both two groups. In conclusion, BFR-RT improves muscle CSA as well as maximal muscle strength, but does not negatively affect arterial stiffness or humeral coagulation factors in older adults. PMID:23730848

  16. CT and MRI assessment and characterization using segmentation and 3D modeling techniques: applications to muscle, bone and brain

    Directory of Open Access Journals (Sweden)

    Paolo Gargiulo

    2014-03-01

    Full Text Available This paper reviews the novel use of CT and MRI data and image processing tools to segment and reconstruct tissue images in 3D to determine characteristics of muscle, bone and brain.This to study and simulate the structural changes occurring in healthy and pathological conditions as well as in response to clinical treatments. Here we report the application of this methodology to evaluate and quantify: 1. progression of atrophy in human muscle subsequent to permanent lower motor neuron (LMN denervation, 2. muscle recovery as induced by functional electrical stimulation (FES, 3. bone quality in patients undergoing total hip replacement and 4. to model the electrical activity of the brain. Study 1: CT data and segmentation techniques were used to quantify changes in muscle density and composition by associating the Hounsfield unit values of muscle, adipose and fibrous connective tissue with different colors. This method was employed to monitor patients who have permanent muscle LMN denervation in the lower extremities under two different conditions: permanent LMN denervated not electrically stimulated and stimulated. Study 2: CT data and segmentation techniques were employed, however, in this work we assessed bone and muscle conditions in the pre-operative CT scans of patients scheduled to undergo total hip replacement. In this work, the overall anatomical structure, the bone mineral density (BMD and compactness of quadriceps muscles and proximal femoral was computed to provide a more complete view for surgeons when deciding which implant technology to use. Further, a Finite element analysis provided a map of the strains around the proximal femur socket when solicited by typical stresses caused by an implant press fitting. Study 3 describes a method to model the electrical behavior of human brain using segmented MR images. The aim of the work is to use these models to predict the electrical activity of the human brain under normal and pathological

  17. Noninvasive functional photoacoustic tomography of blood-oxygen saturation in the brain

    Science.gov (United States)

    Wang, Xueding; Ku, Geng; Xie, Xueyi; Wang, Yiwen; Stoica, George; Wang, Lihong V.

    2004-07-01

    Since optical contrast is sensitive to functional parameters, including the hemoglobin oxygen saturation and the total concentration of hemoglobin, imaging based on optical contrast has been widely employed for the real-time monitoring of tissue oxygen consumption and hemodynamics in biological tissues. However, due to the overwhelming scattering of light in tissues, traditional optical imaging modalities cannot provide satisfactory spatial resolution. Functional photoacoustic tomography is a novel technique that combines high optical contrast and high ultrasonic resolution. Here, we present our study of a laser-based photoacoustic technique that, for the first time to our knowledge, monitors blood oxygenation in the rat brain in vivo. The cerebral blood oxygenation in the rat brain was imaged by photoacoustic detection at two wavelengths. The change in the hemoglobin oxygen saturation in the brain vessels as a result of the alternation from hyperoxia status to hypoxia status was visualized successfully with satisfactory spatial resolution. This work demonstrates that photoacoustic technique, based on the spectroscopic absorption of oxy- and deoxy-hemoglobin, can provide accurate functional imaging of cerebral blood oxygenation in the small-animal brain non-invasively with the skin and skull intact.

  18. New insights into coupling and uncoupling of cerebral blood flow and metabolism in the brain.

    Science.gov (United States)

    Venkat, Poornima; Chopp, Michael; Chen, Jieli

    2016-06-30

    The brain has high metabolic and energy needs and requires continuous cerebral blood flow (CBF), which is facilitated by a tight coupling between neuronal activity, CBF, and metabolism. Upon neuronal activation, there is an increase in energy demand, which is then met by a hemodynamic response that increases CBF. Such regional CBF increase in response to neuronal activation is observed using neuroimaging techniques such as functional magnetic resonance imaging and positron emission tomography. The mechanisms and mediators (eg, nitric oxide, astrocytes, and ion channels) that regulate CBF-metabolism coupling have been extensively studied. The neurovascular unit is a conceptual model encompassing the anatomical and metabolic interactions between the neurons, vascular components, and glial cells in the brain. It is compromised under disease states such as stroke, diabetes, hypertension, dementias, and with aging, all of which trigger a cascade of inflammatory responses that exacerbate brain damage. Hence, tight regulation and maintenance of neurovascular coupling is central for brain homeostasis. This review article also discusses the waste clearance pathways in the brain such as the glymphatic system. The glymphatic system is a functional waste clearance pathway that removes metabolic wastes and neurotoxins from the brain along paravascular channels. Disruption of the glymphatic system burdens the brain with accumulating waste and has been reported in aging as well as several neurological diseases. PMID:27374823

  19. Sex Steroids Influence Brain-Derived Neurotropic Factor Secretion From Human Airway Smooth Muscle Cells.

    Science.gov (United States)

    Wang, Sheng-Yu; Freeman, Michelle R; Sathish, Venkatachalem; Thompson, Michael A; Pabelick, Christina M; Prakash, Y S

    2016-07-01

    Brain derived neurotropic factor (BDNF) is emerging as an important player in airway inflammation, remodeling, and hyperreactivity. Separately, there is increasing evidence that sex hormones contribute to pathophysiology in the lung. BDNF and sex steroid signaling are thought to be intricately linked in the brain. There is currently little information on BDNF and sex steroid interactions in the airway but is relevant to understanding growth factor signaling in the context of asthma in men versus women. In this study, we assessed the effect of sex steroids on BDNF expression and secretion in human airway smooth muscle (ASM). Human ASM was treated with estrogen (E2 ) or testosterone (T, 10 nM each) and intracellular BDNF and secreted BDNF measured. E2 and T significantly reduced secretion of BDNF; effects prevented by estrogen and androgen receptor inhibitor, ICI 182,780 (1 μM), and flutamide (10 μM), respectively. Interestingly, no significant changes were observed in intracellular BDNF mRNA or protein expression. High affinity BDNF receptor, TrkB, was not altered by E2 or T. E2 (but not T) significantly increased intracellular cyclic AMP levels. Notably, Epac1 and Epac2 expression were significantly reduced by E2 and T. Furthermore, SNARE complex protein SNAP25 was decreased. Overall, these novel data suggest that physiologically relevant concentrations of E2 or T inhibit BDNF secretion in human ASM, suggesting a potential interaction of sex steroids with BDNF in the airway that is different from brain. The relevance of sex steroid-BDNF interactions may lie in their overall contribution to airway diseases such as asthma. J. Cell. Physiol. 231: 1586-1592, 2016. © 2015 Wiley Periodicals, Inc. PMID:26566264

  20. Correlation of Ultrastructural Changes of Endothelial Cells and Astrocytes Occurring during Blood Brain Barrier Damage after Traumatic Brain Injury with Biochemical Markers of Blood Brain Barrier Leakage and Inflammatory Response

    Czech Academy of Sciences Publication Activity Database

    Vajtr, D.; Benada, Oldřich; Kukačka, J.; Průša, R.; Houšťava, L.; Toupalík, P.; Kizek, R.

    2009-01-01

    Roč. 58, č. 2 (2009), s. 263-268. ISSN 0862-8408 Institutional research plan: CEZ:AV0Z50200510 Keywords : Blood brain barrier * Expansive contusion * Metalloproteinases Subject RIV: EE - Microbiology, Virology Impact factor: 1.430, year: 2009

  1. Modeling localized delivery of Doxorubicin to the brain following focused ultrasound enhanced blood-brain barrier permeability

    International Nuclear Information System (INIS)

    Doxorubicin (Dox) is a well-established chemotherapeutic agent, however it has limited efficacy in treating brain malignancies due to the presence of the blood-brain barrier (BBB). Recent preclinical studies have demonstrated that focused ultrasound induced BBB disruption (BBBD) enables efficient delivery of Dox to the brain. For future treatment planning of BBBD-based drug delivery, it is crucial to establish a mathematical framework to predict the effect of transient BBB permeability enhancement on the spatiotemporal distribution of Dox at the targeted area. The constructed model considers Dox concentrations within three compartments (plasma, extracellular, intracellular) that are governed by various transport processes (e.g. diffusion in interstitial space, exchange across vessel wall, clearance by cerebral spinal fluid, uptake by brain cells). By examining several clinical treatment aspects (e.g. sonication scheme, permeability enhancement, injection mode), our simulation results support the experimental findings of optimal interval delay between two consecutive sonications and therapeutically-sufficient intracellular concentration with respect to transfer constant Ktrans range of 0.01–0.03 min−1. Finally, the model suggests that infusion over a short duration (20–60 min) should be employed along with single-sonication or multiple-sonication at 10 min interval to ensure maximum delivery to the intracellular compartment while attaining minimal cardiotoxicity via suppressing peak plasma concentration. (paper)

  2. Cellular response of the blood-brain barrier to injury: Potential biomarkers and therapeutic targets for brain regeneration.

    Science.gov (United States)

    Tenreiro, M M; Ferreira, R; Bernardino, L; Brito, M A

    2016-07-01

    Endothelial cells are the main component of the blood-brain barrier (BBB), a vital structure for maintaining brain homeostasis that is seriously disrupted in various neurological pathologies. Therefore, vascular-targeted therapies may bring advantages for the prevention and treatment of brain disorders. In this sense, novel methods to identify and evaluate endothelial damage have been developed and include the detection of circulating endothelial cells, endothelial progenitor cells, endothelial microparticles and exosomes. These cells and cellular structures have been documented in numerous diseases, and increasingly in neurodegenerative disorders, which have led many to assume that they can either be possible biomarkers or tools of repair. Therefore, the purpose of this review is to discuss available data on BBB endothelial damage occurring in two pathologies of the central nervous system, Alzheimer's disease and stroke, which exemplify conditions where chronic and acute vascular damage occur, respectively. The ultimate goal is to identify useful biomarkers and/or therapeutic tools in the healthy and diseased brain that can be used for the treatment of neurodegenerative diseases where BBB permeability and integrity are impaired. PMID:26996728

  3. Mesenchymal Stem Cells Regulate Blood Brain Barrier Integrity in Traumatic Brain Injury Through Production of the Soluble Factor TIMP3

    Science.gov (United States)

    Menge, Tyler; Zhao, Yuhai; Zhao, Jing; Wataha, Kathryn; Geber, Michael; Zhang, Jianhu; Letourneau, Phillip; Redell, John; Shen, Li; Wang, Jing; Peng, Zhalong; Xue, Hasen; Kozar, Rosemary; Cox, Charles S.; Khakoo, Aarif Y.; Holcomb, John B.; Dash, Pramod K.; Pati, Shibani

    2013-01-01

    Mesenchymal stem cells (MCSs) have been shown to have therapeutic potential in multiple disease states associated with vascular instability including traumatic brain injury (TBI). In the present study, Tissue Inhibitor of Matrix Metalloproteinase-3 (TIMP3) is identified as the soluble factor produced by MSCs that can recapitulate the beneficial effects of MSCs on endothelial function and blood brain barrier (BBB) compromise in TBI. Attenuation of TIMP3 expression in MSCs completely abrogates the effect of MSCs on BBB permeability and stability, while intravenous administration of rTIMP3 alone can inhibit BBB permeability in TBI. Our results demonstrate that MSCs increase circulating levels of soluble TIMP3, which inhibits VEGF-A induced breakdown of endothelial AJs in vitro and in vivo. These findings elucidate a clear molecular mechanism for the effects of MSCs on the BBB in TBI, and directly demonstrate a role for TIMP3 in regulation of BBB integrity. PMID:23175708

  4. Dietary Virgin Olive Oil Reduces Blood Brain Barrier Permeability, Brain Edema, and Brain Injury in Rats Subjected to Ischemia-Reperfusion

    Directory of Open Access Journals (Sweden)

    Fatemeh Mohagheghi

    2010-01-01

    Full Text Available Recent studies suggest that dietary virgin olive oil (VOO reduces hypoxia-reoxygenation injury in rat brain slices. We sought to extend these observations in an in vivo study of rat cerebral ischemia-reperfusion injury. Four groups, each consisting of 18 Wistar rats, were studied. One group (control received saline, while three treatment groups received oral VOO (0.25, 0.5, and 0.75 mL/kg/day, respectively. After 30 days, blood lipid profiles were determined, before a 60-min period of middle cerebral artery occlusion (MCAO. After 24-h reperfusion, neurological deficit scores, infarct volume, brain edema, and blood brain barrier permeability were each assessed in subgroups of six animals drawn from each main group. VOO reduced the LDL/HDL ratio in doses of 0.25, 0.5, and 0.75 mL/kg/day in comparison to the control group (p < 0.05, and offered cerebroprotection from ischemia-reperfusion. For controls vs. doses of 0.25 vs. 0.5 vs. 0.75 mL/kg/day, attenuated corrected infarct volumes were 207.82 ± 34.29 vs. 206.41 ± 26.23 vs. 124.21 ± 14.73 vs. 108.46 ± 31.63 mm3; brain water content of the infarcted hemisphere was 82 ±± 0.25 vs. 81.5 ± 0.56 vs. 80.5 ± 0.22 vs. 80.5 ± 0.34%; and blood brain barrier permeability of the infarcted hemisphere was 11.31 ± 2.67 vs. 9.21 ± 2.28 vs. 5.83 ± 1.6 vs. 4.43 ± 0.93 µg/g tissue (p < 0.05 for measures in doses 0.5 and 0.75 mL/kg/day vs. controls. Oral administration of VOO reduces infarct volume, brain edema, blood brain barrier permeability, and improves neurologic deficit scores after transient MCAO in rats.

  5. Insulin Detemir is Not Transported Across the Blood-Brain Barrier

    OpenAIRE

    Banks, William A.; Morley, John E.; Lynch, Jessica L.; Lynch, Kristin M.; Mooradian, Arshag D.

    2010-01-01

    Insulin detemir has a different profile of action on the central nervous system (CNS) than human insulin. It has been hypothesized that this is caused by an altered ability of insulin detemir to cross the blood-brain barrier (BBB). Here, we measured the permeability of the BBB to insulin detemir. We labeled insulin detemir with radioactive iodine (I-Det) and examined its ability to cross the BBB of the mouse. Permeation was assessed after intravenous injection and by brain perfusion in the pr...

  6. In Situ Blood-Brain Barrier Permeability of a C-10 Paclitaxel Carbamate

    OpenAIRE

    Ballatore, Carlo; Zhang, Bin; Trojanowski, John Q.; Lee, Virginia M.-Y.; Smith, Amos B.

    2008-01-01

    We report the synthesis and blood-brain barrier (BBB) permeability of 14C-CNDR-29, a paclitaxel C-10 carbamate derivative shown to be devoid of P-glycoprotein (Pgp)-interactions, in an in situ mouse brain perfusion model, in comparison with 14C-paclitaxel. The results presented reveal a 3–4 fold higher BBB-permeability for the C-10 modified taxane compared to paclitaxel. These results support the notion that circumvention of Pgp-mediated efflux can lead to higher BBB-permeability. Further stu...

  7. Mitochondrial energetic metabolism perturbations in skeletal muscles and brain of zebrafish (Danio rerio) exposed to low concentrations of waterborne uranium

    International Nuclear Information System (INIS)

    Anthropogenic release of uranium (U), originating from the nuclear fuel cycle or military activities, may considerably increase U concentrations in terrestrial and aquatic ecosystems above the naturally occurring background levels found throughout the environment. With a projected increase in the world-wide use of nuclear power, it is important to improve our understanding of the possible effects of this metal on the aquatic fauna at concentrations commensurate with the provisional drinking water guideline value of the World Health Organization (15 μg U/L). The present study has examined the mitochondrial function in brain and skeletal muscles of the zebrafish, Danio rerio, exposed to 30 and 100 μg/L of waterborne U for 10 and 28 days. At the lower concentration, the basal mitochondrial respiration rate was increased in brain at day 10 and in muscles at day 28. This is due to an increase of the inner mitochondrial membrane permeability, resulting in a decrease of the respiratory control ratio. In addition, levels of cytochrome c oxidase subunit IV (COX-IV) increased in brain at day 10, and those of COX-I increased in muscles at day 28. Histological analyses performed by transmission electron microscopy revealed an alteration of myofibrils and a dilatation of endomysium in muscle cells. These effects were largest at the lowest concentration, following 28 days of exposure.

  8. Continuous measurement of boron-10 concentration in rabbit brain tissue and blood using prompt gamma-ray spectrometry

    International Nuclear Information System (INIS)

    One of the important factors which influence the efficacy of boron neutron capture therapy (BNCT) in patients with malignant brain tumor is the boron-10 concentrations in tumors. The boron-10 concentration in normal brain tissue and the tumor/blood concentration in normal brain tissue and the tumor/blood concentration ratio are also valuable factors to decide the irradiation time and protect the normal tissue from radiation injury. Therefore, it is valuable to know the boron-10 concentration in the tumor, normal brain tissue and blood just before and during neutron irradiation. In this study the authors investigated continuously the boron-10 concentrations in the normal brain tissue of living rabbits and blood for 5-24 hours after injection of boron-10 compound using prompt gamma-ray spectrometry

  9. Hemopressins and other hemoglobin-derived peptides in mouse brain: Comparison between brain, blood, and heart peptidome and regulation in Cpefat/fat mice

    OpenAIRE

    Gelman, Julia S.; Sironi, Juan; Castro, Leandro M.; Ferro, Emer S.; Fricker, Lloyd D.

    2010-01-01

    Many hemoglobin-derived peptides are present in mouse brain, and several of these have bioactive properties including the hemopressins, a related series of peptides that bind to cannabinoid CB1 receptors. Although hemoglobin is a major component of red blood cells, it is also present in neurons and glia. To examine whether the hemoglobin-derived peptides in brain are similar to those present in blood and heart, we used a peptidomics approach involving mass spectrometry. Many hemoglobin-derive...

  10. Control of the blood-brain barrier function in cancer cell metastasis.

    Science.gov (United States)

    Blecharz, Kinga G; Colla, Ruben; Rohde, Veit; Vajkoczy, Peter

    2015-10-01

    Cerebral metastases are the most common brain neoplasms seen clinically in the adults and comprise more than half of all brain tumours. Actual treatment options for brain metastases that include surgical resection, radiotherapy and chemotherapy are rarely curative, although palliative treatment improves survival and life quality of patients carrying brain-metastatic tumours. Chemotherapy in particular has also shown limited or no activity in brain metastasis of most tumour types. Many chemotherapeutic agents used systemically do not cross the blood-brain barrier (BBB), whereas others may transiently weaken the BBB and allow extravasation of tumour cells from the circulation into the brain parenchyma. Increasing evidence points out that the interaction between the BBB and tumour cells plays a key role for implantation and growth of brain metastases in the central nervous system. The BBB, as the tightest endothelial barrier, prevents both early detection and treatment by creating a privileged microenvironment. Therefore, as observed in several in vivo studies, precise targetting the BBB by a specific transient opening of the structure making it permeable for therapeutic compounds, might potentially help to overcome this difficult clinical problem. Moreover, a better understanding of the molecular features of the BBB, its interrelation with metastatic tumour cells and the elucidation of cellular mechanisms responsible for establishing cerebral metastasis must be clearly outlined in order to promote treatment modalities that particularly involve chemotherapy. This in turn would substantially expand the survival and quality of life of patients with brain metastasis, and potentially increase the remission rate. Therefore, the focus of this review is to summarise the current knowledge on the role and function of the BBB in cancer metastasis. PMID:26032862

  11. Nonparenchymal cells cultivated from explants of fibrotic liver resemble endothelial and smooth muscle cells from blood vessel walls

    International Nuclear Information System (INIS)

    Tissue specimens from human fibrotic liver obtained by needle biopsy were cultured. Two cell types emerged from the tissue explants. From their morphology and biosynthetic products they resembled smooth muscle cells and endothelial cells from blood vessel walls. In the endothelial cells, factor VIII-associated protein was demonstrated by indirect immunofluorescence. Synthesis of collagen types I and III, basement membrane collagen types IV and V, and fibronectin by both cell types was observed by immunofluorescence microscopy. Homogeneous cultures of smooth muscle cells were observed in subcultures. After incubation with [14C]glycine, collagen was isolated and characterized by CM cellulose chromatography, and consisted mainly of types I and III. These data suggest involvement of mesenchymal cells in hepatic fibrosis; they presumably originate from blood vessel or sinusoidal walls

  12. Optically enhanced blood-brain-barrier crossing of plasmonic-active nanoparticles in preclinical brain tumor animal models

    Science.gov (United States)

    Yuan, Hsiangkuo; Wilson, Christy M.; Li, Shuqin; Fales, Andrew M.; Liu, Yang; Grant, Gerald; Vo-Dinh, Tuan

    2014-02-01

    Nanotechnology provides tremendous biomedical opportunities for cancer diagnosis, imaging, and therapy. In contrast to conventional chemotherapeutic agents where their actual target delivery cannot be easily imaged, integrating imaging and therapeutic properties into one platform facilitates the understanding of pharmacokinetic profiles, and enables monitoring of the therapeutic process in each individual. Such a concept dubbed "theranostics" potentiates translational research and improves precision medicine. One particular challenging application of theranostics involves imaging and controlled delivery of nanoplatforms across blood-brain-barrier (BBB) into brain tissues. Typically, the BBB hinders paracellular flux of drug molecules into brain parenchyma. BBB disrupting agents (e.g. mannitol, focused ultrasound), however, suffer from poor spatial confinement. It has been a challenge to design a nanoplatform not only acts as a contrast agent but also improves the BBB permeation. In this study, we demonstrated the feasibility of plasmonic gold nanoparticles as both high-resolution optical contrast agent and focalized tumor BBB permeation-inducing agent. We specifically examined the microscopic distribution of nanoparticles in tumor brain animal models. We observed that most nanoparticles accumulated at the tumor periphery or perivascular spaces. Nanoparticles were present in both endothelial cells and interstitial matrices. This study also demonstrated a novel photothermal-induced BBB permeation. Fine-tuning the irradiating energy induced gentle disruption of the vascular integrity, causing short-term extravasation of nanomaterials but without hemorrhage. We conclude that our gold nanoparticles are a powerful biocompatible contrast agent capable of inducing focal BBB permeation, and therefore envision a strong potential of plasmonic gold nanoparticle in future brain tumor imaging and therapy.

  13. The Role of Lumbar Sympathetic Nerves in Regulation of Blood Flow to Skeletal Muscle during Anaphylactic Hypotension in Anesthetized Rats.

    Directory of Open Access Journals (Sweden)

    Jie Song

    Full Text Available During hypovolemic shock, skeletal muscle blood flow could be redistributed to vital organs via vasoconstriction in part evoked by activation of the innervating sympathetic nerve activity. However, it is not well known whether this mechanism operates during anaphylactic shock. We determined the femoral artery blood flow (FBF and lumbar sympathetic nerve activity (LSNA mainly regulating the hindquater muscle blood flow during anaphylactic hypotension in anesthetized rats. Anesthetized Sprague-Dawley rats were randomly allocated to the following groups (n = 7/group: (1 non-sensitized, (2 anaphylaxis, (3 anaphylaxis-lumbar sympathectomy (LS and (4 anaphylaxis-sinoaortic denervation (SAD groups. Anaphylaxis was induced by an intravenous injection of the ovalbumin antigen to the sensitized rats. The systemic arterial pressure (SAP, heart rate (HR, central venous pressure (CVP, FBF and LSNA were continuously measured. In the anaphylaxis group, LSNA and HR increased, while SAP and FBF decreased after antigen injection. In the anaphylaxis-SAD group, LSNA did not significantly change during the early phase, but the responses of SAP and FBF were similar to those in the anaphylaxis group. In the anaphylaxis-LS group, both FBF and SAP decreased similarly to the anaphylaxis group during anaphylactic hypotension. These results indicated that LSNA increased via baroreceptor reflex, but this sympathoexcitation or LS did not affect antigen-induced decreases in FBF or SAP. Lumbar sympathetic nerves are not involved in regulation of the blood flow to the hindlimb or systemic blood pressure during anaphylactic hypotension in anesthetized rats.

  14. Leg crossing with muscle tensing, a physical counter-manoeuvre to prevent syncope, enhances leg blood flow

    OpenAIRE

    2006-01-01

    Abstract In patients with orthostatic intolerance the mechanisms to maintain blood pressure fail. A physical counter-manoeuvre to postpone or even prevent orthostatic intolerance in these patients is leg crossing combined with muscle tensing. Although the central haemodynamic effects of physical counter-manoeuvres are well documented, not much is known about the peripheral haemodynamic events. Therefore, the purpose of the present study was to examine the peripheral haemodynamic ef...

  15. Muscle blood flow after amputation with special reference to the influence of osseous plugging of the medullary cavity

    International Nuclear Information System (INIS)

    The muscle blood flow (MBF) in rabbits, subjectd to amputation of the crus was assessed by means of 133 Xenon and Histamine. It was shown that after the operation the flow in the amputation stump was initially reduced. MBF in the stump increased more rapidly and stayed at a higher level after closure by myoplasty than after amputation without myoplasty, and it was still further stimulated after osseous plugging of the medullary cavity. (author)

  16. Management of initial orthostatic hypotension: lower body muscle tensing attenuates the transient arterial blood pressure decrease upon standing from squatting

    OpenAIRE

    Go-Schön, Ingeborg K.; Kim, Yu-Sok; Linzer, Mark; van Lieshout, Johannes J.; Wieling, Wouter; Krediet, C. T. Paul

    2007-01-01

    Abstract Initial orthostatic hypotension (IOH) comprises symptoms of cerebral hypoperfusion caused by an abnormally large transient mean arterial blood pressure (MAP) decrease 5-15 s after arising from a supine, sitting or squatting position. Few treatment options are available. We set out to test the hypothesis that lower body muscle tensing (LBMT) attenuates IOH after rising from squatting and its symptoms in daily life. Thirteen IOH patients (9 males, 27 years) rose twice from s...

  17. Two levels of MCT1 and CD147 expression in the equine red blood cells and muscle

    OpenAIRE

    Koho, Ninna

    2011-01-01

    Monocarboxylate transporters (MCTs), especially the isoforms MCT1 - MCT4, cotransport lactate and protons across the cell membranes. They are thus essential for pH regulation and homeostasis in glycolytic cells such as red blood cells (RBCs), and skeletal muscle cells during intense exercise. In 70% of the Standardbred horses the lactate transport activity (TA) in RBCs is high and transport is mediated mainly by MCTs. In the rest 30% of the Standardbreds MCT mediated transport route is not ac...

  18. Quantitation of blood-brain barrier defect by magnetic resonance imaging and gadolinium-DTPA in patients with multiple sclerosis and brain tumors

    DEFF Research Database (Denmark)

    Larsson, H B; Stubgaard, M; Frederiksen, J L;

    1990-01-01

    In this study quantitation of the degree of deficiency of the blood-brain barrier (BBB) in patients with multiple sclerosis or brain tumors, by using MRI, is shown to be possible. As a measure of permeability of the BBB to Gadolinium-DTPA (Gd-DTPA) the flux per unit of distribution volume per uni...... treatments in intracranial diseases....

  19. Distribution of dearomatised white spirit in brain, blood, and fat tissue after repeated exposure of rats

    DEFF Research Database (Denmark)

    Lof, A.; Lam, Henrik Rye; Gullstrand, E.;

    1999-01-01

    white spirit was 1.5 and 5.6 mg/kg in blood; 7.1 and 17.1 mg/kg in brain; 432 and 1452 mg/kg in fat tissue at the exposure levels of 400 and 800 p.p.m., respectively. The concentrations of n-nonane, n-decane, n-undecane, and total white spirit in blood and brain were not affected by the duration of......-undecane, and total white spirit increased during the 3 weeks of exposure. The time to reach steady-state concentrations is longer than 3 weeks. After the 3 weeks' exposure the fat tissue concentration of n-nonane, n-decane, n-undecane, and total white spirit decreased very slowly compared with the rate of...

  20. Trafficking of Endogenous Immunoglobulins by Endothelial Cells at the Blood-Brain Barrier.

    Science.gov (United States)

    Villaseñor, Roberto; Ozmen, Laurence; Messaddeq, Nadia; Grüninger, Fiona; Loetscher, Hansruedi; Keller, Annika; Betsholtz, Christer; Freskgård, Per-Ola; Collin, Ludovic

    2016-01-01

    The Blood-Brain Barrier (BBB) restricts access of large molecules to the brain. The low endocytic activity of brain endothelial cells (BECs) is believed to limit delivery of immunoglobulins (IgG) to the brain parenchyma. Here, we report that endogenous mouse IgG are localized within intracellular vesicles at steady state in BECs in vivo. Using high-resolution quantitative microscopy, we found a fraction of endocytosed IgG in lysosomes. We observed that loss of pericytes (key components of the BBB) in pdgf-b(ret/ret) mice affects the intracellular distribution of endogenous mouse IgG in BECs. In these mice, endogenous IgG was not detected within lysosomes but instead accumulate at the basement membrane and brain parenchyma. Such IgG accumulation could be due to reduced lysosomal clearance and increased sorting to the abluminal membrane of BECs. Our results suggest that, in addition to low uptake from circulation, IgG lysosomal degradation may be a downstream mechanism by which BECs further restrict IgG access to the brain. PMID:27149947

  1. Expression of Astrocytic Type 2 Angiotensin Receptor in Central Nervous System Inflammation Correlates With Blood-Brain Barrier Breakdown

    DEFF Research Database (Denmark)

    Füchtbauer, Laila; Toft-Hansen, Henrik; Khorooshi, Reza;

    2010-01-01

    The blood-brain barrier (BBB), a complex of endothelial and glial barriers, controls passage of cells and solutes between the blood and central nervous system (CNS). Blood-brain barrier breakdown refers to entry of cells and/or solutes. We were interested whether the renin-angiotensin system is...... involved during BBB breakdown. We studied the type 2 angiotensin receptor AT(2) because of its suggested neuroprotective role. Two models of brain inflammation were used to distinguish solute versus cellular barrier functions. Both leukocytes and horseradish peroxidase (HRP) accumulated in the perivascular...

  2. Cellular Apoptosis and Blood Brain Barrier Permeability Changes in the Pre-Incubated Chicken Embryo’s Brain by Effect of Electromagnetic Fields

    OpenAIRE

    Sima Kalantari; Mohammad Reza Bigdeli; Maryam Shams-Lahijani

    2015-01-01

    Background: Electromagnetic fields (EMF) have teratogenic effects during the embryonic development. In current study, histopathological and physiological effects of sinusoidal EMF on the brain were investigated. We sought to determine the apoptosis level and changes in blood brain barrier permeability in brain tissue of pre-incubated white leghorn hen eggs in the field of EMF. Materials and Methods: In this experimental study, 300 healthy, fresh, and fertilized eggs (55-65 g) were divided ...

  3. Estrogen provides neuroprotection against brain edema and blood brain barrier disruption through both estrogen receptors α and β following traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Vida Naderi

    2015-02-01

    Full Text Available Objective(s:Estrogen (E2 has neuroprotective effects on blood-brain-barrier (BBB after traumatic brain injury (TBI. In order to investigate the roles of estrogen receptors (ERs in these effects, ER-α antagonist (MPP and, ER-β antagonist (PHTPP, or non-selective estrogen receptors antagonist (ICI 182780 were administered. Materials and Methods: Ovariectomized rats were divided into 10 groups, as follows: Sham, TBI, E2, oil, MPP+E2, PHTPP+E2, MPP+PHTPP+E2, ICI+E2, MPP, and DMSO. E2 (33.3 µg/Kg or oil were administered 30 min after TBI. 1 dose (150 µg/Kg of each of MPP, PHTPP, and (4 mg/kg ICI182780 was injected two times, 24 hr apart, before TBI and estrogen treatment. BBB disruption (Evans blue content and brain edema (brain water content evaluated 5 hr and 24 hr after the TBI were evaluated, respectively. Results: The results showed that E2 reduced brain edema after TBI compared to vehicle (P

  4. Tailored delivery of analgesic ziconotide across a blood brain barrier model using viral nanocontainers

    OpenAIRE

    Prachi Anand; Alison O’Neil; Emily Lin; Trevor Douglas; Mandë Holford

    2015-01-01

    The blood brain barrier (BBB) is often an insurmountable obstacle for a large number of candidate drugs, including peptides, antibiotics, and chemotherapeutic agents. Devising an adroit delivery method to cross the BBB is essential to unlocking widespread application of peptide therapeutics. Presented here is an engineered nanocontainer for delivering peptidic drugs across the BBB encapsulating the analgesic marine snail peptide ziconotide (Prialt®). We developed a bi-functional viral nanocon...

  5. Implications of MMP9 for Blood Brain Barrier Disruption and Hemorrhagic Transformation Following Ischemic Stroke

    OpenAIRE

    Renée J Turner; Sharp, Frank R.

    2016-01-01

    Numerous studies have documented increases in matrix metalloproteinases (MMPs), specifically MMP-9 levels following stroke, with such perturbations associated with disruption of the blood brain barrier (BBB), increased risk of hemorrhagic complications, and worsened outcome. Despite this, controversy remains as to which cells release MMP-9 at the normal and pathological BBB, with even less clarity in the context of stroke. This may be further complicated by the influence of tissue plasminogen...

  6. Effect of monocrotaline on blood-brain barrier permeability in rats

    OpenAIRE

    Coll, Carlos; Fernández, María Alejandra; Coll, Sebastián; Coll, Tamara; Malliardi, Pablo; Perazzo, Juan; Filinger, Ester Julia; Lemberg, Abraham

    2011-01-01

    We studied if monocrotaline (MCT) portal hypertensive model modifies blood-brain barrier (BBB) condition. Male Wistar rats were used: Group MCT injected i.p. with MCT (60 mg/kg of body weight) and Group Sham (GS) with saline. Forty-four days after injection rats were sacrificed. Trypan blue and Evans blue tests were performed to evaluate BBB integrity in both groups. In cerebrospinal fluid (CF), protein and glucose were determined. Alanine aminotransferase (ALT), aspartate aminotransferase (A...

  7. The Effects of Psychostimulant Drugs on Blood Brain Barrier Function and Neuroinflammation

    OpenAIRE

    Kousik, Sharanya M.; T. Celeste eNapier; Carvey, Paul M.

    2012-01-01

    The blood brain barrier (BBB) is a highly dynamic interface between the central nervous system (CNS) and periphery. The BBB is comprised of a number of components and is part of the larger neuro(glio)vascular unit. Current literature suggests that psychostimulant drugs of abuse alter the function of the BBB which likely contributes to the neurotoxicities associated with these drugs. In both preclinical and clinical studies, psychostimulants including methamphetamine, MDMA, cocaine, and nicoti...

  8. MicroRNA-155 negatively affects blood-brain barrier function during neuroinflammation.

    OpenAIRE

    Lopez-Ramirez, Miguel Alejandro; Wu, Dongsheng; Pryce, Gareth; Julie E Simpson; Reijerkerk, Arie; King-Robson, Josh; Kay, Oliver; de Vries, Helga E.; Hirst, Mark C; Sharrack, Basil; Baker, David; Male, David Kingsley; Michael, Gregory J.; Romero, Ignacio Andres

    2014-01-01

    Blood-brain barrier (BBB) dysfunction is a hallmark of neurological conditions such as multiple sclerosis (MS) and stroke. However, the molecular mechanisms underlying neurovascular dysfunction during BBB breakdown remain elusive. MicroRNAs (miRNAs) have recently emerged as key regulators of pathogenic responses, although their role in central nervous system (CNS) microvascular disorders is largely unknown. We have identified miR-155 as a critical miRNA in neuroinflammation at the BBB. miR-15...

  9. MAPK and pro-inflammatory mediators in the walls of brain blood vessels following cerebral ischemia

    OpenAIRE

    Maddahi, Aida

    2012-01-01

    INTRODUCTION Stroke is a serious neurological disease which may lead to death and severe disability [1, 2]. There are two major types of stroke: ischemic and hemorrhagic stroke. Both are associated with disruption of blood flow to a part of the brain with rapid depletion of cellular energy and oxygen, resulting in ionic disturbances and eventually neuronal cell death [3]. The pathologic process that develops after stroke is divided into acute (within hours), sub-acute (hours to days), ...

  10. Increases in muscle sympathetic nerve activity, heart rate, respiration and skin blood flow during passive viewing of exercise

    Directory of Open Access Journals (Sweden)

    RachaelBrown

    2013-06-01

    Full Text Available The cardiovascular and respiratory effects of exercise have been widely studied, as have the autonomic effects of imagined and observed exercise. However, the effects of observed exercise in the first person have not been documented, nor have direct recordings of muscle sympathetic nerve activity (MSNA been obtained during observed or imagined exercise. The aim of the current study was to measure blood pressure, heart rate, respiration, skin blood flow, sweat release and muscle sympathetic nerve activity (via microelectrodes inserted into the common peroneal nerve, during observation of exercise from the first person point of view. It was hypothesised that the moving stimuli would produce robust compensatory increases in the above-mentioned parameters as effectively as those generated by mental imagery and - to a lesser extent - actual exercise. Nine subjects watched a first-person running video, allowing them to view the action from the perspective of the runner rather than viewing someone else perform the exercise. On average, statistically significant increases from baseline during the running phase were seen in heart rate, respiratory rate, skin blood flow and burst amplitude of muscle sympathetic nerve activity. These results suggest that observation of exercise in the first person is a strong enough stimulus to evoke “physiologically appropriate” autonomic responses that have a purely psychogenic origin.

  11. Iron supplement prevents lead-induced disruption of the blood-brain barrier during rat development

    International Nuclear Information System (INIS)

    Children are known to be venerable to lead (Pb) toxicity. The blood-brain barrier (BBB) in immature brain is particularly vulnerable to Pb insults. This study was designed to test the hypothesis that Pb exposure damaged the integrity of the BBB in young animals and iron (Fe) supplement may prevent against Pb-induced BBB disruption. Male weanling Sprague-Dawley rats were divided into four groups. Three groups of rats were exposed to Pb in drinking water containing 342 μg Pb/mL as Pb acetate, among which two groups were concurrently administered by oral gavage once every other day with 7 mg Fe/kg and 14 mg Fe/kg as FeSO4 solution as the low and high Fe treatment group, respectively, for 6 weeks. The control group received sodium acetate in drinking water. Pb exposure significantly increased Pb concentrations in blood by 6.6-folds (p < 0.05) and brain tissues by 1.5-2.0-folds (p < 0.05) as compared to controls. Under the electron microscope, Pb exposure in young animals caused an extensive extravascular staining of lanthanum nitrate in brain parenchyma, suggesting a leakage of cerebral vasculature. Western blot showed that Pb treatment led to 29-68% reduction (p < 0.05) in the expression of occludin as compared to the controls. Fe supplement among Pb-exposed rats maintained the normal ultra-structure of the BBB and restored the expression of occludin to normal levels. Moreover, the low dose Fe supplement significantly reduced Pb levels in blood and brain tissues. These data suggest that Pb exposure disrupts the structure of the BBB in young animals. The increased BBB permeability may facilitate the accumulation of Pb. Fe supplement appears to protect the integrity of the BBB against Pb insults, a beneficial effect that may have significant clinical implications

  12. Autoradiographic evidence for passage of vincamine through the blood-brain barrier

    Energy Technology Data Exchange (ETDEWEB)

    Sprumont, P.; Lintermans, J.

    1982-01-01

    Autoradiographies of the brain and of the cerebellum were performed in 8-month old rats after intraperitoneal injection of /sup 3/H-labelled vincamine. Only those samples that were processed by freezedrying or by freezesubstitution gave interpretable results. Some specifically labelled cells were found in the molecular layer of the cerebellar cortex as well as in the internal granular and in the deeper layers of the cerebral cortex. They did not belong to the vascular system. It was concluded that vincamine or its metabolites crosses the blood-brain barrier. Any attempt to explain a possible action of the substance on the brain function should thus also consider the cellular components of the central nervous system and not only the haemodynamics of the cerebral circulation.

  13. Autoradiographic evidence for passage of vincamine through the blood-brain barrier

    International Nuclear Information System (INIS)

    Autoradiographies of the brain and of the cerebellum were performed in 8-month old rats after intraperitoneal injection of 3H-labelled vincamine. Only those samples that were processed by freezedrying or by freezesubstitution gave interpretable results. Some specifically labelled cells were found in the molecular layer of the cerebellar cortex as well as in the internal granular and in the deeper layers of the cerebral cortex. They did not belong to the vascular system. It was concluded that vincamine or its metabolites crosses the blood-brain barrier. Any attempt to explain a possible action of the substance on the brain function should thus also consider the cellular components of the central nervous system and not only the haemodynamics of the cerebral circulation. (orig.)

  14. Measurement and pharmacokinetics of vincamine in rat blood and brain using microdialysis.

    Science.gov (United States)

    Juan, Ying-Ping; Tsai, Tung-Hu

    2005-09-23

    Vincamine is an alkaloid compound derived from the Vinca minor plant. Since little is known concerning its pharmacokinetics and appropriate analytical method, this study focuses on its pharmacokinetics as well the possible roles of the multidrug transporter P-glycoprotein on its distribution and disposition. We develop a rapid and sensitive method using a microdialysis coupled with liquid chromatography for the concurrent determination of unbound vincamine in rat blood and brain. Microdialysis probes were simultaneously inserted into the jugular vein toward heart and brain hippocampus of male Sprague-Dawley rats for sampling in biological fluids following the administration of vincamine (10 and 30 mg/kg) through the femoral vein. Samples were eluted with a mobile phase containing methanol-1% diethylamine (pH 7.15) in water (75:25, v/v) and the flow rate of the mobile phase was 0.7 ml/min. Pharmacokinetic parameters of vincamine were derived using compartmental model. The decline of protein-unbound vincamine in the hippocampus and blood suggested that there was rapid exchange and equilibration between the peripheral compartment and the central nervous system. In the presence of cyclosporine, unbound vincamine levels in both blood and brain were significantly increased. PMID:16130744

  15. Ictal lack of binding to brain parenchyma suggests integrity of the blood-brain barrier for 11C-dihydroergotamine during glyceryl trinitrate-induced migraine.

    Science.gov (United States)

    Schankin, Christoph J; Maniyar, Farooq H; Seo, Youngho; Kori, Shashidar; Eller, Michael; Chou, Denise E; Blecha, Joseph; Murphy, Stephanie T; Hawkins, Randall A; Sprenger, Till; VanBrocklin, Henry F; Goadsby, Peter J

    2016-07-01

    SEE DREIER DOI 101093/AWW112 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: For many decades a breakdown of the blood-brain barrier has been postulated to occur in migraine. Hypothetically this would facilitate access of medications, such as dihydroergotamine or triptans, to the brain despite physical properties otherwise restricting their entry. We studied the permeability of the blood-brain barrier in six migraineurs and six control subjects at rest and during acute glyceryl trinitrate-induced migraine attacks using positron emission tomography with the novel radioligand (11)C-dihydroergotamine, which is chemically identical to pharmacologically active dihydroergotamine. The influx rate constant Ki, average dynamic image and time activity curve were assessed using arterial blood sampling and served as measures for receptor binding and thus blood-brain barrier penetration. At rest, there was binding of (11)C-dihydroergotamine in the choroid plexus, pituitary gland, and venous sinuses as expected from the pharmacology of dihydroergotamine. However, there was no binding to the brain parenchyma, including the hippocampus, the area with the highest density of the highest-affinity dihydroergotamine receptors, and the raphe nuclei, a postulated brainstem site of action during migraine, suggesting that dihydroergotamine is not able to cross the blood-brain barrier. This binding pattern was identical in migraineurs during glyceryl trinitrate-induced migraine attacks as well as in matched control subjects. We conclude that (11)C-dihydroergotamine is unable to cross the blood-brain barrier interictally or ictally demonstrating that the blood-brain barrier remains tight for dihydroergotamine during acute glyceryl trinitrate-induced migraine attacks. PMID:27234268

  16. A stable and reproducible human blood-brain barrier model derived from hematopoietic stem cells.

    Directory of Open Access Journals (Sweden)

    Romeo Cecchelli

    Full Text Available The human blood brain barrier (BBB is a selective barrier formed by human brain endothelial cells (hBECs, which is important to ensure adequate neuronal function and protect the central nervous system (CNS from disease. The development of human in vitro BBB models is thus of utmost importance for drug discovery programs related to CNS diseases. Here, we describe a method to generate a human BBB model using cord blood-derived hematopoietic stem cells. The cells were initially differentiated into ECs followed by the induction of BBB properties by co-culture with pericytes. The brain-like endothelial cells (BLECs express tight junctions and transporters typically observed in brain endothelium and maintain expression of most in vivo BBB properties for at least 20 days. The model is very reproducible since it can be generated from stem cells isolated from different donors and in different laboratories, and could be used to predict CNS distribution of compounds in human. Finally, we provide evidence that Wnt/β-catenin signaling pathway mediates in part the BBB inductive properties of pericytes.

  17. Brain Atrophy, Anti-Smooth Muscle Antibody and Cognitive Impairment: An Association Study.

    Science.gov (United States)

    Giulia, Paroni; Michele, Lauriola; Andrea, Fontana; Grazia, D'Onofrio; Filomena, Ciccone; Francesco, Paris; Leandro, Cascavilla; Maria, Urbano; Carolina, Gravina; Massimiliano, Copetti; Antonio, Greco

    2016-08-01

    Cortical atrophy, neuronal loss, beta-amyloid deposition, neuritic plaques, and neurofibrillary tangles are neuropathological key features in the Alzheimer's disease (AD). Antibodies against beta-amyloid, neurotransmitters, microvascular endothelium components and microglial cells have been detected in AD serum suggesting that AD could be another autoimmune disease and provides a link between vascular pathology, endothelium dysfunction and neuronal cells death. Aim of the present study was to evaluate the association between autoantibody profile and cognitive impairment in geriatric patients, accounting for ApoE genotype as a potential confounding factor. Three hundred and forty-four geriatric patients, attending the clinic for the cognitive decline, underwent a biochemical and immunological profile, chest X-ray, cerebral computed tomography scan and complete cognitive evaluation. All patients were also screened for the ApoE genotype. A significantly higher prevalence of Anti-Smooth Muscle Antibody (ASMA) positivity was found in 89/204 (43.63%) patients with diagnosed neuroradiological signs of cerebral atrophy compared with 15/140 (10.71%) patients without the condition (page, gender and Mini-Mental State Examination (OR=8.25, 95%CI: 4.26-15.99) and achieved a good discriminatory power (c-statistic=0.783). Results were also independent of ApoE genotype, which resulted not associated both with the presence of brain atrophy and with the presence of ASMA positivity. Our results shows a strong association between brain atrophy and ASMA positivity and are consistent with several studies that focused attention on the mechanisms of endothelial immune response in the development of dementia. PMID:27493830

  18. Omega-3 polyunsaturated fatty acids mitigate blood-brain barrier disruption after hypoxic-ischemic brain injury.

    Science.gov (United States)

    Zhang, Wenting; Zhang, Hui; Mu, Hongfeng; Zhu, Wen; Jiang, Xiaoyan; Hu, Xiaoming; Shi, Yejie; Leak, Rehana K; Dong, Qiang; Chen, Jun; Gao, Yanqin

    2016-07-01

    Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been shown to protect the neonatal brain against hypoxic/ischemic (H/I) injury. However, the mechanism of n-3 PUFA-afforded neuroprotection is not well understood. One major determinant of H/I vulnerability is the permeability of the blood-brain barrier (BBB). Therefore, we examined the effects of n-3 PUFAs on BBB integrity after neonatal H/I. Female rats were fed a diet with or without n-3 PUFA enrichment from day 2 of pregnancy to 14days after parturition. H/I was introduced in 7day-old offspring. We observed relatively rapid BBB penetration of the small molecule cadaverine (640Da) at 4h post-H/I and a delayed penetration of larger dextrans (3kD-40kD) 24-48h after injury. Surprisingly, the neonatal BBB was impermeable to Evans Blue or 70kD dextran leakage for up to 48h post-H/I, despite evidence of IgG extravasation at this time. As expected, n-3 PUFAs ameliorated H/I-induced BBB damage, as shown by reductions in tracer efflux and IgG extravasation, preservation of BBB ultrastructure, and enhanced tight junction protein expression. Furthermore, n-3 PUFAs prevented the elevation in matrix metalloproteinase (MMP) activity in the brain and blood after H/I. Thus, n-3 PUFAs may protect neonates against BBB damage by blunting MMPs activation after H/I. PMID:26921472

  19. Human blood-brain barrier insulin-like growth factor receptor

    International Nuclear Information System (INIS)

    Insulin-like growth factor (IGF)-1 and IGF-2, may be important regulatory molecules in the CNS. Possible origins of IGFs in brain include either de novo synthesis or transport of circulating IGFs from blood into brain via receptor mediated transcytosis mechanisms at the brain capillary endothelial wall, ie, the blood-brain barrier (BBB). In the present studies, isolated human brain capillaries are used as an in vitro model system of the human BBB and the characteristics of IGF-1 or IGF-2 binding to this preparation were assessed. The total binding of IGF-2 at 37 degrees C exceeded 130% per mg protein and was threefold greater than the total binding for IGF-1. However, at 37 degrees C nonsaturable binding equaled total binding, suggesting that endocytosis is rate limiting at physiologic temperatures. Binding studies performed at 4 degrees C slowed endocytosis to a greater extent than membrane binding, and specific binding of either IGF-1 or IGF-2 was detectable. Scatchard plots for either peptide were linear and the molar dissociation constant of IGF-1 and IGF-2 binding was 2.1 +/- 0.4 and 1.1 +/- 0.1 nmol/L, respectively. Superphysiologic concentrations of porcine insulin inhibited the binding of both IGF-1 (ED50 = 2 micrograms/mL) and IGF-2 (ED50 = 0.5 microgram/mL). Affinity cross linking of 125I-IGF-1, 125I-IGF-2, and 125I-insulin to isolated human brain capillaries was performed using disuccinimidylsuberate (DSS). These studies revealed a 141 kd binding site for both IGF-1 and IGF-2, and a 133 kd binding site for insulin

  20. Comparison of blood variables, fiber intensity, and muscle metabolites in hot-boned muscles from electrical- and gas-stunned broilers.

    Science.gov (United States)

    Xu, L; Yue, H Y; Wu, S G; Zhang, H J; Ji, F; Zhang, L; Qi, G H

    2011-08-01

    The aim of this study was to compare the effects of gas stunning (GS) and electrical stunning (ES) on energy metabolism in Arbor Acres broilers. Thirty-six birds were slaughtered without stunning (control) or after stunning with the following treatments: 40% CO(2) + 21% O(2) + N(2) (G40%); 60% CO(2) + 21% O(2) + N(2) (G60%); 35 V, 47 mA, 400 Hz (E35V); 50 V, 67 mA, 160 Hz (E50V); and 65 V, 86 mA, 1,000 Hz (E65V). Muscle samples were obtained from the pectoralis major (breast) and tibialis anterior (leg) muscles in ambient temperature within 45 min postmortem and stored at -80°C. Blood pH decreased consistently with GS (G40% and G60%) compared with ES and the control (P 0.05) from ES at low current (E35V) in either breast or leg muscle. In conclusion, no essential difference in energy metabolism was found in broilers stunned with ES and GS when ES was based on low current and high frequency and GS was based on hypercapnic moderate oxygenation. This study indicated that G40% was potentially a superior stunning variable. PMID:21753223

  1. Influence of passive stretch on muscle blood flow, oxygenation and central cardiovascular responses in healthy young males.

    Science.gov (United States)

    Kruse, Nicholas T; Silette, Christopher R; Scheuermann, Barry W

    2016-05-01

    The aim of this study was to examine the effect of skeletal muscle stretching on peripheral, central, and autonomic cardiovascular responses in humans. Twelve healthy males completed a controlled passive stretch of the plantar flexors for 4 min at three different intensities. Doppler ultrasound velocimetry and imaging techniques assessed mean leg blood flow (MLBF), antegrade blood flow, and retrograde blood flow of the popliteal artery. Near-infrared spectroscopy assessed the concentration of deoxygenated hemoglobin + myoglobin ([HHb]) and the sum of its deoxygenated and oxygenated forms [i.e., blood volume ([Hbtot])]. Heart rate (HR) and mean arterial pressure were measured simultaneously to peripheral hemodynamic responses. During stretch there was an increase (P < 0.05) in antegrade and retrograde blood flow along with [HHb] and [Hbtot] relative to baseline, whereas MLBF was not altered. HR increased (P < 0.01) in a stretch intensity- and time-dependent manner, suggesting a threshold tension must be met that results in a mechanoreflex-mediated increase in HR. After stretch there was an increase (P < 0.05) in [Hbtot] and MLBF in each condition, suggesting that stretch creates a poststretch hyperemic response. Furthermore, retrograde blood flow was decreased (P < 0.05) after stretch in each stretch condition. Mean arterial pressure was decreased (P < 0.05) after moderate-intensity stretching. Collectively, our data provide novel mechanistic evidence on cardiovascular responses to skeletal muscle stretching in humans. Moreover, the reductions in MAP and retrograde blood flow suggest that stretch transiently reduces myogenic vascular tone in a poststretch resting period. PMID:26945077

  2. Autoregulation of spinal cord blood flow: is the cord a microcosm of the brain

    International Nuclear Information System (INIS)

    The autoregulatory capability of regional areas of the brain and spinal cord was demonstrated in 18 rats anesthetized with a continuous infusion of intravenous pentothal. Blood flow was measured by the injection of radioactive microspheres (Co57, Sn113, Ru103, Sc46). Blood flow measurements were made at varying levels of mean arterial pressure (MAP) which was altered by neosynephrine to raise MAP or trimethaphan to lower MAP. Autoregulation of the spinal cord mirrored that of the brain, with an autoregulatory range of 60 to 120 mm Hg for both tissues. Within this range, cerebral blood flow (CBF) was 59.2 +/- 3.2 ml/100 g/min (SEM) and spinal cord blood flow (SCBF) was 61.1 +/- 3.6. There was no significant difference in CBF and SCBF in the autoregulatory range. Autoregulation was also demonstrated regionally in the left cortex, right cortex, brainstem, thalamus, cerebellum, hippocampus and cervical, thoracic and lumbar cord. This data provides a coherent reference point in establishing autoregulatory curves under barbiturate anesthesia. Further investigation of the effects of other anesthetic agents on autoregulation of the spinal cord is needed. It is possible that intraspinal cord compliance, like intracranial compliance, might be adversely affected by the effects of anesthetics on autoregulation

  3. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis

    Directory of Open Access Journals (Sweden)

    Hunter Kerry

    2012-03-01

    Full Text Available Abstract Background Type 2 diabetes is a risk factor for Alzheimer's disease (AD, most likely linked to an impairment of insulin signalling in the brain. Therefore, drugs that enhance insulin signalling may have therapeutic potential for AD. Liraglutide (Victoza and exenatide (Byetta are novel long-lasting analogues of the GLP-1 incretin hormone and are currently available to treat diabetes. They facilitate insulin signalling via the GLP-1 receptor (GLP-1R. Numerous in vitro and in vivo studies have shown that GLP-1 analogues have a range of neuroprotective properties. GLP-1Rs are expressed in the hippocampal area of the brain an important site of adult neurogenesis and maintenance of cognition and memory formation. Therefore, if GLP-1 analogues can cross the blood brain barrier, diffuse through the brain to reach the receptors and most importantly activate them, their neuroprotective effects may be realized. Results In the present study we profiled the GLP-1 receptor agonists liraglutide (Victoza and lixisenatide (Lyxumia. We measured the kinetics of crossing the blood brain barrier (BBB, activation of the GLP-1R by measuring cAMP levels, and physiological effects in the brain on neuronal stem cell proliferation and neurogenesis. Both drugs were able to cross the BBB. Lixisenatide crossed the BBB at all doses tested (2.5, 25, or 250 nmol/kg bw ip. when measured 30 min post-injection and at 2.5-25 nmol/kg bw ip. 3 h post-injection. Lixisenatide also enhanced neurogenesis in the brain. Liraglutide crossed the BBB at 25 and 250 nmol/kg ip. but no increase was detectable at 2.5 nmol/kg ip. 30 min post-injection, and at 250 nmol/kg ip. at 3 h post-injection. Liraglutide and lixisenatide enhanced cAMP levels in the brain, with lixisenatide being more effective. Conclusions Our results suggest that these novel incretin analogues cross the BBB and show physiological activity and neurogenesis in the brain, which may be of use as a treatment of

  4. Measurement of cerebral blood flow rate and its relationship with brain function using optical coherence tomography

    Science.gov (United States)

    Liu, Jian; Wang, Yi; Zhao, Yuqian; Dou, Shidan; Ma, Yushu; Ma, Zhenhe

    2016-03-01

    Activity of brain neurons will lead to changes in local blood flow rate (BFR). Thus, it is important to measure the local BFR of cerebral cortex on research of neuron activity in vivo, such as rehabilitation evaluation after stroke, etc. Currently, laser Doppler flowmetry is commonly used for blood flow measurement, however, relatively low resolution limits its application. Optical coherence tomography (OCT) is a powerful noninvasive 3D imaging modality with high temporal and spatial resolutions. Furthermore, OCT can provide flow distribution image by calculating Doppler frequency shift which makes it possible for blood flow rate measurement. In this paper, we applied OCT to measure the blood flow rate of the primary motor cortex in rats. The animal was immobilized and anesthetized with isoflurane, an incision was made along the sagittal suture, and bone was exposed. A skull window was opened on the primary motor cortex. Then, blood flow rate changes in the primary motor cortex were monitored by our homemade spectral domain OCT with a stimulation of the passive movement of the front legs. Finally, we established the relationship between blood flow rate and the test design. The aim is to demonstrate the potential of OCT in the evaluation of cerebral cortex function.

  5. Carbenoxolone does not cross the blood brain barrier: an HPLC study

    Directory of Open Access Journals (Sweden)

    Burnham William M

    2006-01-01

    Full Text Available Abstract Background Carbenoxolone (CBX is a widely used gap junctional blocker. Considering several reports indicating that transient gap junctional blockade could be a favourable intervention following injuries to central nervous tissue, and some current enthusiasm in studies using systemic injections of CBX, it is imperative to consider the penetration of CBX into central nervous tissue after systemic administrations. So far, only very indirect evidence suggests that CBX penetrates into the central nervous system after systemic administrations. We thus determined the amounts of CBX present in the blood and the cerebrospinal fluid of rats after intraperitoneal administration, using high performance liquid chromatography Results CBX was found in the blood of the animals, up to 90 minutes post-injection. However, the cerebrospinal fluid concentration of CBX was negligible. Conclusion Thus, we conclude that, most likely, CBX does not penetrate the blood brain barrier and therefore recommend careful consideration in the manner of administration, when a central effect is desired.

  6. Brain and muscle of Wistar rats are the main targets of intravenous dendrimeric sulfadiazine.

    Science.gov (United States)

    Prieto, M J; Schilrreff, P; Tesoriero, M V Defain; Morilla, M J; Romero, E L

    2008-08-01

    Cytotoxicity of sulfadiazine (SDZ) complexed with PAMAM dendrimers of fourth generation (SDZ-DG4) determined by MTT assay and LDH leakage, was reduced on covered (with mucins) but not on nude (without mucins) Caco-2 cell line. SDZ-DG4 adsorption and uptake on nude and covered Caco-2 cells, determined by flow cytometry and fluorescence confocal microscopy indicated that positively charged DG4 remained electrostatically attracted to the negatively charged mucins macromolecules. Hence, the in vivo accession of cationic dendrimers to epithelial cells could partly be impaired by their entrapment into mucins. This fact could account for an in vivo decreased cytotoxicity. Besides this finding, when orally administered to Wistar rats, no differences in SDZ biodistribution were found between SDZ-DG4 and free SDZ. However, when intravenously administered at 1.5 mg SDZ per kg body weight, Cmax for free SDZ was 0.7+/-0.2 microg vs. 2.7+/-0.4 microg/ml for SDZ-DG4, whereas AUC0-3 for free SDZ was 0.8+/-0.6 microg/h ml vs. 5.2+/-2 microg/h ml for SDZ-DG4. SDZ-DG4 initial volume distribution (Vd) was 2.6-fold lower than for free SDZ. Remarkably, 3 h upon SDZ-DG4 administration, SDZ concentration in muscle and in brain were 17- and 10-fold higher, respectively, than those achieved with free SDZ. PMID:18565704

  7. Effect of some drugs on ethanol-induced changes in blood brain barrier permeability for 14C-tyrosine

    International Nuclear Information System (INIS)

    This investigation seeks to compare the effects of membrane stabilizers chlorpromazine and alpha-tocopherol, and also the dopaminergic antagonist haloperidol, in changes in permeability of the blood-brain barrier for carbon 14-labelled tyrosine

  8. Analysis of the effects of androgens and training on myostatin propeptide and follistatin concentrations in blood and skeletal muscle using highly sensitive Immuno PCR

    OpenAIRE

    Diel, Patrick; Schiffer, Thorsten; Geisler, Stephan; Hertrampf, Torsten; Mosler, Stephanie; Schulz, Sven; Wintgens, Karl Florian; Adler, Michael

    2010-01-01

    Abstract Myostatin propeptide (MYOPRO) and follistatin (FOLLI) are potent myostatin inhibitors. In this study we analysed effects of training and androgens on MYOPRO and FOLLI concentrations in blood and skeletal muscle using Immuno PCR. Young healthy males performed either a 3-month endurance-training or a strength-training. Blood and biopsy samples were analysed. Training did not significantly affect MYOPRO and FOLLI concentrations in serum and muscle. To investigate whether tota...

  9. Mechanisms and regulation of iron trafficking across the capillary endothelial cells of the blood-brain barrier

    Directory of Open Access Journals (Sweden)

    Daniel J. Kosman

    2015-07-01

    Full Text Available The transcellular trafficking of iron from the blood into the brain interstitium depends on iron uptake proteins in the apical membrane of brain microvascular capillary endothelial cells and efflux proteins at the basolateral, abluminal membrane. In this review, we discuss the three mechanisms by which these cells take-up iron from the blood and the sole mechanism by which they efflux this iron into the abluminal space. We then focus on the regulation of this efflux pathway by exocrine factors that are released from neighboring astrocytes. Also discussed are the cytokines secreted by capillary cells that regulate the expression of these glial cell signals. Among the interstitial factors that regulate iron efflux into the brain is the amyloid precursor protein. The role of this amyliodogenic species in brain iron metabolism is discussed. Last, we speculate on the potential relationship between iron transport at the blood-brain barrier and neurological disorders associated with iron mismanagement.

  10. Overweight worsens apoptosis, neuroinflammation and blood-brain barrier damage after hypoxic ischemia in neonatal brain through JNK hyperactivation

    Directory of Open Access Journals (Sweden)

    Wu Hsin-Chieh

    2011-04-01

    Full Text Available Abstract Background Apoptosis, neuroinflammation and blood-brain barrier (BBB damage affect the susceptibility of the developing brain to hypoxic-ischemic (HI insults. c-Jun N-terminal kinase (JNK is an important mediator of insulin resistance in obesity. We hypothesized that neonatal overweight aggravates HI brain damage through JNK hyperactivation-mediated upregulation of neuronal apoptosis, neuroinflammation and BBB leakage in rat pups. Methods Overweight (OF pups were established by reducing the litter size to 6, and control (NF pups by keeping the litter size at 12 from postnatal (P day 1 before HI on P7. Immunohistochemistry and immunoblotting were used to determine the TUNEL-(+ cells and BBB damage, cleaved caspase-3 and poly (ADP-ribose polymerase (PARP, and phospho-JNK and phospho-BimEL levels. Immunofluorescence was performed to determine the cellular distribution of phospho-JNK. Results Compared with NF pups, OF pups had a significantly heavier body-weight and greater fat deposition on P7. Compared with the NF-HI group, the OF-HI group showed significant increases of TUNEL-(+ cells, cleaved levels of caspase-3 and PARP, and ED1-(+ activated microglia and BBB damage in the cortex 24 hours post-HI. Immunofluorescence of the OF-HI pups showed that activated-caspase 3 expression was found mainly in NeuN-(+ neurons and RECA1-(+ vascular endothelial cells 24 hours post-HI. The OF-HI group also had prolonged escape latency in the Morris water maze test and greater brain-volume loss compared with the NF-HI group when assessed at adulthood. Phospho-JNK and phospho-BimEL levels were higher in OF-HI pups than in NF-HI pups immediately post-HI. JNK activation in OF-HI pups was mainly expressed in neurons, microglia and vascular endothelial cells. Inhibiting JNK activity by AS601245 caused more attenuation of cleaved caspase-3 and PARP, a greater reduction of microglial activation and BBB damage post-HI, and significantly reduced brain damage in

  11. Generation of a High Resistance in vitro Blood-Brain-Barrier Model and Investigations of Brain-to-Blood Glutamate Efflux

    DEFF Research Database (Denmark)

    Helms, Hans Christian

    Blod-hjernebarrieren (blood-brain barrier, BBB) opretholder den generelle homeostase i hjernens væsker. BBB kan også spille en rolle i homeostasen for den eksitatoriske aminosyre, L-glutamat. In vitro modeller kan være effektive værktøjer til at få mekanistiske informationer om transcellulær...... af claudin-5 ved en direkte påvirkning eller som en afledt konsekvens. mRNA ekspression af en række vigtige BBB markører blev bekræftet, og breat cancer resistance protein- og P-glycoprotein-ekspression blev vist funktionelt. EAAT-substraterne, L-aspartat, L-glutamat, men ikke D-aspartat udviste...

  12. Blood brain barrier is impermeable to solutes and permeable to water after experimental pediatric cardiac arrest.

    Science.gov (United States)

    Tress, Erika E; Clark, Robert S B; Foley, Lesley M; Alexander, Henry; Hickey, Robert W; Drabek, Tomas; Kochanek, Patrick M; Manole, Mioara D

    2014-08-22

    Pediatric asphyxial cardiac arrest (CA) results in unfavorable neurological outcome in most survivors. Development of neuroprotective therapies is contingent upon understanding the permeability of intravenously delivered medications through the blood brain barrier (BBB). In a model of pediatric CA we sought to characterize BBB permeability to small and large molecular weight substances. Additionally, we measured the percent brain water after CA. Asphyxia of 9 min was induced in 16-18 day-old rats. The rats were resuscitated and the BBB permeability to small (sodium fluorescein and gadoteridol) and large (immunoglobulin G, IgG) molecules was assessed at 1, 4, and 24 h after asphyxial CA or sham surgery. Percent brain water was measured post-CA and in shams using wet-to-dry brain weight. Fluorescence, gadoteridol uptake, or IgG staining at 1, 4h and over the entire 24 h post-CA did not differ from shams, suggesting absence of BBB permeability to these solutes. Cerebral water content was increased at 3h post-CA vs. sham. In conclusion, after 9 min of asphyxial CA there is no BBB permeability over 24h to conventional small or large molecule tracers despite the fact that cerebral water content is increased early post-CA indicating the development of brain edema. Evaluation of novel therapies targeting neuronal death after pediatric CA should include their capacity to cross the BBB. PMID:24937271

  13. Blood-brain barrier proteomics: towards the understanding of neurodegenerative diseases.

    Science.gov (United States)

    Karamanos, Yannis; Gosselet, Fabien; Dehouck, Marie-Pierre; Cecchelli, Roméo

    2014-11-01

    The blood-brain barrier (BBB) regulates the passage of endogenous and exogenous compounds and thus contributes to the brain homeostasis with the help of well-known proteins such as tight junction proteins, plasma membrane transporters and metabolic barrier proteins. In the last decade, proteomics have emerged as supplementary tools for BBB research. The development of proteomic technologies has provided several means to extend knowledge on the BBB and to investigate additional routes for the bypass of this barrier. Proteomics approaches have been used in vivo and also using in vitro BBB models to decipher the physiological characteristics and, under stress conditions, to understand the molecular mechanisms of brain diseases. This work has demonstrated that both quantitative global and targeted proteomics approaches are powerful and provide significant information on the brain microvessel endothelium. However, current knowledge is only partial and it is necessary to increase the studies using proteomics tools that will provide additional information concerning brain pathologies or BBB metabolism. Highly sensitive, accurate and specific protein quantification by quantitative targeted proteomics appears as an essential methodology for human BBB studies. PMID:25446619

  14. Vascular endothelial growth factors enhance the permeability of the mouse blood-brain barrier.

    Directory of Open Access Journals (Sweden)

    Shize Jiang

    Full Text Available The blood-brain barrier (BBB impedes entry of many drugs into the brain, limiting clinical efficacy. A safe and efficient method for reversibly increasing BBB permeability would greatly facilitate central nervous system (CNS drug delivery and expand the range of possible therapeutics to include water soluble compounds, proteins, nucleotides, and other large molecules. We examined the effect of vascular endothelial growth factor (VEGF on BBB permeability in Kunming (KM mice. Human VEGF165 was administered to treatment groups at two concentrations (1.6 or 3.0 µg/mouse, while controls received equal-volume saline. Changes in BBB permeability were measured by parenchymal accumulation of the contrast agent Gd-DTPA as assessed by 7 T magnetic resonance imaging (MRI. Mice were then injected with Evans blue, sacrificed 0.5 h later, and perfused transcardially. Brains were removed, fixed, and sectioned for histological study. Both VEGF groups exhibited a significantly greater signal intensity from the cerebral cortex and basal ganglia than controls (P<0.001. Evans blue fluorescence intensity was higher in the parenchyma and lower in the cerebrovasculature of VEGF-treated animals compared to controls. No significant brain edema was observed by diffusion weighted MRI (DWI or histological staining. Exogenous application of VEGF can increase the permeability of the BBB without causing brain edema. Pretreatment with VEGF may be a feasible method to facilitate drug delivery into the CNS.

  15. Effect of extraluminal ATP application on vascular tone and blood flow in skeletal muscle

    DEFF Research Database (Denmark)

    Nyberg, Michael Permin; Al-Khazraji, Baraa K; Mortensen, Stefan P; Jackson, Dwayne N; Ellis, Christopher G; Hellsten, Ylva

    2013-01-01

    NO and prostanoid formation. Inhibition of these systems abolished the vasodilator effect of ATP. Cell-culture experiments verified ATP-induced formation of NO and prostacyclin in rat skeletal muscle microvascular endothelial cells and ATP-induced formation of NO in rat skeletal muscle cells. To...

  16. Recruitment of neutrophils across the blood-brain barrier: the role of posttraumatic hepatic ischemia

    Directory of Open Access Journals (Sweden)

    Mantovani Mario

    2003-01-01

    Full Text Available PURPOSE: To study the effects of total hepatic ischemia, and reperfusion on the accumulation of neutrophils in the brain of rats submitted to normovolemic conditions as well as to controlled hemorrhagic shock state. METHODS: Thirty two adult male Wistar rats, were divided into four groups: the Control group, was submitted to the standard procedures for a period of 60 min of observation; Shock group, was submitted to controlled hemorrhagic shock (mean arterial blood pressure=40mmHg, 20min followed by volemic resuscitation (lactated Ringer's solution + blood, 3:1 and reperfusion for 60min; Pringle group, was submitted to total hepatic ischemia for 15min and reperfusion for 60min. The total group was submitted to controlled hemorrhagic shock for 20min followed by volemic resuscitation (lactated Ringer's solution + blood, 3:1, total hepatic ischemia for 15min and reperfusion for 60min. Measurements of serum lactate and base excess were used to characterize the hemorrhagic shock state with low tissue perfusion. The counting of neutrophils on the brain was performed after the euthanasia of animals. RESULTS: The values for the counting of neutrophils on the brain indicate that did not occur difference among studied groups (p=0.196 (Control 0.12± 0.11, Shock 0.12± 0.13, Pringle 0.02± 0.04, Total 0.14± 0.16. CONCLUSION: Hemorrhagic shock associated to total hepatic ischemia for 15 minutes, followed by 60 minutes of reperfusion, did not causes significant neutrophils accumulation in the brain of rats.

  17. DNA and RNA analysis of blood and muscle from bodies with variable postmortem intervals

    DEFF Research Database (Denmark)

    Hansen, Jakob; Lesnikova, Iana; Funder, Anette Mariane Daa;

    2014-01-01

    formalin fixed and paraffin embedded (FFPE) muscle specimens. A quality assessment of muscle-derived DNA showed increased fragmentation with advancing body decomposition and generally more fragmentation in DNA from FFPE tissue than in DNA from frozen tissue. It was possible to amplify 1,000 basepair (bp......) DNA fragments from all samples with postmortem intervals below 3 days whereas 400-600 bp long fragments typically could be amplified from the most decomposed muscle specimens. RNA was less stable than DNA in postmortem muscle tissue, yet selected mRNA molecules could be detected by reverse......-transcriptase PCR in all samples up to 3 days after death. We conclude that analysis of DNA from bodies with a wide postmortem interval range is usually possible whereas the consistency of RNA analyses decreases considerably 3 days postmortem. We showed that muscle tissue is a highly usable source of DNA and RNA...

  18. Tempol modulates changes in xenobiotic permeability and occludin oligomeric assemblies at the blood-brain barrier during inflammatory pain

    OpenAIRE

    Lochhead, Jeffrey J; McCaffrey, Gwen; Sanchez-Covarrubias, Lucy; Finch, Jessica D.; DeMarco, Kristin M; Quigley, Colleen E.; Davis, Thomas P.; Ronaldson, Patrick T

    2011-01-01

    Our laboratory has shown that λ-carrageenan-induced peripheral inflammatory pain (CIP) can alter tight junction (TJ) protein expression and/or assembly leading to changes in blood-brain barrier xenobiotic permeability. However, the role of reactive oxygen species (ROS) and subsequent oxidative stress during CIP is unknown. ROS (i.e., superoxide) are known to cause cellular damage in response to pain/inflammation. Therefore, we examined oxidative stress-associated effects at the blood-brain ba...

  19. Preparation of Silica Nanoparticles Loaded with Nootropics and Their In Vivo Permeation through Blood-Brain Barrier

    OpenAIRE

    Josef Jampilek; Kamil Zaruba; Michal Oravec; Martin Kunes; Petr Babula; Pavel Ulbrich; Ingrid Brezaniova; Radka Opatrilova; Jan Triska; Pavel Suchy

    2015-01-01

    The blood-brain barrier prevents the passage of many drugs that target the central nervous system. This paper presents the preparation and characterization of silica-based nanocarriers loaded with piracetam, pentoxifylline, and pyridoxine (drugs from the class of nootropics), which are designed to enhance the permeation of the drugs from the circulatory system through the blood-brain barrier. Their permeation was compared with non-nanoparticle drug substances (bulk materials) by means of an i...

  20. Abnormal blood-brain barrier permeability in normal appearing white matter in multiple sclerosis investigated by MRI

    DEFF Research Database (Denmark)

    Cramer, Stig Præstekær; Simonsen, Helle Juhl; Frederiksen, Jette Lautrup Battistini;

    2013-01-01

    To investigate whether blood-brain barrier (BBB) permeability is disrupted in normal appearing white matter in MS patients, when compared to healthy controls and whether it is correlated with MS clinical characteristics.......To investigate whether blood-brain barrier (BBB) permeability is disrupted in normal appearing white matter in MS patients, when compared to healthy controls and whether it is correlated with MS clinical characteristics....

  1. Conjunctival microcirculatory blood flow is altered but not abolished in brain dead patients: a prospective observational study

    OpenAIRE

    Tamosuitis, Tomas; Pranskunas, Andrius; Balciuniene, Neringa; Pilvinis, Vidas; Boerma, E Christiaan

    2016-01-01

    Background The conjunctival microcirculation has potential as a window to cerebral perfusion due to related blood supply, close anatomical proximity and easy accessibility for microcirculatory imaging technique, such as sidestream dark field (SDF) imaging. Our study aims to evaluate conjunctival and sublingual microcirculation in brain dead patients and to compare it with healthy volunteers in two diametrically opposed conditions: full stop versus normal arterial blood supply to the brain. Me...

  2. Chronic hypoxia increases arterial blood pressure and reduces adenosine and ATP induced vasodilatation in skeletal muscle in healthy humans

    DEFF Research Database (Denmark)

    Calbet, J A L; Boushel, Robert Christopher; Robach, P;

    2014-01-01

    altitude than at sea level (P < 0.05). At altitude, the high doses of adenosine and ATP reduced mean arterial blood pressure by 9-12%, independently of FI O2 . The change in vascular conductance in response to ATP was lower at altitude than at sea level by 24 and 38%, during the low and high ATP doses...... protein expression was determined in muscle biopsies after 4 weeks at 3454 m by Western blot. RESULTS: At altitude, mean arterial blood pressure was 13% higher (91 ± 2 vs. 102 ± 3 mmHg, P < 0.05) than at sea level and was unaltered by hyperoxic breathing. Baseline leg vascular conductance was 25% lower at...... blood pressure and reduces the vasodilatory responses to adenosine and ATP....

  3. Relative value of diverse brain MRI and blood-based biomarkers for predicting cognitive decline in the elderly

    Science.gov (United States)

    Madsen, Sarah K.; Ver Steeg, Greg; Daianu, Madelaine; Mezher, Adam; Jahanshad, Neda; Nir, Talia M.; Hua, Xue; Gutman, Boris A.; Galstyan, Aram; Thompson, Paul M.

    2016-03-01

    Cognitive decline accompanies many debilitating illnesses, including Alzheimer's disease (AD). In old age, brain tissue loss also occurs along with cognitive decline. Although blood tests are easier to perform than brain MRI, few studies compare brain scans to standard blood tests to see which kinds of information best predict future decline. In 504 older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we first used linear regression to assess the relative value of different types of data to predict cognitive decline, including 196 blood panel biomarkers, 249 MRI biomarkers obtained from the FreeSurfer software, demographics, and the AD-risk gene APOE. A subset of MRI biomarkers was the strongest predictor. There was no specific blood marker that increased predictive accuracy on its own, we found that a novel unsupervised learning method, CorEx, captured weak correlations among blood markers, and the resulting clusters offered unique predictive power.

  4. Quantitation of blood-brain barrier defect by magnetic resonance imaging and gadolinium-DTPA in patients with multiple sclerosis and brain tumors

    DEFF Research Database (Denmark)

    Larsson, H B; Stubgaard, M; Frederiksen, Jette Lautrup Battistini; Jensen, M; Henriksen, O; Paulson, O B

    1990-01-01

    In this study quantitation of the degree of deficiency of the blood-brain barrier (BBB) in patients with multiple sclerosis or brain tumors, by using MRI, is shown to be possible. As a measure of permeability of the BBB to Gadolinium-DTPA (Gd-DTPA) the flux per unit of distribution volume per unit...... of brain mass was used. This quantity was found by introducing the longitudinal relaxation rate (R1) as a measure of concentration of Gd-DTPA in the brain tissue in the mathematical model for the transcapillary transport over the BBB. High accordance between the observed data points and the model was...

  5. Transport of Arylsulfatase A across the Blood-Brain Barrier in Vitro*

    Science.gov (United States)

    Matthes, Frank; Wölte, Philipp; Böckenhoff, Annika; Hüwel, Sabine; Schulz, Mareike; Hyden, Pia; Fogh, Jens; Gieselmann, Volkmar; Galla, Hans-Joachim; Matzner, Ulrich

    2011-01-01

    Enzyme replacement therapy is an option to treat lysosomal storage diseases caused by functional deficiencies of lysosomal hydrolases as intravenous injection of therapeutic enzymes can correct the catabolic defect within many organ systems. However, beneficial effects on central nervous system manifestations are very limited because the blood-brain barrier (BBB) prevents the transfer of enzyme from the circulation to the brain parenchyma. Preclinical studies in mouse models of metachromatic leukodystrophy, however, showed that arylsulfatase A (ASA) is able to cross the BBB to some extent, thus reducing lysosomal storage in brain microglial cells. The present study aims to investigate the routing of ASA across the BBB and to improve the transfer in vitro using a well established cell culture model consisting of primary porcine brain capillary endothelial cells cultured on Transwell filter inserts. Passive apical-to-basolateral ASA transfer was observed, which was not saturable up to high ASA concentrations. No active transport could be determined. The passive transendothelial transfer was, however, charge-dependent as reduced concentrations of negatively charged monosaccharides in the N-glycans of ASA or the addition of polycations increased basolateral ASA levels. Adsorptive transcytosis is therefore considered to be the major transport pathway. Partial inhibition of the transcellular ASA transfer by mannose 6-phosphate indicated a second route depending on the insulin-like growth factor II/mannose 6-phosphate receptor, MPR300. We conclude that cationization of ASA and an increase of the mannose 6-phosphate content of the enzyme may promote blood-to-brain transfer of ASA, thus leading to an improved therapeutic efficacy of enzyme replacement therapy behind the BBB. PMID:21454621

  6. Transport of arylsulfatase A across the blood-brain barrier in vitro.

    Science.gov (United States)

    Matthes, Frank; Wölte, Philipp; Böckenhoff, Annika; Hüwel, Sabine; Schulz, Mareike; Hyden, Pia; Fogh, Jens; Gieselmann, Volkmar; Galla, Hans-Joachim; Matzner, Ulrich

    2011-05-20

    Enzyme replacement therapy is an option to treat lysosomal storage diseases caused by functional deficiencies of lysosomal hydrolases as intravenous injection of therapeutic enzymes can correct the catabolic defect within many organ systems. However, beneficial effects on central nervous system manifestations are very limited because the blood-brain barrier (BBB) prevents the transfer of enzyme from the circulation to the brain parenchyma. Preclinical studies in mouse models of metachromatic leukodystrophy, however, showed that arylsulfatase A (ASA) is able to cross the BBB to some extent, thus reducing lysosomal storage in brain microglial cells. The present study aims to investigate the routing of ASA across the BBB and to improve the transfer in vitro using a well established cell culture model consisting of primary porcine brain capillary endothelial cells cultured on Transwell filter inserts. Passive apical-to-basolateral ASA transfer was observed, which was not saturable up to high ASA concentrations. No active transport could be determined. The passive transendothelial transfer was, however, charge-dependent as reduced concentrations of negatively charged monosaccharides in the N-glycans of ASA or the addition of polycations increased basolateral ASA levels. Adsorptive transcytosis is therefore considered to be the major transport pathway. Partial inhibition of the transcellular ASA transfer by mannose 6-phosphate indicated a second route depending on the insulin-like growth factor II/mannose 6-phosphate receptor, MPR300. We conclude that cationization of ASA and an increase of the mannose 6-phosphate content of the enzyme may promote blood-to-brain transfer of ASA, thus leading to an improved therapeutic efficacy of enzyme replacement therapy behind the BBB. PMID:21454621

  7. Melatonin reduces traumatic brain injur y-induced oxidative stress in the cerebral cortex and blood of rats

    Institute of Scientific and Technical Information of China (English)

    Nilgnenol; Mustafa Nazrolu

    2014-01-01

    Free radicals induced by traumatic brain injury have deleterious effects on the function and antioxidant vitamin levels of several organ systems including the brain. Melatonin possesses antioxidant effect on the brain by maintaining antioxidant enzyme and vitamin levels. We in-vestigated the effects of melatonin on antioxidant ability in the cerebral cortex and blood of traumatic brain injury rats. Results showed that the cerebral cortex β-carotene, vitamin C, vita-min E, reduced glutathione, and erythrocyte reduced glutathione levels, and plasma vitamin C level were decreased by traumatic brain injury whereas they were increased following melatonin treatment. In conclusion, melatonin seems to have protective effects on traumatic brain inju-ry-induced cerebral cortex and blood toxicity by inhibiting free radical formation and supporting antioxidant vitamin redox system.

  8. Transport characteristics of guanidino compounds at the blood-brain barrier and blood-cerebrospinal fluid barrier: relevance to neural disorders

    Directory of Open Access Journals (Sweden)

    Tachikawa Masanori

    2011-02-01

    Full Text Available Abstract Guanidino compounds (GCs, such as creatine, phosphocreatine, guanidinoacetic acid, creatinine, methylguanidine, guanidinosuccinic acid, γ-guanidinobutyric acid, β-guanidinopropionic acid, guanidinoethane sulfonic acid and α-guanidinoglutaric acid, are present in the mammalian brain. Although creatine and phosphocreatine play important roles in energy homeostasis in the brain, accumulation of GCs may induce epileptic discharges and convulsions. This review focuses on how physiologically important and/or neurotoxic GCs are distributed in the brain under physiological and pathological conditions. Transporters for GCs at the blood-brain barrier (BBB and the blood-cerebrospinal fluid (CSF barrier (BCSFB have emerged as substantial contributors to GCs distribution in the brain. Creatine transporter (CRT/solute carrier (SLC 6A8 expressed at the BBB regulates creatine concentration in the brain, and represents a major pathway for supply of creatine from the circulating blood to the brain. CRT may be a key factor facilitating blood-to-brain guanidinoacetate transport in patients deficient in S-adenosylmethionine:guanidinoacetate N-methyltransferase, the creatine biosynthetic enzyme, resulting in cerebral accumulation of guanidinoacetate. CRT, taurine transporter (TauT/SLC6A6 and organic cation transporter (OCT3/SLC22A3 expressed at the BCSFB are involved in guanidinoacetic acid or creatinine efflux transport from CSF. Interestingly, BBB efflux transport of GCs, including guanidinoacetate and creatinine, is negligible, though the BBB has a variety of efflux transport systems for synthetic precursors of GCs, such as amino acids and neurotransmitters. Instead, the BCSFB functions as a major cerebral clearance system for GCs. In conclusion, transport of GCs at the BBB and BCSFB appears to be the key determinant of the cerebral levels of GCs, and changes in the transport characteristics may cause the abnormal distribution of GCs in the brain seen

  9. Lactate, Glucose and Oxygen Uptake in Human Brain During Recovery from Maximal Exercise

    DEFF Research Database (Denmark)

    Kojiro, I.; Schmalbruch, I.K.; Quistorff, B.; Horn, A.; Secher, Niels Henry

    Skeletal muscle, brain lactate uptake, brain oxygen uptake, energy metabolism, brain glucose uptake......Skeletal muscle, brain lactate uptake, brain oxygen uptake, energy metabolism, brain glucose uptake...

  10. Software development for estimating the concentration of radioactive cesium in the skeletal muscles of cattle from blood samples.

    Science.gov (United States)

    Fukuda, Tomokazu; Hiji, Masahiro; Kino, Yasushi; Abe, Yasuyuki; Yamashiro, Hideaki; Kobayashi, Jin; Shimizu, Yoshinaka; Takahashi, Atsushi; Suzuki, Toshihiko; Chiba, Mirei; Inoue, Kazuya; Kuwahara, Yoshikazu; Morimoto, Motoko; Katayama, Masafumi; Donai, Kenichiro; Shinoda, Hisashi; Sekine, Tsutomu; Fukumoto, Manabu; Isogai, Emiko

    2016-06-01

    The 2011 earthquake severely damaged the Fukushima Daiichi Nuclear Power Plant (FNPP), resulting in the release of large quantities of radioactive material into the environment. The deposition of these radionuclides in rice straw as livestock feed led to the circulation of contaminated beef in the market. Based on the safety concern of the consumers, a reliable method for estimating concentrations of radioactive cesium in muscle tissue is needed. In this study, we analyzed the concentrations of radioactive cesium in the blood and skeletal muscle of 88 cattle, and detected a linear correlation between them. We then developed software that can be used to estimate radioactive cesium concentrations in muscle tissue from blood samples. Distribution of this software to the livestock production field would allow us to easily identify high-risk cattle, which would be beyond the safety regulation, before shipping out to the market. This software is planned to be released as freeware. This software would contribute to food safety, and aid the recovery of the livestock industry from the damage creacted by the 2011 Tohoku earthquake and tsunami. PMID:26420060

  11. Altering blood flow does not reveal differences between nitrogen and helium kinetics in brain or in skeletal miracle in sheep.

    Science.gov (United States)

    Doolette, David J; Upton, Richard N; Grant, Cliff

    2015-03-01

    In underwater diving, decompression schedules are based on compartmental models of nitrogen and helium tissue kinetics. However, these models are not based on direct measurements of nitrogen and helium kinetics. In isoflurane-anesthetized sheep, nitrogen and helium kinetics in the hind limb (n = 5) and brain (n = 5) were determined during helium-oxygen breathing and after return to nitrogen-oxygen breathing. Nitrogen and helium concentrations in arterial, femoral vein, and sagittal sinus blood samples were determined using headspace gas chromatography, and venous blood flows were monitored continuously using ultrasonic Doppler. The experiment was repeated at different states of hind limb blood flow and cerebral blood flow. Using arterial blood gas concentrations and blood flows as input, parameters and model selection criteria of various compartmental models of hind limb and brain were estimated by fitting to the observed venous gas concentrations. In both the hind limb and brain, nitrogen and helium kinetics were best fit by models with multiexponential kinetics. In the brain, there were no differences in nitrogen and helium kinetics. Hind limb models fit separately to the two gases indicated that nitrogen kinetics were slightly faster than helium, but models with the same kinetics for both gases fit the data well. In the hind limb and brain, the blood:tissue exchange of nitrogen is similar to that of helium. On the basis of these results, it is inappropriate to assign substantially different time constants for nitrogen and helium in all compartments in decompression algorithms. PMID:25525213

  12. Multimodal investigations of trans-endothelial cell trafficking under condition of disrupted blood-brain barrier integrity

    OpenAIRE

    Masaryk Thomas; Desai Nirav K; Franic Linda; Nguyen Minh T; Teng Qingshan; Marchi Nicola; Rasmussen Peter; Trasciatti Silvia; Janigro Damir

    2010-01-01

    Abstract Background Stem cells or immune cells targeting the central nervous system (CNS) bear significant promises for patients affected by CNS disorders. Brain or spinal cord delivery of therapeutic cells is limited by the blood-brain barrier (BBB) which remains one of the recognized rate-limiting steps. Osmotic BBB disruption (BBBD) has been shown to improve small molecule chemotherapy for brain tumors, but successful delivery of cells in conjunction with BBBD has never been reported. We h...

  13. Global brain blood-oxygen level responses to autonomic challenges in obstructive sleep apnea.

    Directory of Open Access Journals (Sweden)

    Paul M Macey

    Full Text Available Obstructive sleep apnea (OSA is accompanied by brain injury, perhaps resulting from apnea-related hypoxia or periods of impaired cerebral perfusion. Perfusion changes can be determined indirectly by evaluation of cerebral blood volume and oxygenation alterations, which can be measured rapidly and non-invasively with the global blood oxygen level dependent (BOLD signal, a magnetic resonance imaging procedure. We assessed acute BOLD responses in OSA subjects to pressor challenges that elicit cerebral blood flow changes, using a two-group comparative design with healthy subjects as a reference. We separately assessed female and male patterns, since OSA characteristics and brain injury differ between sexes. We studied 94 subjects, 37 with newly-diagnosed, untreated OSA (6 female (age mean ± std: 52.1±8.1 yrs; apnea/hypopnea index [AHI]: 27.7±15.6 events/hr and 31 male 54.3±8.4 yrs; AHI: 37.4±19.6 events/hr, and 20 female (age 50.5±8.1 yrs and 37 male (age 45.6±9.2 yrs healthy control subjects. We measured brain BOLD responses every 2 s while subjects underwent cold pressor, hand grip, and Valsalva maneuver challenges. The global BOLD signal rapidly changed after the first 2 s of each challenge, and differed in magnitude between groups to two challenges (cold pressor, hand grip, but not to the Valsalva maneuver (repeated measures ANOVA, p<0.05. OSA females showed greater differences from males in response magnitude and pattern, relative to healthy counterparts. Cold pressor BOLD signal increases (mean ± adjusted standard error at the 8 s peak were: OSA 0.14±0.08% vs. Control 0.31±0.06%, and hand grip at 6 s were: OSA 0.08±0.03% vs. Control at 0.30±0.02%. These findings, indicative of reduced cerebral blood flow changes to autonomic challenges in OSA, complement earlier reports of altered resting blood flow and reduced cerebral artery responsiveness. Females are more affected than males, an outcome which may contribute to the sex

  14. Computational and in vitro studies of blast-induced blood-brain barrier disruption

    CERN Document Server

    Del Razo, Mauricio J; Meabon, James S; Huber, B Russell; Peskind, Elaine R; Banks, William A; Mourad, Pierre D; Leveque, Randall J; Cook, David G

    2015-01-01

    There is growing concern that blast-exposed individuals are at risk of developing neurological disorders later in life. Therefore, it is important to understand the dynamic properties of blast forces on brain cells, including the endothelial cells that maintain the blood-brain barrier (BBB), which regulates the passage of nutrients into the brain and protects it from toxins in the blood. To better understand the effect of shock waves on the BBB we have investigated an {\\em in vitro} model in which BBB endothelial cells are grown in transwell vessels and exposed in a shock tube, confirming that BBB integrity is directly related to shock wave intensity. It is difficult to directly measure the forces acting on these cells in the transwell container during the experiments, and so a computational tool has been developed and presented in this paper. Two-dimensional axisymmetric Euler equations with the Tammann equation of state were used to model the transwell materials, and a high-resolution finite volume method b...

  15. Molecular anatomy of interendothelial junctions in human blood-brain barrier microvessels.

    Directory of Open Access Journals (Sweden)

    Andrzej W Vorbrodt

    2004-07-01

    Full Text Available Immunogold cytochemical procedure was used to study the localization at the ultrastructural level of interendothelial junction-associated protein molecules in the human brain blood microvessels, representing the anatomic site of the blood-brain barrier (BBB. Ultrathin sections of Lowicryl K4M-embedded biopsy specimens of human cerebral cortex obtained during surgical procedures were exposed to specific antibodies, followed by colloidal gold-labeled secondary antibodies. All tight junction-specific integral membrane (transmembrane proteins--occludin, junctional adhesion molecule (JAM-1, and claudin-5--as well as peripheral zonula occludens protein (ZO-1 were highly expressed. Immunoreactivity of the adherens junction-specific transmembrane protein VE-cadherin was of almost similar intensity. Immunolabeling of the adherens junction-associated peripheral proteins--alpha-catenin, beta-catenin, and p120 catenin--although positive, was evidently less intense. The expression of gamma-catenin (plakoglobin was considered questionable because solitary immunosignals (gold particles appeared in only a few microvascular profiles. Double labeling of some sections made possible to observe strict colocalization of the junctional molecules, such as occludin and ZO-1 or JAM-1 and VE-cadherin, in the interendothelial junctions. We found that in human brain microvessels, the interendothelial junctional complexes contain molecular components specific for both tight and adherens junctions. It is assumed that the data obtained can help us find the immunodetectable junctional molecules that can serve as sensitive markers of normal or abnormal function of the BBB.

  16. Blood-brain barrier permeability to morphine-6-glucuronide is markedly reduced compared with morphine.

    Science.gov (United States)

    Wu, D; Kang, Y S; Bickel, U; Pardridge, W M

    1997-06-01

    The blood-brain barrier (BBB) permeability to morphine and morphine-6-glucuronide (M6G) is measured under identical conditions using an intravenous injection method in the rat and HPLC separation of morphine from its metabolites. The brain uptake of M6G expressed as %ID/g was 32-fold lower than that of morphine, and the BBB permeability surface area product (PS) of M6G was 57-fold lower as compared with that of morphine. Consistent with these in vivo data, the 1-octanol/buffer partition study showed the liposolubility of M6G was 187-fold lower than that of morphine. The CNS origin of M6G analgesia after peripheral administration was confirmed because the analgesia was completely blocked by naloxone, which crosses BBB, but not by naloxone methiodide, which does not enter brain from blood. In conclusion, the BBB permeability to M6G is markedly reduced as compared with morphine, consistent with the much lower lipid solubility of M6G relative to morphine. PMID:9193881

  17. Tight junctions at the blood brain barrier: physiological architecture and disease-associated dysregulation

    Directory of Open Access Journals (Sweden)

    Luissint Anny-Claude

    2012-11-01

    Full Text Available Abstract The Blood–brain barrier (BBB, present at the level of the endothelium of cerebral blood vessels, selectively restricts the blood-to-brain paracellular diffusion of compounds; it is mandatory for cerebral homeostasis and proper neuronal function. The barrier properties of these specialized endothelial cells notably depend on tight junctions (TJs between adjacent cells: TJs are dynamic structures consisting of a number of transmembrane and membrane-associated cytoplasmic proteins, which are assembled in a multimolecular complex and acting as a platform for intracellular signaling. Although the structural composition of these complexes has been well described in the recent years, our knowledge about their functional regulation still remains fragmentary. Importantly, pericytes, embedded in the vascular basement membrane, and perivascular microglial cells, astrocytes and neurons contribute to the regulation of endothelial TJs and BBB function, altogether constituting the so-called neurovascular unit. The present review summarizes our current understanding of the structure and functional regulation of endothelial TJs at the BBB. Accumulating evidence points to a correlation between BBB dysfunction, alteration of TJ complexes and progression of a variety of CNS diseases, such as stroke, multiple sclerosis and brain tumors, as well as neurodegenerative diseases like Parkinson’s and Alzheimer’s diseases. Understanding how TJ integrity is controlled may thus help improve drug delivery across the BBB and the design of therapeutic strategies for neurological disorders.

  18. Blood oxygenation level-dependent MRI of the skeletal muscle during ischemia in patients with peripheral arterial occlusive disease

    International Nuclear Information System (INIS)

    Purpose: to compare calf muscle Blood Oxygenation Level-Dependent (BOLD) response during ischemia in patients suffering from peripheral arterial occlusive disease (PAOD) and age-matched non-PAOD subjects. Materials and methods: PAOD patients with symptoms of intermittent calf claudication and an age-matched control group underwent T2*-weighted single-shot multi-echo planar imaging on a whole-body MR scanner at 1.5 T. The muscle BOLD signal in the calf was acquired during 60 sec of baseline and 240 sec of ischemia induced by cuff compression. T2* time courses in four calf muscles were evaluated. Results: significant differences in the mean T2* values were noted after 150 sec of measurement (p < 0.05). Patients with PAOD revealed a significantly reduced BOLD signal decrease compared to an age-matched control group. Conclusion: potential cause for this observation may be changes in the structure and/or the metabolic turnover of the muscle in PAOD patients. (orig.)

  19. Blood oxygenation level-dependent MRI of the skeletal muscle during ischemia in patients with peripheral arterial occlusive disease

    Energy Technology Data Exchange (ETDEWEB)

    Potthast, Silke [Unispital Basel, Inst. fuer Radiologie (Switzerland); Schulte, A. [Univ. Hospital Ulm (Germany). Clinic for Radiation Therapy and Radiooncology; Kos, S.; Bilecen, D. [Unispital Basel, Interventional Radiology (Switzerland); Aschwanden, M. [Unispital Basel (Switzerland). Angiologie

    2009-12-15

    Purpose: to compare calf muscle Blood Oxygenation Level-Dependent (BOLD) response during ischemia in patients suffering from peripheral arterial occlusive disease (PAOD) and age-matched non-PAOD subjects. Materials and methods: PAOD patients with symptoms of intermittent calf claudication and an age-matched control group underwent T2*-weighted single-shot multi-echo planar imaging on a whole-body MR scanner at 1.5 T. The muscle BOLD signal in the calf was acquired during 60 sec of baseline and 240 sec of ischemia induced by cuff compression. T2* time courses in four calf muscles were evaluated. Results: significant differences in the mean T2* values were noted after 150 sec of measurement (p < 0.05). Patients with PAOD revealed a significantly reduced BOLD signal decrease compared to an age-matched control group. Conclusion: potential cause for this observation may be changes in the structure and/or the metabolic turnover of the muscle in PAOD patients. (orig.)

  20. Toward the restoration of hand use to a paralyzed monkey: brain-controlled functional electrical stimulation of forearm muscles.

    Directory of Open Access Journals (Sweden)

    Eric A Pohlmeyer

    Full Text Available Loss of hand use is considered by many spinal cord injury survivors to be the most devastating consequence of their injury. Functional electrical stimulation (FES of forearm and hand muscles has been used to provide basic, voluntary hand grasp to hundreds of human patients. Current approaches typically grade pre-programmed patterns of muscle activation using simple control signals, such as those derived from residual movement or muscle activity. However, the use of such fixed stimulation patterns limits hand function to the few tasks programmed into the controller. In contrast, we are developing a system that uses neural signals recorded from a multi-electrode array implanted in the motor cortex; this system has the potential to provide independent control of multiple muscles over a broad range of functional tasks. Two monkeys were able to use this cortically controlled FES system to control the contraction of four forearm muscles despite temporary limb paralysis. The amount of wrist force the monkeys were able to produce in a one-dimensional force tracking task was significantly increased. Furthermore, the monkeys were able to control the magnitude and time course of the force with sufficient accuracy to track visually displayed force targets at speeds reduced by only one-third to one-half of normal. Although these results were achieved by controlling only four muscles, there is no fundamental reason why the same methods could not be scaled up to control a larger number of muscles. We believe these results provide an important proof of concept that brain-controlled FES prostheses could ultimately be of great benefit to paralyzed patients with injuries in the mid-cervical spinal cord.

  1. Branched-chain amino acids increase arterial blood ammonia in spite of enhanced intrinsic muscle ammonia metabolism in patients with cirrhosis and healthy subjects

    DEFF Research Database (Denmark)

    Dam, Gitte; Keiding, Susanne; Munk, Ole Lajord; Ott, Peter; Buhl, Mads; Vilstrup, Hendrik; Bak, Lasse Kristoffer; Waagepetersen, Helle Sønderby; Schousboe, Arne; Møller, Niels; Sørensen, Michael

    2011-01-01

    Branched-chain amino acids (BCAA) are used in attempts to reduce blood ammonia in patients with cirrhosis and intermittent hepatic encephalopathy based on the hypothesis that BCAA stimulate muscle ammonia detoxification. We studied the effects of an oral dose of BCAA on the skeletal muscle...... metabolism of ammonia and amino acids in 14 patients with cirrhosis and in 7 healthy subjects by combining [(13)N]ammonia positron emission tomography (PET) of the thigh muscle with measurements of blood flow and arteriovenous (A-V) concentrations of ammonia and amino acids. PET was used to measure the...

  2. In vivo evidence of a functional association between immune cells in blood and brain in healthy human subjects.

    Science.gov (United States)

    Kanegawa, Naoki; Collste, Karin; Forsberg, Anton; Schain, Martin; Arakawa, Ryosuke; Jucaite, Aurelija; Lekander, Mats; Olgart Höglund, Caroline; Kosek, Eva; Lampa, Jon; Halldin, Christer; Farde, Lars; Varrone, Andrea; Cervenka, Simon

    2016-05-01

    Microglia, the resident macrophages in the central nervous system, are thought to be maintained by a local self-renewal mechanism. Although preclinical and in vitro studies have suggested that the brain may contain immune cells also from peripheral origin, the functional association between immune cells in the periphery and brain at physiological conditions is poorly understood. We examined 32 healthy individuals using positron emission tomography (PET) and [(11)C]PBR28, a radioligand for the 18-kDa translocator protein (TSPO) which is expressed both in brain microglia and blood immune cells. In 26 individuals, two measurements were performed with varying time intervals. In a subgroup of 19 individuals, of which 12 had repeat examinations, leukocyte numbers in blood was measured on each day of PET measurements. All individuals were genotyped for TSPO polymorphism and categorized as high, mixed, and low affinity binders. We assessed TSPO binding expressed as total distribution volume of [(11)C]PBR28 in brain and in blood cells. TSPO binding in brain was strongly and positively correlated to binding in blood cells both at baseline and when analyzing change between two PET examinations. Furthermore, there was a significant correlation between change of leukocyte numbers and change in TSPO binding in brain, and a trend-level correlation to change in TSPO binding in blood cells. These in vivo findings indicate an association between immunological cells in blood and brain via intact BBB, suggesting a functional interaction between these two compartments, such as interchange of peripherally derived cells or a common regulatory mechanism. Measurement of radioligand binding in blood cells may be a way to control for peripheral immune function in PET studies using TSPO as a marker of brain immune activation. PMID:26820224

  3. Over-expression of Slit2 induces vessel formation and changes blood vessel permeability in mouse brain

    Institute of Scientific and Technical Information of China (English)

    Hai-xiong HAN; Jian-guo GENG

    2011-01-01

    Aim:To investigate the effect of the axon guidance cue Slit2 on the density of blood vessels and permeability of the blood-brain barrier in mouse brain.Methods:hSlit2 transgenic mouse line was constructed,and the phenotypes of the mice were compared with wild-type mice in respect to the lateral ventricle (LV),ventricle pressure,and the choroids plexus.An in vivo Miles permeability assay and an amyloid-β permeability assay were used to assess the permeability of brain blood vessels.Brain vessel casting and intracerebral hemorrhage models were built to investigate vessel density in the transgenic mice.An in vitro permeability assay was used to test whether Slit2 could change the permeability and tight junctions of blood vessel endothelial cells.Results:Hydrocephalus occurred in some transgenic mice,and a significantly larger lateral ventricle area and significantly higher ventricle pressure were observed in the transgenic mice.The transgenic mice displayed changed construction of the choroids plexus,which had more micro vessels,dilated vessels,gaps between epithelial cells and endothelial cells than wild-type mice.Slit2 significantly increased brain vessel density and the permeability of brain vessels to large molecules.These blood vessels were more sensitive to cues that induce brain hemorrhage.At the cellular level,Slit2 disturbed the integrity of tight junctions in blood vessel endothelial cells and improved the permeability of the endothelial cell layer.Thus,it promoted the entry of amyloid-β peptides from the serum into the central nervous system,where they bound to neurons.Conclusion:Slit2 increases vessel density and permeability in the brains of transgenic mice.Thus,Slit2 induces numerous changes in brain vessels and the barrier system.

  4. Protective actions of des-acylated ghrelin on brain injury and blood-brain barrier disruption after stroke in mice.

    Science.gov (United States)

    Ku, Jacqueline M; Taher, Mohammadali; Chin, Kai Yee; Barsby, Tom; Austin, Victoria; Wong, Connie H Y; Andrews, Zane B; Spencer, Sarah J; Miller, Alyson A

    2016-09-01

    The major ghrelin forms, acylated ghrelin and des-acylated ghrelin, are novel gastrointestinal hormones. Moreover, emerging evidence indicates that these peptides may have other functions including neuro- and vaso-protection. Here, we investigated whether post-stroke treatment with acylated ghrelin or des-acylated ghrelin could improve functional and histological endpoints of stroke outcome in mice after transient middle cerebral artery occlusion (tMCAo). We found that des-acylated ghrelin (1 mg/kg) improved neurological and functional performance, reduced infarct and swelling, and decreased apoptosis. In addition, it reduced blood-brain barrier (BBB) disruption in vivo and attenuated the hyper-permeability of mouse cerebral microvascular endothelial cells after oxygen glucose deprivation and reoxygenation (OGD + RO). By contrast, acylated ghrelin (1 mg/kg or 5 mg/kg) had no significant effect on these endpoints of stroke outcome. Next we found that des-acylated ghrelin's vasoprotective actions were associated with increased expression of tight junction proteins (occludin and claudin-5), and decreased cell death. Moreover, it attenuated superoxide production, Nox activity and expression of 3-nitrotyrosine. Collectively, these results demonstrate that post-stroke treatment with des-acylated ghrelin, but not acylated ghrelin, protects against ischaemia/reperfusion-induced brain injury and swelling, and BBB disruption, by reducing oxidative and/or nitrosative damage. PMID:27303049

  5. Effects of blood-flow-restricted resistance training on muscle function in a 74-year-old male with sporadic inclusion body myositis: a case report

    DEFF Research Database (Denmark)

    Jørgensen, A N; Aagaard, P; Nielsen, J L;

    2016-01-01

    restriction to the working muscles (blood-flow-restricted (BFR) training) in a patient with sIBM. The training consisted of 12 weeks of lower extremity BFR training with low training loads (~25-RM). The patient was tested for mechanical muscle function and functional capacity before and after 6 and 12 weeks...... of training. Maximal horizontal gait speed increased by 19%, which was accompanied by 38-92% improvements in mechanical muscle function (maximal isometric strength, rate of force development and muscle power). In conclusion, BFR training was well tolerated by the patient with sIBM and led to...

  6. Melatonin promotes blood-brain barrier integrity in methamphetamine-induced inflammation in primary rat brain microvascular endothelial cells.

    Science.gov (United States)

    Jumnongprakhon, Pichaya; Govitrapong, Piyarat; Tocharus, Chainarong; Tocharus, Jiraporn

    2016-09-01

    Melatonin is a neurohormone and has high potent of antioxidant that is widely reported to be active against methamphetamine (METH)-induced toxicity to neuron, glial cells, and brain endothelial cells. However, the role of melatonin on the inflammatory responses which are mostly caused by blood-brain barrier (BBB) impairment by METH administration has not been investigated. This study used the primary rat brain microvascular endothelial cells (BMVECs) to determine the protective mechanism of melatonin on METH-induced inflammatory responses in the BBB via nuclear factor-ĸB (NF-κB) and nuclear factor erythroid 2-related factor-2 (Nrf2) signaling. Herein, we demonstrated that melatonin reduced the level of the inflammatory mediators, including intercellular adhesion molecules (ICAM)-1, vascular cell adhesion molecules (VCAM)-1, matrix metallopeptidase (MMP)-9, inducible nitric oxide synthase (iNOS), and nitric oxide (NO) caused by METH. These responses were related to the decrease of the expression and translocation of the NF-κB p65 subunit and the activity of NADPH oxidase (NOX)-2. In addition, melatonin promoted the antioxidant processes, modulated the expression and translocation of Nrf2, and also increased the level of heme oxygenase (HO)-1, NAD (P) H: quinone oxidoreductase (NQO)-1, γ-glutamylcysteine synthase (γ-GCLC), and the activity of superoxide dismutase (SOD) through NOX2 mechanism. In addition, we found that the protective role of melatonin in METH-induced inflammatory responses in the BBB was mediated through melatonin receptors (MT1/2). We concluded that the interaction of melatonin with its receptor prevented METH-induced inflammatory responses by suppressing the NF-κB signaling and promoting the Nrf2 signaling before BBB impairment. PMID:27268413

  7. Separation methods that are capable of revealing blood-brain barrier permeability.

    Science.gov (United States)

    Dash, Alekha K; Elmquist, William F

    2003-11-25

    The objective of this review is to emphasize the application of separation science in evaluating the blood-brain barrier (BBB) permeability to drugs and bioactive agents. Several techniques have been utilized to quantitate the BBB permeability. These methods can be classified into two major categories: in vitro or in vivo. The in vivo methods used include brain homogenization, cerebrospinal fluid (CSF) sampling, voltametry, autoradiography, nuclear magnetic resonance (NMR) spectroscopy, positron emission tomography (PET), intracerebral microdialysis, and brain uptake index (BUI) determination. The in vitro methods include tissue culture and immobilized artificial membrane (IAM) technology. Separation methods have always played an important role as adjunct methods to the methods outlined above for the quantitation of BBB permeability and have been utilized the most with brain homogenization, in situ brain perfusion, CSF sampling, intracerebral microdialysis, in vitro tissue culture and IAM chromatography. However, the literature published to date indicates that the separation method has been used the most in conjunction with intracerebral microdialysis and CSF sampling methods. The major advantages of microdialysis sampling in BBB permeability studies is the possibility of online separation and quantitation as well as the need for only a small sample volume for such an analysis. Separation methods are preferred over non-separation methods in BBB permeability evaluation for two main reasons. First, when the selectivity of a determination method is insufficient, interfering substances must be separated from the analyte of interest prior to determination. Secondly, when large number of analytes is to be detected and quantitated by a single analytical procedure, the mixture must be separated to each individual component prior to determination. Chiral separation in particular can be essential to evaluate the stereo-selective permeation and distribution of agents into the

  8. The effects of psychostimulant drugs on blood brain barrier function and neuroinflammation

    Directory of Open Access Journals (Sweden)

    Sharanya M Kousik

    2012-06-01

    Full Text Available The blood brain barrier (BBB is a highly dynamic interface between the central nervous system and periphery. The BBB is comprised of a number of components and is part of the larger neuro(gliovascular unit. Current literature suggests that psychostimulant drugs of abuse alter the function of the BBB which likely contributes to the neurotoxicities associated with these drugs. In both preclinical and clinical studies, psychostimulants including methamphetamine, MDMA, cocaine, and nicotine, produce BBB dysfunction through alterations in tight junction protein expression and conformation, increased glial activation, increased enzyme activation related to BBB cytoskeleton remodeling, and induction of neuroinflammatory pathways. These detrimental changes lead to increased permeability of the BBB and subsequent vulnerability of the brain to peripheral toxins. In fact, abuse of these psychostimulants, notably methamphetamine and cocaine, has been shown to increase the invasion of peripheral bacteria and viruses into the brain. Much work in this field has focused on the co-morbidity of psychostimulant abuse and human immunodeficiency virus (HIV infection. As psychostimulants alter BBB permeability, it is likely that this BBB dysfunction results in increased penetration of the HIV virus into the brain thus increasing the risk of and severity of neuroAIDS. This review will provide an overview of the specific changes in components within the BBB associated with psychostimulant abuse as well as the implications of these changes in exacerbating the neuropathology associated with psychostimulant drugs and HIV co-morbidity.

  9. Polymeric nanoparticles assembled with microfluidics for drug delivery across the blood-brain barrier

    Science.gov (United States)

    Tavares, M. R.; de Menezes, L. R.; do Nascimento, D. F.; Souza, D. H. S.; Reynaud, F.; Marques, M. F. V.; Tavares, M. I. B.

    2016-07-01

    The blood-brain barrier (BBB) is a challenge in the treatment of some diseases, since it prevents many drugs from reaching therapeutic concentrations in the brain. In this context, there is a growing interest in nanoparticles for drug delivery, since they are able to cross this barrier and target the brain. The use of polymeric materials in the development of these nanoparticles has been extensively studied. It has already been demonstrated that these nanosystems have the ability to cross the BBB, which allows effective drug release into the brain. Biodegradable polymers provide a great advantage in the development of nanosystems, but modifications of the nanoparticles' surface is essential. The traditional batch methods lack precise control over the processes of nucleation and growth, resulting in poor control over final properties of the nanoparticles. Therefore, microfluidics could be used to achieve a better production environment for the fabrication of nano- structured drug delivery systems. This study provides a brief review of: the BBB, the polymeric nanoparticles with the ability to overcome the barrier, the properties of the most used polymeric matrices, and the nanostructured drug delivery systems assembled with microfluidics.

  10. MicroRNA-155 negatively affects blood-brain barrier function during neuroinflammation.

    Science.gov (United States)

    Lopez-Ramirez, Miguel Alejandro; Wu, Dongsheng; Pryce, Gareth; Simpson, Julie E; Reijerkerk, Arie; King-Robson, Josh; Kay, Oliver; de Vries, Helga E; Hirst, Mark C; Sharrack, Basil; Baker, David; Male, David Kingsley; Michael, Gregory J; Romero, Ignacio Andres

    2014-06-01

    Blood-brain barrier (BBB) dysfunction is a hallmark of neurological conditions such as multiple sclerosis (MS) and stroke. However, the molecular mechanisms underlying neurovascular dysfunction during BBB breakdown remain elusive. MicroRNAs (miRNAs) have recently emerged as key regulators of pathogenic responses, although their role in central nervous system (CNS) microvascular disorders is largely unknown. We have identified miR-155 as a critical miRNA in neuroinflammation at the BBB. miR-155 is expressed at the neurovascular unit of individuals with MS and of mice with experimental autoimmune encephalomyelitis (EAE). In mice, loss of miR-155 reduced CNS extravasation of systemic tracers, both in EAE and in an acute systemic inflammation model induced by lipopolysaccharide. In cultured human brain endothelium, miR-155 was strongly and rapidly upregulated by inflammatory cytokines. miR-155 up-regulation mimicked cytokine-induced alterations in junctional organization and permeability, whereas inhibition of endogenous miR-155 partially prevented a cytokine-induced increase in permeability. Furthermore, miR-155 modulated brain endothelial barrier function by targeting not only cell-cell complex molecules such as annexin-2 and claudin-1, but also focal adhesion components such as DOCK-1 and syntenin-1. We propose that brain endothelial miR-155 is a negative regulator of BBB function that may constitute a novel therapeutic target for CNS neuroinflammatory disorders. PMID:24604078

  11. 'À la carte' peptide shuttles: tools to increase their passage across the blood-brain barrier.

    Science.gov (United States)

    Malakoutikhah, Morteza; Guixer, Bernat; Arranz-Gibert, Pol; Teixidó, Meritxell; Giralt, Ernest

    2014-07-01

    Noninvasive methods for efficient drug delivery to the brain is an unmet need. Molecular access to the brain is regulated by the blood-brain barrier (BBB) established by the endothelial cells of brain vessels. Passive diffusion is one of the main mechanisms that organic compounds use to travel through these endothelial cells. This passage across the BBB is determined mainly by certain physicochemical properties of the molecule such as lipophilicity, size, and the presence of hydrogen bond donors and acceptors. One emerging strategy to facilitate the passage of organic compounds across the BBB is the use of peptide shuttles.1 In using this approach the permeability in front the BBB is, clearly, determined by the combined physicochemical properties of both the cargo and the shuttle. Herein we report the synthesis of a series of variations of one of the more efficient peptide shuttles, (N-MePhe)n . These include diverse structural features such as various backbone stereochemistries or the presence of non-natural amino acids, including halogenated residues. In several cases, we assessed the BBB permeability of both the shuttles alone and linked to a few cargos. Our results show how factors such as stereochemistry or halogen content influences the passage across the BBB and, more importantly, opens the way to a strategy of peptide shuttles 'à la carte', in which a particular fine-tuned shuttle is used for each specific cargo. PMID:24665021

  12. Tailored delivery of analgesic ziconotide across a blood brain barrier model using viral nanocontainers

    Science.gov (United States)

    Anand, Prachi; O'Neil, Alison; Lin, Emily; Douglas, Trevor; Holford, Mandë

    2015-08-01

    The blood brain barrier (BBB) is often an insurmountable obstacle for a large number of candidate drugs, including peptides, antibiotics, and chemotherapeutic agents. Devising an adroit delivery method to cross the BBB is essential to unlocking widespread application of peptide therapeutics. Presented here is an engineered nanocontainer for delivering peptidic drugs across the BBB encapsulating the analgesic marine snail peptide ziconotide (Prialt®). We developed a bi-functional viral nanocontainer based on the Salmonella typhimurium bacteriophage P22 capsid, genetically incorporating ziconotide in the interior cavity, and chemically attaching cell penetrating HIV-Tat peptide on the exterior of the capsid. Virus like particles (VLPs) of P22 containing ziconotide were successfully transported in several BBB models of rat and human brain microvascular endothelial cells (BMVEC) using a recyclable noncytotoxic endocytic pathway. This work demonstrates proof in principle for developing a possible alternative to intrathecal injection of ziconotide using a tunable VLP drug delivery nanocontainer to cross the BBB.

  13. Study on permeability of β-NGF through blood brain barrier by 125I tracing

    International Nuclear Information System (INIS)

    β-NGF is extracted from fetus brain by centrifugation, dialysing and ion-exchange chromatography. The molecular weight of β-NGF is 13 kD detected by SDS-PAGE electrophoresis; the isoelectric point of β-NGF are 9.0, 9.2 and 9.3 respectively detected by isoelectric focusing electrophoresis; the β-NGF shows the effect of stimulating neurite growth by PC12 cells culture. Using the 125I tracing technique, the animal experiments indicate (2.41 +- 0.12)% of injected 125I-β-NGF could go through the blood brain barrier at 15 min, and increase to (4.20 +- 0.07)% at 30 min. The results provides scientific basis for research of β-NGF in clinical therapeutic application

  14. Age-related changes in regional cerebral blood flow and brain volume in healthy subjects

    International Nuclear Information System (INIS)

    Using the xenon-133 inhalation method, we studied the age-related decline in regional cerebral blood flow, calculated as the initial slope index (ISI), in neurologically normal subjects without any risk factors for cerebral arteriosclerosis (154 men and 123 women), ranging in age from 19 to 88 years. The decline in the ISI was rapid in younger age groups and gradual in older age groups. The ISI was higher in women than in men older than 40 years. Using computed tomography, we studied the age-related decline in brain volume index (BVI; 100% X brain volume/cranial cavity volume) in neurologically normal subjects without any risk factors for cerebral arteriosclerosis (92 men and 49 women), ranging in age from 37 to 86 years. The decline in the BVI was gradual in younger age groups and rapid in older age groups. The BVI was higher in women than in men older than 60 years

  15. Blood-brain barrier disruption: mechanistic links between Western diet consumption and dementia

    Directory of Open Access Journals (Sweden)

    Ted Menghsiung Hsu

    2014-05-01

    Full Text Available Both obesity and Alzheimer’s disease are major health burdens in Western societies. While commonly viewed as having separate etiologies, this review highlights data suggesting that intake of Western diets, diets high in saturated fatty acids and simple carbohydrates, may pose a common environmental risk factor contributing to the development of both of these adverse pathologies. We discuss the effects of Western Diet intake on learning and memory processes that are dependent on the hippocampus, as well as the importance of this brain region in both obesity development and the onset of Alzheimer’s and other dementias. A putative mechanism is discussed that mechanistically links Western diet consumption, blood brain barrier degradation, and subsequent hippocampal damage and dementia pathology.

  16. In vitro model of the blood-brain barrier established by co-culture of primary cerebral microvascular endothelial and astrocyte cells

    Directory of Open Access Journals (Sweden)

    Yan Wang

    2015-01-01

    Full Text Available Drugs for the treatment and prevention of nervous system diseases must permeate the blood-brain barrier to take effect. In vitro models of the blood-brain barrier are therefore important in the investigation of drug permeation mechanisms. However, to date, no unified method has been described for establishing a blood-brain barrier model. Here, we modified an in vitro model of the blood-brain barrier by seeding brain microvascular endothelial cells and astrocytes from newborn rats on a polyester Transwell cell culture membrane with 0.4-µm pores, and conducted transepithelial electrical resistance measurements, leakage tests and assays for specific blood-brain barrier enzymes. We show that the permeability of our model is as low as that of the blood-brain barrier in vivo. Our model will be a valuable tool in the study of the mechanisms of action of neuroprotective drugs.

  17. Challenges in understanding the impact of blood pressure management on cerebral oxygenation in the preterm brain

    Directory of Open Access Journals (Sweden)

    Aminath eAzhan

    2012-12-01

    Full Text Available Systemic hypotension in preterm infants has been related to increased mortality, cerebrovascular lesions and neurodevelopmental morbidity. Treatment of hypotension with inotropic medications aims at preservation of end organ perfusion and oxygen delivery, especially the brain. The common inotropic medications in preterm infants include dopamine, dobutamine, adrenalin, with adjunctive use of corticosteroids in cases of refractory hypotension. Whether maintenance of mean arterial blood pressure (MAP by use of inotropic medication is neuroprotective or not remains unclear. This review explores the different inotropic agents and their effects on perfusion and oxygenation in the preterm brain, in clinical studies as well as in animal models. Dopamine and adrenalin, because of their -adrenergic vasoconstrictor actions, have raised concerns of reduction in cerebral blood flow (CBF. Several studies in hypotensive preterm infants have shown that dopamine elevates CBF together with increased MAP, in keeping with limited cerebro-autoregulation. Adrenaline is also effective in raising cerebral perfusion together with MAP in preterm infants. Experimental studies in immature animals show no cerebro-vasoconstrictive effects of dopamine or adrenaline, but demonstrate the consistent findings of increased cerebral perfusion and oxygenation with the use of dopamine, dobutamine and adrenaline, alongside with raised MAP. Both clinical and animal studies report the transitory effects of adrenaline in increasing plasma lactate, and blood glucose, which might render its use as a 2nd line therapy. To investigate the cerebral effects of inotropic agents in long-term outcome in hypotensive preterm infants, carefully designed prospective research possibly including preterm infants with permissive hypotension is required. Preterm animal models would be useful in investigating the relationship between the physiological effects of inotropes and histopathology outcomes in

  18. Cellular Apoptosis and Blood Brain Barrier Permeability Changes in the Pre-Incubated Chicken Embryo’s Brain by Effect of Electromagnetic Fields

    Directory of Open Access Journals (Sweden)

    Sima Kalantari

    2015-02-01

    Full Text Available Background: Electromagnetic fields (EMF have teratogenic effects during the embryonic development. In current study, histopathological and physiological effects of sinusoidal EMF on the brain were investigated. We sought to determine the apoptosis level and changes in blood brain barrier permeability in brain tissue of pre-incubated white leghorn hen eggs in the field of EMF. Materials and Methods: In this experimental study, 300 healthy, fresh, and fertilized eggs (55-65 g were divided into experimental (3 groups, N=50, control (N=75 and sham (N=75 groups. Experimental eggs (inside the coil were exposed to 3 different intensities of 1.33, 2.66 and 7.32 mT and sham groups were also located inside the same coil but with no exposure, for 24 hrs before incubation. Control, sham and experimental groups were incubated in an incubator (38±0.5ºC, 60% humidity. Brains of 14 day old chicken embryos of all groups were removed, fixed in formalin (10%, stained with H & E and TUNEL, apoptotic cells were studied under light microscope. Brains of other embryos were prepared for scanning electron microscope. By injections of Evans blue, any possible changes in brain vessels were also investigated. Results: Our results showed electromagnetic fields have toxic effects on cell organelles and cell membranes. EMF would increase the level of cellular apoptosis in the brain. They also would tear up the blood vessels. Thereafter, they would affect the permeability of blood brain barrier of exposed chicken embryos. Conclusion: These findings suggest that electromagnetic fields induce different degrees of brain damages in chicken embryos brain tissue.

  19. Disruption of the blood-brain interface in neonatal rat neocortex induces a transient expression of metallothionein in reactive astrocytes

    DEFF Research Database (Denmark)

    Penkowa, M; Moos, T

    1995-01-01

    rats were subjected to a localized freeze lesion of the neocortex of the right temporal cortex. This lesion results in a disrupted blood-brain interface, leading to extravasation of plasma proteins. From 16 h, reactive astrocytosis, defined as an increase in the number and size of cells expressing GFAP......Exposure of the adult rat brain parenchyma to zinc induces an increase in the intracerebral expression of the metal-binding protein, metallothionein, which is normally confined to astrocytes, ependymal cells, choroid plexus epithelial cells, and brain endothelial cells. Metallothionein is expressed...... only in diminutive amounts in astrocytes of the neonatal rat brain, which could imply that neonatal rats are devoid of the capacity to detoxify free metals released from a brain wound. In order to examine the influence of a brain injury on the expression of metallothionein in the neonatal brain, PO...

  20. A study of the blood brain barrier and an evaluation of demyelination in tuberculous meningitis

    International Nuclear Information System (INIS)

    The blood brain barrier (BBB) plays an important role in the regulation of homeostasis of the CNS. The effect of tuberculous meningitis (TBM) on the BBB was studied using a ratio of serum albumin-CSF albumin levels. During the acute stage of meningitis 80% of the patients had moderate to severe disturbances in the BBB that persisted 1 to 3 months post therapy. Neurological damage was assessed using Myelin Basic Protein (CBP) as marker. Over 62% of patients with TBM had a significantly high level of MBP. (author). 19 refs, 5 tabs

  1. Does sumatriptan cross the blood-brain barrier in animals and man?

    DEFF Research Database (Denmark)

    Tfelt-Hansen, Peer

    2010-01-01

    Sumatriptan, a relatively hydrophilic triptan, based on several animal studies has been regarded to be unable to cross the blood-brain barrier (BBB). In more recent animal studies there are strong indications that sumatriptan to some extent can cross the BBB. The CNS adverse events of sumatriptan...... in migraine patients and normal volunteers also indicate a more general effect of sumatriptan on CNS indicating that the drug can cross the BBB in man. It has been discussed whether a defect in the BBB during migraine attacks could be responsible for a possible central effect of sumatriptan in migraine...

  2. Human Umbilical Cord Blood Stem Cells: Rational for Use as a Neuroprotectant in Ischemic Brain Disease

    Directory of Open Access Journals (Sweden)

    Hadar Arien-Zakay

    2010-09-01

    Full Text Available The use of stem cells for reparative medicine was first proposed more than three decades ago. Hematopoietic stem cells from bone marrow, peripheral blood and human umbilical cord blood (CB have gained major use for treatment of hematological indications. CB, however, is also a source of cells capable of differentiating into various non-hematopoietic cell types, including neural cells. Several animal model reports have shown that CB cells may be used for treatment of neurological injuries. This review summarizes the information available on the origin of CB-derived neuronal cells and the mechanisms proposed to explain their action. The potential use of stem/progenitor cells for treatment of ischemic brain injuries is discussed. Issues that remain to be resolved at the present stage of preclinical trials are addressed.

  3. Probing Brain Oxygenation with Near Infrared spectroscopy, the Role of Carbon Dioxide and Blood Pressure

    CERN Document Server

    Gersten, Alexander

    2015-01-01

    The fundamentals of near infrared spectroscopy (NIRS) are reviewed. Among the major factors controlling the cerebral blood flow (CBF), the effect of PaCO2 is peculiar in that it violates autoregulatory CBF mechanisms and allows to explore the full range of the CBF. A simple physical model, with a four parameter formula, relating the CBF to PaCO2 is presented. It can be used to transform the fits of one animal to the fits of another one. It enable the use of rats data as monkeys data simply by rescaling the PaCO2 values and the CBF data. Controlled breathing can change the PaCO2. Experiments on human subjects relating the PaCO2 to rSO2, measured with brain oximeters, are presented. A simple model relating the mean blood pressure to CBF is worked out.

  4. Effect of Dietary Supplementation of Blood Meal and Additional Magnesium on Carnosine and Anserine Concentrations of Pig Muscles

    OpenAIRE

    Park, Se Won; Kim, Chan Ho; Kim, Jong Woong; Shin, Hye Seong; Paik, In Kee; Kil, Dong Yong

    2014-01-01

    The objective of this study was to investigate the effect of dietary supplementation of blood meal as a source of L-histidine, and the addition of magnesium (Mg) as a catalyst of carnosine synthetase for the carnosine and anserine concentrations of pig muscles (longissimus dorsi, LD and vastus intermedius, VI). A total of twenty-four pigs with an average body weight of 60.2±4.2 kg were randomly allotted to one of three dietary treatments (eight replicates), during 56 d of the feeding trial. D...

  5. The state of glutathion system of blood, brain and liver of white rats after chronic gamma-irradiation

    International Nuclear Information System (INIS)

    The effects of 3-fold gamma-irradiation in total dose 0,75 Gy on the glutathion system in different periods after exposure (1 hour, 1 day, 1 and 4 weeks) in blood, brain and liver of white rats were studied. It was concluded that liver and brain have higher ability to maintain the stability of antioxidant system than blood has. After shot disturbances caused by irradiation in brain and liver the state of glutathion system of detoxication has normalized, while concentration of malonic dialdehyde was raised in all terms. The most pronounced changes of antioxidant system were registered in blood at early terms (1 hour) after irradiation that was manifested in increasing of reduced glutathion content, raising of glutathion reductase and catalase activity. In remote period the activity of this system in blood was exhausted

  6. The effect of high energy electron irradiation on blood-brain barrier permeability to haloperidol and stobadin in rats

    International Nuclear Information System (INIS)

    The heads of rats were irradiated by 4 MeV electrons in doses 90, 180, and 360 Gy. The observed times of deaths ranged 120-600, 60-420, and 150-370 min after 90, 180, and 360 Gy, respectively. A dose dependent decrease of the brain uptake index of haloperidol was observed 1 and 3 h post radiation. On the other hand an increased brain uptake index was found for stobadin after head irradiation with doses of 180 and 360 Gy. Regional cerebral blood flow, blood pressure, and heart rate were not significantly altered in the period following irradiation with 180 Gy. The observed changes in blood-brain barrier (BBB) permeability seem to be the result of the damaged function of morphological structures forming the BBB rather than altered regional blood flow. (orig.)

  7. Experimental studies on local radiation injuries of the brain as a result of sup(99m)Tc penetration through the blood-brain barrier

    Energy Technology Data Exchange (ETDEWEB)

    Zolotov, V.A.; Lomanov, M.F.; Luk' yashin, V.E.; Shimchuk, G.G.; Minakova, E.I.; Lundkvist, Kh.; Rozander, Ch. (Gosudarstvennyj Komitet po Ispol' zovaniyu Atomnoj Ehnergii SSSR, Moscow. Inst. Teoreticheskoj i Ehksperimental' noj Fiziki; Akademiya Meditsinskikh Nauk SSSR, Moscow. Inst. Nevrologii)

    1982-07-01

    Studies on the blood-brain barrier have shown that disturbance of its permeability with reference to some dyes and radioactive tracers precedes histological changes found in the brain tissues. The paper is concerned with the techniques of detection of early changes in the blood-brain barrier during life-time after local irradiation of the brain with the proton beam, 5-7 mm in diameter. The use of sup(99m)Tc-pertechnate makes it possible to give a qualitative evaluation of the time course of radiation reactions in animals and to gain quite rapidly experimental data on the development of radiation injuries without killing large groups of experimental animals.

  8. Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase

    DEFF Research Database (Denmark)

    Matthews, V B; Åström, Maj-Brit; Chan, M H S;

    2009-01-01

    AIMS/HYPOTHESIS: Brain-derived neurotrophic factor (BDNF) is produced in skeletal muscle, but its functional significance is unknown. We aimed to determine the signalling processes and metabolic actions of BDNF. METHODS: We first examined whether exercise induced BDNF expression in humans. Next, C2......(79)) were analysed, as was fatty acid oxidation (FAO). Finally, we electroporated a Bdnf vector into the tibialis cranialis muscle of mice. RESULTS: BDNF mRNA and protein expression were increased in human skeletal muscle after exercise, but muscle-derived BDNF appeared not to be released...

  9. The interaction of carbon nanotubes with an in vitro blood-brain barrier model and mouse brain in vivo

    OpenAIRE

    Kafa, Houmam; Wang, Julie Tzu-Wen; Rubio, Noelia; Venner, Kerrie; Anderson, Glenn; Pach, Elzbieta; Ballesteros, Belén; Preston, Jane E.; Abbott, N. Joan; Al-Jamal, Khuloud T.

    2015-01-01

    Carbon nanotubes (CNTs) are a novel nanocarriers with interesting physical and chemical properties. Here we investigate the ability of amino-functionalized multi-walled carbon nanotubes (MWNTs-NH3(+)) to cross the Blood-Brain Barrier (BBB) in vitro using a co-culture BBB model comprising primary porcine brain endothelial cells (PBEC) and primary rat astrocytes, and in vivo following a systemic administration of radiolabelled f-MWNTs. Transmission Electron microscopy (TEM) confirmed that MWNTs...

  10. Lack of independent effect of type 2 diabetes beyond characteristic comorbidities and medications on small muscle mass exercising muscle blood flow and exercise tolerance.

    Science.gov (United States)

    Poitras, Veronica J; Bentley, Robert F; Hopkins-Rosseel, Diana H; LaHaye, Stephen A; Tschakovsky, Michael E

    2015-08-01

    Persons with type 2 diabetes (T2D) are believed to have reduced exercise tolerance; this may be partly due to impaired exercising muscle blood flow (MBF). Whether there is an impact of T2D on exercising MBF within the typical constellation of comorbidities (hypertension, dyslipidemia, obesity) and their associated medications has not been investigated. We tested the hypothesis that small muscle mass exercise tolerance is reduced in persons with T2D versus Controls (matched for age, body mass index, fitness, comorbidities, non-T2D medications) and that this is related to blunted MBF. Eight persons with T2D and eight controls completed a forearm critical force (fCFimpulse) test as a measure of exercise tolerance (10-min intermittent maximal effort forearm contractions; the average contraction impulse in the last 30 sec quantified fCFimpulse). Forearm blood flow (FBF; ultrasound) and mean arterial pressure (MAP; finger photoplethysmography) were measured; forearm vascular conductance (FVK) was calculated. Data are means ± SD, T2D versus Control. fCFimpulse was not different between groups (136.9 ± 47.3  N·sec vs. 163.1 ± 49.7 N·sec, P = 0.371) nor was the ∆FBF from rest to during exercise at fCFimpulse (502.9 ± 144.6 vs. 709.1 ± 289.2 mL/min, P = 0.092), or its determinants ∆FVK and ∆MAP (both P > 0.05), although there was considerable interindividual variability. ∆FBF was strongly related to fCFimpulse (r = 0.727, P = 0.002), providing support for the relationship between oxygen delivery and exercise tolerance. We conclude that small muscle mass exercising MBF and exercise tolerance are not impaired in representative persons with T2D versus appropriately matched controls. This suggests that peripheral vascular control impairment does not contribute to reduced exercise tolerance in this population. PMID:26265750

  11. Effects of ionizing radiation on the blood brain barrier permeability to pharmacologically active substances

    Energy Technology Data Exchange (ETDEWEB)

    Trnovec, T.; Kallay, Z.; Bezek, S. (Institute of Experimental Pharmacology, Bratislava (Yugoslavia))

    1990-12-01

    Ionizing radiation can impair the integrity of the blood brain barrier (BBB). Data on early and late damage after brain irradiation are usually reported separately, yet a gradual transition between these two types has become evident. Signs appearing within 3 weeks after irradiation are considered to be early manifestations. The mechanism of radiation-effected integrity impairment of the BBB is discussed in relation to changes in morphological structures forming the BBB, the endothelium of intracerebral vessels, and in the surrounding astrocytes. Alterations in the function of the BBB are manifested in the endothelium by changes in the ultrastructural location of the activity of phosphatases and by the activation of pinocytotic vesicular transport, and in astrocyte cytoplasm by glycogen deposition. The changes in ultrastructure were critically surveyed with regard to increasing doses of radiation to the brain in the range of 5 Gy to 960 Gy. The qualitative as well as the semiquantitative and quantitative observations on the passage of substances across the damaged BBB were treated separately. Qualitative changes are based mainly on findings of extravasation of vital stains and of labelled proteins. The quantitative studies established differences in radiation-induced changes in the permeability of the BBB depending on the structure and physico-chemical properties of the barrier penetrating tracers. Indirect evaluation of radiation-induced BBB changes is based on studies of pharmacological effects of substances acting on the CNS. In conclusion, radiation impairs significantly the integrity of the BBB following single irradiation of the brain with a dose exceeding 10-15 Gy. The response of the BBB to ionizing radiation is dependent both on the dose to which the brain is exposed and on specific properties of the tracer. 68 references.

  12. A novel platform for engineering blood-brain barrier-crossing bispecific biologics.

    Science.gov (United States)

    Farrington, Graham K; Caram-Salas, Nadia; Haqqani, Arsalan S; Brunette, Eric; Eldredge, John; Pepinsky, Blake; Antognetti, Giovanna; Baumann, Ewa; Ding, Wen; Garber, Ellen; Jiang, Susan; Delaney, Christie; Boileau, Eve; Sisk, William P; Stanimirovic, Danica B

    2014-11-01

    The blood-brain barrier (BBB) prevents the access of therapeutic antibodies to central nervous system (CNS) targets. The engineering of bispecific antibodies in which a therapeutic "arm" is combined with a BBB-transcytosing arm can significantly enhance their brain delivery. The BBB-permeable single-domain antibody FC5 was previously isolated by phenotypic panning of a naive llama single-domain antibody phage display library. In this study, FC5 was engineered as a mono- and bivalent fusion with the human Fc domain to optimize it as a modular brain delivery platform. In vitro studies demonstrated that the bivalent fusion of FC5 with Fc increased the rate of transcytosis (Papp) across brain endothelial monolayer by 25% compared with monovalent fusion. Up to a 30-fold enhanced apparent brain exposure (derived from serum and cerebrospinal fluid pharmacokinetic profiles) of FC5- compared with control domain antibody-Fc fusions after systemic dosing in rats was observed. Systemic pharmacological potency was evaluated in the Hargreaves model of inflammatory pain using the BBB-impermeable neuropeptides dalargin and neuropeptide Y chemically conjugated with FC5-Fc fusion proteins. Improved serum pharmacokinetics of Fc-fused FC5 contributed to a 60-fold increase in pharmacological potency compared with the single-domain version of FC5; bivalent and monovalent FC5 fusions with Fc exhibited similar systemic pharmacological potency. The study demonstrates that modular incorporation of FC5 as the BBB-carrier arm in bispecific antibodies or antibody-drug conjugates offers an avenue to develop pharmacologically active biotherapeutics for CNS indications. PMID:25070367

  13. In the unloaded lower leg, vibration extrudes venous blood out of the calf muscles probably by direct acceleration and without arterial vasodilation

    OpenAIRE

    Zange, Jochen; Molitor, Sven; Illbruck, Agnes; Müller, Klaus; Schönau, Eckhard; Kohl-Bareis, Matthias; Rittweger, Jörn

    2014-01-01

    Purpose During vibration of the whole unloaded lower leg, effects on capillary blood content and blood oxygenation were measured in the calf muscle. The hypotheses predicted extrusion of venous blood by a tonic reflex contraction and that reactive hyperaemia could be observed after vibration. Methods Twelve male subjects sat in front of a vibration platform with their right foot affixed to the platform. In four intervals of 3-min duration vibration was applied with a peak-to-peak displacement...

  14. In the unloaded lower leg, vibration extrudes venous blood out of the calf muscles probably by direct acceleration and without arterial vasodilation

    OpenAIRE

    Zange, Jochen; Molitor, Sven; Illbruck, Agnes; Müller, Klaus; Schönau, Eckhard; Kohl-Bareis, Matthias; Rittweger, Jörn

    2014-01-01

    Purpose During vibration of the whole unloaded lower leg, effects on capillary blood content and blood oxygenation were measured in the calf muscle. The hypotheses predicted extrusion of venous blood by a tonic reflex contraction and that reactive hyperaemia could be observed after vibration. Methods T welve male subjects sat in front of a vibration platform with their right foot affixed to the platform. In four intervals of 3-min duration vibration was applied with ...

  15. Effects of MDMA on blood glucose levels and brain glucose metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Soto-Montenegro, M.L.; Vaquero, J.J.; Garcia-Barreno, P.; Desco, M. [Hospital General Universitario Gregorio Maranon, Laboratorio de Imagen, Medicina Experimental, Madrid (Spain); Arango, C. [Hospital General Gregorio Maranon, Departamento de Psiquiatria, Madrid (Spain); Ricaurte, G. [Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD (United States)

    2007-06-15

    This study was designed to assess changes in glucose metabolism in rats administered single or repeated doses of MDMA. Two different experiments were performed: (1) A single-dose study with four groups receiving 20 mg/kg, 40 mg/kg, saline or heat, and (2) a repeated-dose study with two groups receiving three doses, at intervals of 2 h, of 5 mg/kg or saline. Rats were imaged using a dedicated small-animal PET scanner 1 h after single-dose administration or 7 days after repeated doses. Glucose metabolism was measured in 12 cerebral regions of interest. Rectal temperature and blood glucose were monitored. Peak body temperature was reached 1 h after MDMA administration. Blood glucose levels decreased significantly after MDMA administration. In the single-dose experiment, brain glucose metabolism showed hyperactivation in cerebellum and hypo-activation in the hippocampus, amygdala and auditory cortex. In the repeated-dose experiment, brain glucose metabolism did not show any significant change at day 7. These results are the first to indicate that MDMA has the potential to produce significant hypoglycaemia. In addition, they show that MDMA alters glucose metabolism in components of the motor, limbic and somatosensory systems acutely but not on a long-term basis. (orig.)

  16. Effects of MDMA on blood glucose levels and brain glucose metabolism

    International Nuclear Information System (INIS)

    This study was designed to assess changes in glucose metabolism in rats administered single or repeated doses of MDMA. Two different experiments were performed: (1) A single-dose study with four groups receiving 20 mg/kg, 40 mg/kg, saline or heat, and (2) a repeated-dose study with two groups receiving three doses, at intervals of 2 h, of 5 mg/kg or saline. Rats were imaged using a dedicated small-animal PET scanner 1 h after single-dose administration or 7 days after repeated doses. Glucose metabolism was measured in 12 cerebral regions of interest. Rectal temperature and blood glucose were monitored. Peak body temperature was reached 1 h after MDMA administration. Blood glucose levels decreased significantly after MDMA administration. In the single-dose experiment, brain glucose metabolism showed hyperactivation in cerebellum and hypo-activation in the hippocampus, amygdala and auditory cortex. In the repeated-dose experiment, brain glucose metabolism did not show any significant change at day 7. These results are the first to indicate that MDMA has the potential to produce significant hypoglycaemia. In addition, they show that MDMA alters glucose metabolism in components of the motor, limbic and somatosensory systems acutely but not on a long-term basis. (orig.)

  17. Accuracy of PET RCBF measurements: effect of time shift between blood and brain radioactivity curves

    International Nuclear Information System (INIS)

    Analytic expressions were derived for estimating the error in PET RCBF measurements associated with the time lag between brain and blood radioactivity following bolus H215O injection and during non-steady-state CO15O inhalation. This lag time reflects the physiological difference in arrival times of 15O activity at brain and radial arterial sampling site as well as the experimentally introduced resistance to flow offered by the arterial catheter/stopcock assembly. Multiple measurements of this time lag ranged between 1 and 10 s. For non-steady-state CO15O PET measurements, estimated errors in RCBF ranged from 0.02 to 30% for delays of 2-8 s and scan lengths of 30-180 s. In the range 20-100 ml min-1 per 100 g, variations in RCBF only marginally affected these errors. Errors increased with longer delays but decreased sharply with scan durations greater than 60 s. For 30-180 s scans, even larger errors are associated with the H215O injection technique (peak blood activity at 10 s): 1-60% for delays of 2-8 s. A 'slow' bolus peaking at 20 s decreased the error by 40%. For the H215O method it is essential to estimate the time shift to within 2 s if accurate flow measurements (error less than 5%) are to be obtained from 40-60 s scans. (author)

  18. Role of Microfluidics in Blood-Brain Barrier Permeability Cell Culture Modeling: Relevance to CNS Disorders.

    Science.gov (United States)

    Rusanov, Alexander L; Luzgina, Natalia G; Barreto, George E; Aliev, Gjumrakch

    2016-01-01

    In vitro modeling of the human blood-brain barrier (BBB) is critical for pre-clinical evaluation and predicting the permeability of newly developed potentially neurotoxic and neurotrophic drugs. Here we summarize the specific structural and functional features of endothelial cells as a key component of the BBB and compare analysis of different cell culture models in reflecting these features. Particular attention is paid to cellular models of the BBB in microfluidic devices capable of circulating nutrient media to simulate the blood flow of the brain. In these conditions, it is possible to reproduce a number of factors affecting endothelial cells under physiological conditions, including shear stress. In comparison with static cell models, concentration gradients, which determine the velocity of transport of substances, reproduce more accurately conditions of nutrient medium flow, since they eliminate the accumulation of substances near the basal membrane of cells, not typical for the situation in vivo. Co-cultivation of different types of cells forming the BBB, in separate cell chambers connected by microchannels, allows to evaluate the mutual influences of cells under normal conditions and when exposed to the test substance. New experimental possibilities that can be achieved through modeling of BBB in microfluidic devices determine the feasibility of their use in the practice for pre-clinical studies of novel drugs against neurodegenerative diseases. PMID:26831260

  19. Contrasted study on the opening degree of blood-brain barriier after radiation therapy with SPECT and MRI

    International Nuclear Information System (INIS)

    The blood-brain barrier(BBB) is the largest barrier responsible for preventing direct contact between chemotherapeutic drugs in blood and tumors in brain, the permeability of BBB incease at different degree after brain irradiation in clinical brain tumors radiotherapy. Methods: In our study, 26 patients with metastatic brain tumors(21 cases in pr/mary lung carcinoma, 5 cases in breast carcinoma) were accepted the full brain irradiation. The detructive effects of radiation on the BBB were determined by the 99mTc-DTPA SPECT and the concentration ratio of methotrexate(MTX) in cerebrospinal fluid(CSF) and blood, the brain MRI before and after radiotherapy were retrospective contrasted study with SPECT. Results: the degree of destructive effect on the BBB was directly proportional to radiation doses. After a dose of 20Gy radiation to brain, the permeability of BBB inceased markedly(P<0.01). But in cases the dexamethasone(DXM) was administrated to decease the brain edema during radiotherapy, the permeability inceased less than that in patients without DXM(P<0.05). Conclutions: After 20Gy irradiation, the BBB would gradually open. At this time, chemotherapy is the best choice to improving the therapeutic effect. Dexamethasone was found to cause the decease in BBB permeability but no significant remission of brain edema. So, if the combination of radiotherapy and chemotherapy in treatment of metastatic brain tumors will be plan, the dexamethasone may be not used in expecting to deceasing the side effect and that no affecting the therapeutic effect. (authors)

  20. Altered blood-brain barrier permeability in rats with prehepatic portal hypertension turns to normal when portal pressure is lowered

    Institute of Scientific and Technical Information of China (English)

    Francisco Eizayaga; Camila Scorticati; Juan P Prestifilippo; Salvador Romay; Maria A Fernandez; José L Castro; Abraham Lemberg; Juan C Perazzo

    2006-01-01

    AIM: To study the blood-brain barrier integrity in prehepatic portal hypertensive rats induced by partial portal vein ligation, at 14 and 40 d after ligation when portal pressure is spontaneously normalized.METHODS: Adult male Wistar rats were divided into four groups: Group Ⅰ: Sham14d, sham operated; Group Ⅱ: PH14d, portal vein stenosis; (both groups were used 14 days after surgery); Group Ⅲ: Sham40d, Sham operated and Group Ⅳ: PH40d Portal vein stenosis (Groups Ⅱ and Ⅳ used 40 d after surgery). Plasma ammonia,plasma and cerebrospinal fluid protein and liver enzymes concentrations were determined. Trypan and Evans blue dyes, systemically injected, were investigated in hippocampus to study blood-brain barrier integrity. Portal pressure was periodically recorded.RESULTS: Forty days after stricture, portal pressure was normalized, plasma ammonia was moderately high,and both dyes were absent in central nervous system parenchyma. All other parameters were reestablished.When portal pressure was normalized and ammonia level was lowered, but not normal, the altered integrity of blood-brain barrier becomes reestablished.CONCLUSION: The impairment of blood-brain barrier and subsequent normalization could be a mechanism involved in hepatic encephalopathy reversibility. Hemodynamic changes and ammonia could trigger blood-brain barrier alterations and its reestablishment.

  1. Agent based modeling of the effects of potential treatments over the blood-brain barrier in multiple sclerosis.

    Science.gov (United States)

    Pennisi, Marzio; Russo, Giulia; Motta, Santo; Pappalardo, Francesco

    2015-12-01

    Multiple sclerosis is a disease of the central nervous system that involves the destruction of the insulating sheath of axons, causing severe disabilities. Since the etiology of the disease is not yet fully understood, the use of novel techniques that may help to understand the disease, to suggest potential therapies and to test the effects of candidate treatments is highly advisable. To this end we developed an agent based model that demonstrated its ability to reproduce the typical oscillatory behavior observed in the most common form of multiple sclerosis, relapsing-remitting multiple sclerosis. The model has then been used to test the potential beneficial effects of vitamin D over the disease. Many scientific studies underlined the importance of the blood-brain barrier and of the mechanisms that influence its permeability on the development of the disease. In the present paper we further extend our previously developed model with a mechanism that mimics the blood-brain barrier behavior. The goal of our work is to suggest the best strategies to follow for developing new potential treatments that intervene in the blood-brain barrier. Results suggest that the best treatments should potentially prevent the opening of the blood-brain barrier, as treatments that help in recovering the blood-brain barrier functionality could be less effective. PMID:26343337

  2. Interaction of Acupuncture and Electroacupuncture on the Pharmacokinetics of Aspirin and the Effect of Brain Blood Flow in Rats

    Directory of Open Access Journals (Sweden)

    Ming-Tsang Wu

    2013-01-01

    Full Text Available Acupuncture and electroacupuncture have been used to improve the brain and motor functions of poststroke patients, and aspirin is used for the prevention of stroke recurrence. Our hypothesis is that acupuncture and electroacupuncture treatments may interact with aspirin in terms of pharmacokinetics via affecting the brain blood flow. The aim of this study is to investigate the potential interactions of acupuncture and electroacupuncture on the pharmacokinetics of aspirin. The effects of acupuncture treatments on brain blood flow were measured by the laser Doppler blood flow imager. The parallel pharmacokinetic study design included three groups: control, acupuncture, and electroacupuncture groups. Two acupoints, namely, Quchi (LI 11 and Zusanli (ST 36, were needled and stimulated electronically in anaesthetized rats. The concentrations of aspirin and its metabolite, salicylic acid were determined by microdialysis and HPLC analysis after aspirin administration (30 mg/kg, i.v.. The brain blood flow responded to electroacupuncture treatments, but the pharmacokinetic parameters of aspirin and salicylic acid in blood and brain were not significantly changed by acupuncture and electroacupuncture treatments. This study may, in part, offer some evidence to support the contention that there is no significant interaction for the combination of aspirin with acupuncture or electroacupuncture.

  3. Interaction of acupuncture and electroacupuncture on the pharmacokinetics of aspirin and the effect of brain blood flow in rats.

    Science.gov (United States)

    Wu, Ming-Tsang; Shaw, Lee-Hsin; Wu, Yu-Tse; Tsai, Tung-Hu

    2013-01-01

    Acupuncture and electroacupuncture have been used to improve the brain and motor functions of poststroke patients, and aspirin is used for the prevention of stroke recurrence. Our hypothesis is that acupuncture and electroacupuncture treatments may interact with aspirin in terms of pharmacokinetics via affecting the brain blood flow. The aim of this study is to investigate the potential interactions of acupuncture and electroacupuncture on the pharmacokinetics of aspirin. The effects of acupuncture treatments on brain blood flow were measured by the laser Doppler blood flow imager. The parallel pharmacokinetic study design included three groups: control, acupuncture, and electroacupuncture groups. Two acupoints, namely, Quchi (LI 11) and Zusanli (ST 36), were needled and stimulated electronically in anaesthetized rats. The concentrations of aspirin and its metabolite, salicylic acid were determined by microdialysis and HPLC analysis after aspirin administration (30 mg/kg, i.v.). The brain blood flow responded to electroacupuncture treatments, but the pharmacokinetic parameters of aspirin and salicylic acid in blood and brain were not significantly changed by acupuncture and electroacupuncture treatments. This study may, in part, offer some evidence to support the contention that there is no significant interaction for the combination of aspirin with acupuncture or electroacupuncture. PMID:24371465

  4. Development of brain damage as measured by brain impedance recordings, and changes in heart rate, and blood pressure induced by different stunning and killing methods.

    Science.gov (United States)

    Savenije, B; Lambooij, E; Gerritzen, M A; Korf, J

    2002-04-01

    Poultry are electrically stunned before slaughter to induce unconsciousness and to immobilize the chickens for easier killing. From a welfare point of view, electrical stunning should induce immediate and lasting unconsciousness in the chicken. As an alternative to electroencephalography, which measures brain electrical activity, this study used brain impedance recordings, which measure brain metabolic activity, to determine the onset and development of brain damage. Fifty-six chickens were surgically equipped with brain electrodes and a canula in the wing artery and were subjected to one of seven stunning and killing methods: whole body electrical stunning; head-only electrical stunning at 50, 100 or 150 V; or an i.v. injection with MgCl2. After 30 s, the chickens were exsanguinated. Brain impedance and blood pressure were measured. Extracellular volume was determined from the brain impedance data and heart rate from the blood pressure data. An immediate and progressive reduction in extracellular volume in all chickens was found only with whole body stunning at 150 V. This treatment also caused cardiac fibrillation or arrest in all chickens. With all other electrical stunning treatments, extracellular volume was immediately reduced in some but not all birds, and cardiac fibrillation or arrest was not often found. Ischemic conditions, caused by cessation of the circulation, stimulated this epileptic effect. A stunner setting of 150 V is therefore recommended to ensure immediate and lasting unconsciousness, which is a requirement for humane slaughter. PMID:11989758

  5. Metal levels in blood, muscle and liver of water snakes (Nerodia spp.) from New Jersey, Tennessee and South Carolina

    International Nuclear Information System (INIS)

    Reptiles, particularly snakes, could serve as bioindicators of contamination because some are comparatively long-lived, exhibit different trophic levels, and are at the top of their food chains. We test the null hypothesis that there are no differences in the concentrations of heavy metals in the blood, muscle and liver of water snakes (Nerodia spp.) from rivers in New Jersey, Tennessee and South Carolina. While the former site is in an urban/suburban area, the latter two sites are relatively rural and are located on Department of Energy sites. For the snakes from New Jersey, there were significant differences in metal concentrations among tissues for all metals, the highest levels for arsenic and selenium were in liver and kidney, for cadmium were in the liver, for chromium and lead were in skin, and for mercury and manganese were in the muscle. Body length was not correlated with metal levels, and there were more significant correlations for skin with internal tissues than for blood with other tissues. There were more significant correlations for mercury than for other metals. In comparing metal levels among states, levels were generally higher for snakes collected from South Carolina. These data indicate that, since water snakes accumulate contaminants differentially as a function of location, they can be useful bioindicators of environmental exposure to contaminants. Moreover, because of their wide geographical distribution and use of varying trophic compartments, this genus can be useful for cross-site comparisons

  6. Clinical trial of blood-brain barrier disruption by pulsed ultrasound.

    Science.gov (United States)

    Carpentier, Alexandre; Canney, Michael; Vignot, Alexandre; Reina, Vincent; Beccaria, Kevin; Horodyckid, Catherine; Karachi, Carine; Leclercq, Delphine; Lafon, Cyril; Chapelon, Jean-Yves; Capelle, Laurent; Cornu, Philippe; Sanson, Marc; Hoang-Xuan, Khê; Delattre, Jean-Yves; Idbaih, Ahmed

    2016-06-15

    The blood-brain barrier (BBB) limits the delivery of systemically administered drugs to the brain. Methods to circumvent the BBB have been developed, but none are used in standard clinical practice. The lack of adoption of existing methods is due to procedural invasiveness, serious adverse effects, and the complications associated with performing such techniques coincident with repeated drug administration, which is customary in chemotherapeutic protocols. Pulsed ultrasound, a method for disrupting the BBB, was shown to effectively increase drug concentrations and to slow tumor growth in preclinical studies. We now report the interim results of an ultrasound dose-escalating phase 1/2a clinical trial using an implantable ultrasound device system, SonoCloud, before treatment with carboplatin in patients with recurrent glioblastoma (GBM). The BBB of each patient was disrupted monthly using pulsed ultrasound in combination with systemically injected microbubbles. Contrast-enhanced magnetic resonance imaging (MRI) indicated that the BBB was disrupted at acoustic pressure levels up to 1.1 megapascals without detectable adverse effects on radiologic (MRI) or clinical examination. Our preliminary findings indicate that repeated opening of the BBB using our pulsed ultrasound system, in combination with systemic microbubble injection, is safe and well tolerated in patients with recurrent GBM and has the potential to optimize chemotherapy delivery in the brain. PMID:27306666

  7. Drug and xenobiotic biotransformation in the blood-brain barrier: A neglected issue.

    Directory of Open Access Journals (Sweden)

    José A.G. Agúndez

    2014-10-01

    Full Text Available Drug biotransformation is a crucial mechanism for facilitating the elimination of chemicals from the organism and for decreasing their pharmacological activity. Published evidence suggests that brain drug metabolism may play a role in the development of adverse drug reactions and in the clinical response to drugs and xenobiotics. The blood-brain barrier (BBB has been regarded mainly as a physical barrier for drugs and xenobiotics, and little attention has been paid to BBB as a drug-metabolizing barrier. The presence of drug metabolizing enzymes in the BBB is likely to have functional implications because local metabolism may inactivate drugs or may modify the drug's ability to cross the BBB, thus modifying the drug response and the risk of developing adverse drug reactions. In this perspective paper, we discuss the expression of relevant xenobiotic metabolizing enzymes in the brain and in the BBB, and we cover current advances and future directions on the potential role of these BBB drug-metabolizing enzymes as modifiers of drug response.

  8. Blood-Brain Barrier Dysfunction as a Hallmark Pathology in Chronic Traumatic Encephalopathy.

    Science.gov (United States)

    Doherty, Colin P; O'Keefe, Eoin; Wallace, Eugene; Loftus, Teresa; Keaney, James; Kealy, John; Humphries, Marian M; Molloy, Michael G; Meaney, James F; Farrell, Michael; Campbell, Matthew

    2016-07-01

    Chronic traumatic encephalopathy (CTE) is a neurodegenerative condition associated with repetitive mild traumatic brain injury. In recent years, attention has focused on emerging evidence linking the development of CTE to concussive injuries in athletes and military personnel; however, the underlying molecular pathobiology of CTE remains unclear. Here, we provide evidence that the blood-brain barrier (BBB) is disrupted in regions of dense perivascular p-Tau accumulation in a case of CTE. Immunoreactivity patterns of the BBB-associated tight junction components claudin-5 and zonula occludens-1 were markedly discontinuous or absent in regions of perivascular p-Tau deposition; there was also immunohistochemical evidence of a BBB in these foci. Because the patient was diagnosed premortem clinically as having progressive supranuclear palsy (PSP), we also compromised that the CTE alterations appear to be distinct from those in the brain of a patient with PSP. This report represents the first description of BBB dysfunction in a pathologically proven CTE case and suggests a vascular component in the postconcussion cascade of events that may ultimately lead to development of a progressive degenerative disorder. BBB dysfunction may represent a correlate of neural dysfunction in live subjects suspected of being at risk for development of CTE. PMID:27245243

  9. Study on permeability of the recombinant β-NGF through blood-brain barrier

    International Nuclear Information System (INIS)

    Objective: Study on the permeability of rhβ-nerve growth factors (NGF) through blood brain barrier (BBB) to provide scientific basis for research of β-NGF in clinical therapeutic application. Methods: to transfect the COS-7 cell line with recombination expressive vector, PcDNA3-β-NGF, by lipofectamine. The proteins, produced in the supernatant by the transfected cells, was isolated and purified by ion exchange chromatography on carboxymethyl cellulose. The biological activity of the purified protein was analyzed by the prospection of processes grow out from PC12 cell line; and the protein was labelled with 125I and injected i.v into rats, and then the radioactivity of rat brain tissue was analyzed by γ scintillometer. Results: The purified protein could stimulate the process growth of PC12 cell line and the results of γ scintigraphy analysis showed that the radioactivity achieved high level in rat brain tissue 30 min after the protein injection. Conclusion: Purified rhβ-NGF has good biological activity and it could partially penetrate the BBB

  10. Addressing safety liabilities of TfR bispecific antibodies that cross the blood-brain barrier.

    Science.gov (United States)

    Couch, Jessica A; Yu, Y Joy; Zhang, Yin; Tarrant, Jacqueline M; Fuji, Reina N; Meilandt, William J; Solanoy, Hilda; Tong, Raymond K; Hoyte, Kwame; Luk, Wilman; Lu, Yanmei; Gadkar, Kapil; Prabhu, Saileta; Ordonia, Benjamin A; Nguyen, Quyen; Lin, Yuwen; Lin, Zhonghua; Balazs, Mercedesz; Scearce-Levie, Kimberly; Ernst, James A; Dennis, Mark S; Watts, Ryan J

    2013-05-01

    Bispecific antibodies using the transferrin receptor (TfR) have shown promise for boosting antibody uptake in brain. Nevertheless, there are limited data on the therapeutic properties including safety liabilities that will enable successful development of TfR-based therapeutics. We evaluate TfR/BACE1 bispecific antibody variants in mouse and show that reducing TfR binding affinity improves not only brain uptake but also peripheral exposure and the safety profile of these antibodies. We identify and seek to address liabilities of targeting TfR with antibodies, namely, acute clinical signs and decreased circulating reticulocytes observed after dosing. By eliminating Fc effector function, we ameliorated the acute clinical signs and partially rescued a reduction in reticulocytes. Furthermore, we show that complement mediates a residual decrease in reticulocytes observed after Fc effector function is eliminated. These data raise important safety concerns and potential mitigation strategies for the development of TfR-based therapies that are designed to cross the blood-brain barrier. PMID:23636093

  11. Microfluidic modeling of the effects of nanoparticles on the blood-brain barrier in flow

    Science.gov (United States)

    Schwait, Craig; Hartman, Ryan; Bao, Yuping; Xu, Yaolin

    2011-11-01

    The difficulty of diffusing drugs across the blood-brain barrier (BBB) has caused an impasse for many brain treatments. Nanoparticles (NPs), to which drugs can adsorb, attach, or be entrapped, have the potential to deliver drugs past the BBB. Before nanoparticles can be used, their effects on the BBB and brain must be ascertained. Previous steady-state studies fall short for closely modeling in vivo conditions . Convection of nanoparticles is ignored, and endothelial cells' (ECs) morphology differs based on loading conditions; in vitro loading with continuous flow exhibit ECs indicating a more similar in vivo phenotype. NPs interact with monocytes prior to the BBB, and their toxicity effects were measured in flow conditions using both Trypan Blue cell counting and cell proliferation assays. The microfluidic device designed to model the BBB contained a concentric PES hollow fiber porous membrane in PFA tubing. Full use of the device will include ECs adhered on the inner surface and astrocytes adhered to the outer surface of the PES membrane to model cerebrovascular capillaries. Funded by NSF REU Site 1062611.

  12. The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity.

    Science.gov (United States)

    Miner, Jonathan J; Daniels, Brian P; Shrestha, Bimmi; Proenca-Modena, Jose L; Lew, Erin D; Lazear, Helen M; Gorman, Matthew J; Lemke, Greg; Klein, Robyn S; Diamond, Michael S

    2015-12-01

    The TAM receptors Tyro3, Axl and Mertk are receptor tyrosine kinases that dampen host innate immune responses following engagement with their ligands Gas6 and Protein S, which recognize phosphatidylserine on apoptotic cells. In a form of apoptotic mimicry, many enveloped viruses display phosphatidylserine on the outer leaflet of their membranes, enabling TAM receptor activation and downregulation of antiviral responses. Accordingly, we hypothesized that a deficiency of TAM receptors would enhance antiviral responses and protect against viral infection. Unexpectedly, mice lacking Mertk and/or Axl, but not Tyro3, exhibited greater vulnerability to infection with neuroinvasive West Nile and La Crosse encephalitis viruses. This phenotype was associated with increased blood-brain barrier permeability, which enhanced virus entry into and infection of the brain. Activation of Mertk synergized with interferon-β to tighten cell junctions and prevent virus transit across brain microvascular endothelial cells. Because TAM receptors restrict pathogenesis of neuroinvasive viruses, these findings have implications for TAM antagonists that are currently in clinical development. PMID:26523970

  13. Blood-brain barrier properties in vitro depend on composition and assembly of endogenous extracellular matrices.

    Science.gov (United States)

    Zobel, Kathrin; Hansen, Uwe; Galla, Hans-Joachim

    2016-08-01

    Brain capillary endothelial cells, which constitute the blood-brain barrier (BBB), are enveloped by the extracellular matrix (ECM) produced by endothelial cells, pericytes and astrocytes. The contribution of matrix components secreted by the various cell types at the neurovascular unit, however, remains unclear with respect to their effect on endothelial barrier function. In this study, a new in vitro model was established by growing endothelial cells on an ECM produced by pericytes, astrocytes or a serial combination of both. The last-mentioned was found to be more in vivo-like. We investigated the role of the composition and morphology of ECM supra-structures in maintaining BBB function. The composition was analysed by protein analysis (enzyme-linked immunosorbent assay) and the ultrastructure of generated matrices was analysed by transmission electron microscopy including immunogold labelling. We could show by electric cell-substrate impedance sensing measurements that pericytes and combined matrices significantly improved the barrier tightness of porcine brain capillary endothelial cells (PBCEC). The increase of the resistance was verified by enhanced expression of tight junction proteins. Thus, for the first time, we have shown that barrier integrity is strictly controlled by the ECM, which is a product of all cells involved in the secretion of ECM components and their modification by corresponding cells. Moreover, we have demonstrated that complex matrices by the various cells of the BBB induce barrier marker enzymes in PBCEC, such as alkaline phosphatase. PMID:27053246

  14. Early CT perfusion changes and blood-brain barrier permeability after aneurysmal subarachnoid hemorrhage

    International Nuclear Information System (INIS)

    Early brain injury (EBI) can occur within 72 h of aneurysmal subarachnoid hemorrhage (aSAH). The objective of this study was to determine if there are differences in early CTP parameters (<72 h) with respect to delayed cerebral ischemia (DCI), cerebral infarction, and functional outcome. We performed a prospective cohort study of aSAH patients admitted to a single tertiary care center. MTT, CBF and blood-brain barrier permeability (PS) were quantified with CTP within 72 h of aneurysm rupture. Primary outcomes were functional outcome by the Modified Rankin Scale (mRS) at 3 months and cerebral infarction. Secondary outcome was the development of DCI. Differences between early CTP parameters were determined with respect to primary and secondary outcomes. Fifty aSAH patients were included in the final analysis. MTT was significantly higher in patients who developed DCI (6.7 ± 1.2 vs 5.9 ± 1.0; p = 0.03) and cerebral infarction (7.0 ± 1.2 vs 5.9 ± 0.9; p = 0.007); however, no difference in MTT was found between patients with and without a poor outcome (mRS > 2). Early CBF and PS did not differ with respect to functional outcome, DCI, and cerebral infarction. Elevated MTT within 72 h of aneurysm rupture is associated with DCI and cerebral infarction but not with long-term functional outcome. Blood-brain barrier permeability, as assessed by CT perfusion, was not associated with DCI or worse outcome in this cohort. (orig.)

  15. Early CT perfusion changes and blood-brain barrier permeability after aneurysmal subarachnoid hemorrhage

    Energy Technology Data Exchange (ETDEWEB)

    Murphy, Amanda; Bharatha, Aditya [University of Toronto, Department of Medical Imaging, Toronto, ON (Canada); De Oliveira Manoel, Airton Leonardo; Kouzmina, Ekaterina [St. Michael' s Hospital, Toronto (Canada); Burgers, Kyle; Lee, Ting [Robarts Research Institute, London (Canada); Macdonald, R.L. [St. Michael' s Hospital, Department of Neurosurgery, Toronto (Canada)

    2015-08-15

    Early brain injury (EBI) can occur within 72 h of aneurysmal subarachnoid hemorrhage (aSAH). The objective of this study was to determine if there are differences in early CTP parameters (<72 h) with respect to delayed cerebral ischemia (DCI), cerebral infarction, and functional outcome. We performed a prospective cohort study of aSAH patients admitted to a single tertiary care center. MTT, CBF and blood-brain barrier permeability (PS) were quantified with CTP within 72 h of aneurysm rupture. Primary outcomes were functional outcome by the Modified Rankin Scale (mRS) at 3 months and cerebral infarction. Secondary outcome was the development of DCI. Differences between early CTP parameters were determined with respect to primary and secondary outcomes. Fifty aSAH patients were included in the final analysis. MTT was significantly higher in patients who developed DCI (6.7 ± 1.2 vs 5.9 ± 1.0; p = 0.03) and cerebral infarction (7.0 ± 1.2 vs 5.9 ± 0.9; p = 0.007); however, no difference in MTT was found between patients with and without a poor outcome (mRS > 2). Early CBF and PS did not differ with respect to functional outcome, DCI, and cerebral infarction. Elevated MTT within 72 h of aneurysm rupture is associated with DCI and cerebral infarction but not with long-term functional outcome. Blood-brain barrier permeability, as assessed by CT perfusion, was not associated with DCI or worse outcome in this cohort. (orig.)

  16. Preparation of Silica Nanoparticles Loaded with Nootropics and Their In Vivo Permeation through Blood-Brain Barrier

    Science.gov (United States)

    Zaruba, Kamil; Kunes, Martin; Ulbrich, Pavel; Brezaniova, Ingrid; Triska, Jan; Suchy, Pavel

    2015-01-01

    The blood-brain barrier prevents the passage of many drugs that target the central nervous system. This paper presents the preparation and characterization of silica-based nanocarriers loaded with piracetam, pentoxifylline, and pyridoxine (drugs from the class of nootropics), which are designed to enhance the permeation of the drugs from the circulatory system through the blood-brain barrier. Their permeation was compared with non-nanoparticle drug substances (bulk materials) by means of an in vivo model of rat brain perfusion. The size and morphology of the nanoparticles were characterized by transmission electron microscopy. The content of the drug substances in silica-based nanocarriers was analysed by elemental analysis and UV spectrometry. Microscopic analysis of visualized silica nanocarriers in the perfused brain tissue was performed. The concentration of the drug substances in the tissue was determined by means of UHPLC-DAD/HRMS LTQ Orbitrap XL. It was found that the drug substances in silica-based nanocarriers permeated through the blood brain barrier to the brain tissue, whereas bulk materials were not detected in the brain. PMID:26075264

  17. Preparation of Silica Nanoparticles Loaded with Nootropics and Their In Vivo Permeation through Blood-Brain Barrier

    Directory of Open Access Journals (Sweden)

    Josef Jampilek

    2015-01-01

    Full Text Available The blood-brain barrier prevents the passage of many drugs that target the central nervous system. This paper presents the preparation and characterization of silica-based nanocarriers loaded with piracetam, pentoxifylline, and pyridoxine (drugs from the class of nootropics, which are designed to enhance the permeation of the drugs from the circulatory system through the blood-brain barrier. Their permeation was compared with non-nanoparticle drug substances (bulk materials by means of an in vivo model of rat brain perfusion. The size and morphology of the nanoparticles were characterized by transmission electron microscopy. The content of the drug substances in silica-based nanocarriers was analysed by elemental analysis and UV spectrometry. Microscopic analysis of visualized silica nanocarriers in the perfused brain tissue was performed. The concentration of the drug substances in the tissue was determined by means of UHPLC-DAD/HRMS LTQ Orbitrap XL. It was found that the drug substances in silica-based nanocarriers permeated through the blood brain barrier to the brain tissue, whereas bulk materials were not detected in the brain.

  18. Blood vessels and desmin control the positioning of nuclei in skeletal muscle fibers

    DEFF Research Database (Denmark)

    Ralston, E; Lu, Z; Biscocho, N;

    2006-01-01

    Skeletal muscle fibers contain hundreds to thousands of nuclei which lie immediately under the plasmalemma and are spaced out along the fiber, except for a small cluster of specialized nuclei at the neuromuscular junction. How the nuclei attain their positions along the fiber is not understood...

  19. Matrix metalloproteinase-9 expression and blood brain barrier permeability in the rat brain after cerebral ischemia/reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    Lifang Lei; Xiaohong Zi; Qiuyun Tu

    2008-01-01

    BACKGROUND: The integrity of the blood brain barrier (BBB) plays an important role in the patho-physiological process of cerebral ischemia/reperfusion injury. It has been recently observed that metalloproteinase-9 (MMP-9) is closely related to cerebral ischemia/reperfusion injuryOBJECTIVE: This study was designed to observe MMP-9 expression in the rat brain after cerebral ischemia/reperfusion injury and to investigate its correlation to BBB permeability.DESIGN, TIME AND SETTING: This study, a randomized controlled animal experiment, was performed at the Institute of Neurobiology, Central South University between September 2005 and March 2006.MATERIALS: Ninety healthy male SD rats, aged 3-4 months, weighing 200-280g, were used in the present study. Rabbit anti-rat MMP-9 polyclonal antibody (Boster, Wuhan, China) and Evans blue (Sigma, USA) were also used.METHODS: All rats were randomly divided into 9 groups with 10 rats in each group: normal control group, sham-operated group, and ischemia for 2 hours followed by reperfusion for 3,6,12 hours, 1,2,4 and 7 days groups. In the ischemia/reperfusion groups, rats were subjected to ischemia/reperfusion injury by suture occlusion of the right middle cerebral artery. In the sham-operated group, rats were merely subjected to vessel dissociation. In the normal control group, rats were not modeled.MAIN OUTCOME MEASURES: BBB permeability was assessed by determining the level of effusion of Evans blue. MMP-9 expression was detected by an immunohistochemical method.RESULTS: All 90 rats were included in the final analysis. BBB permeability alteration was closely correlated to ischemia/reperfusion time. BBB permeability began to increase at ischemia/reperfusion for 3 hours, then it gradually reached a peak level at ischemia/reperfusion for 1 day, and thereafter it gradually decreased. MMP-9 expression began to increase at ischemia/reperfusion for 3 hours, then gradually reached its peak level 2 days after perfusion, and thereafter

  20. Multiple brain parenchymal neurocysticercosis with extraocular muscle cysticercosis affecting levator palpebral superioris and superior rectus complex: an unusual association

    OpenAIRE

    Verma, Rajesh; Jaiswal, Anupam

    2013-01-01

    An 8-year-old girl presented to the neurology department with a complaint of insidious onset of left-sided ptosis and restricted elevation of the left eye. A CT scan orbit and brain revealed a ring-enhancing lesion in the levator palpebral superioris (LPS) and superior rectus (SR) muscle complex of the left eye and left parietal and right temporal region. She was started on steroid, followed by albendazole with improvement. The LPS/SR complex is the least common site of involvement among extr...

  1. In vivo field dependence of proton relaxation times in human brain, liver and skeletal muscle: a multicenter study

    DEFF Research Database (Denmark)

    Henriksen, O; de Certaines, J D; Spisni, A; Cortsen, M; Muller, R N; Ring, P B

    1993-01-01

    T1 and T2 relaxation times are fundamental parameters for signal contrast behaviour in MRI. A number of ex vivo relaxometry studies have dealt with the magnetic field dispersion of T1. By means of multicenter study within the frame of the COMAC BME Concerted Action on Tissue Characterization by MRI...... and MRS, the in vivo field dispersion of T1 and T2 has been measured in order to evaluate whether ex vivo data are representative for the in vivo situation. Brain, skeletal muscle, and liver of healthy human volunteers were studied. Fifteen MR units with a field strength ranging from 0.08 T to 1.5 T...

  2. Consequences of repeated blood-brain barrier disruption in football players.

    Science.gov (United States)

    Marchi, Nicola; Bazarian, Jeffrey J; Puvenna, Vikram; Janigro, Mattia; Ghosh, Chaitali; Zhong, Jianhui; Zhu, Tong; Blackman, Eric; Stewart, Desiree; Ellis, Jasmina; Butler, Robert; Janigro, Damir

    2013-01-01

    The acknowledgement of risks for traumatic brain injury in American football players has prompted studies for sideline concussion diagnosis and testing for neurological deficits. While concussions are recognized etiological factors for a spectrum of neurological sequelae, the consequences of sub-concussive events are unclear. We tested the hypothesis that blood-brain barrier disruption (BBBD) and the accompanying surge of the astrocytic protein S100B in blood may cause an immune response associated with production of auto-antibodies. We also wished to determine whether these events result in disrupted white matter on diffusion tensor imaging (DT) scans. Players from three college football teams were enrolled (total of 67 volunteers). None of the players experienced a concussion. Blood samples were collected before and after games (n = 57); the number of head hits in all players was monitored by movie review and post-game interviews. S100B serum levels and auto-antibodies against S100B were measured and correlated by direct and reverse immunoassays (n = 15 players; 5 games). A subset of players underwent DTI scans pre- and post-season and after a 6-month interval (n = 10). Cognitive and functional assessments were also performed. After a game, transient BBB damage measured by serum S100B was detected only in players experiencing the greatest number of sub-concussive head hits. Elevated levels of auto-antibodies against S100B were elevated only after repeated sub-concussive events characterized by BBBD. Serum levels of S100B auto-antibodies also predicted persistence of MRI-DTI abnormalities which in turn correlated with cognitive changes. Even in the absence of concussion, football players may experience repeated BBBD and serum surges of the potential auto-antigen S100B. The correlation of serum S100B, auto-antibodies and DTI changes support a link between repeated BBBD and future risk for cognitive changes. PMID:23483891

  3. Slowed muscle oxygen uptake kinetics with raised metabolism are not dependent on blood flow or recruitment dynamics.

    Science.gov (United States)

    Wüst, Rob C I; McDonald, James R; Sun, Yi; Ferguson, Brian S; Rogatzki, Matthew J; Spires, Jessica; Kowalchuk, John M; Gladden, L Bruce; Rossiter, Harry B

    2014-04-15

    Oxygen uptake kinetics (τVO2) are slowed when exercise is initiated from a raised metabolic rate. Whether this reflects the recruitment of muscle fibres differing in oxidative capacity, or slowed blood flow (Q) kinetics is unclear. This study determined τVO2 in canine muscle in situ, with experimental control over muscle activation and Q during contractions initiated from rest and a raised metabolic rate. The gastrocnemius complex of nine anaesthetised, ventilated dogs was isolated and attached to a force transducer. Isometric tetanic contractions (50 Hz; 200 ms duration) via supramaximal sciatic nerve stimulation were used to manipulate metabolic rate: 3 min stimulation at 0.33 Hz (S1), followed by 3 min at 0.67 Hz (S2). Circulation was initially intact (SPON), and subsequently isolated for pump-perfusion (PUMP) above the greatest value in SPON. Muscle VO2 was determined contraction-by-contraction using an ultrasonic flowmeter and venous oximeter, and normalised to tension-time integral (TTI). τVO2/TTI and τQ were less in S1SPON (mean ± s.d.: 13 ± 3 s and 12 ± 4 s, respectively) than in S2SPON (29 ± 19 s and 31 ± 13 s, respectively; P < 0.05). τVO2/TTI was unchanged by pump-perfusion (S1PUMP, 12 ± 4 s; S2PUMP, 24 ± 6 s; P < 0.001) despite increased O2 delivery; at S2 onset, venous O2 saturation was 21 ± 4% and 65 ± 5% in SPON and PUMP, respectively. VO2 kinetics remained slowed when contractions were initiated from a raised metabolic rate despite uniform muscle stimulation and increased O2 delivery. The intracellular mechanism may relate to a falling energy state, approaching saturating ADP concentration, and/or slowed mitochondrial activation; but further study is required. These data add to the evidence that muscle VO2 control is more complex than previously suggested. PMID:24469073

  4. Opening of the blood-brain barrier by intravenous contrast media in euvolemic and dehydrated rabbits

    International Nuclear Information System (INIS)

    It has been suggested that intravenous injections of hypertonic contrast media when used in computed tomography and digital subtraction angiography might raise plasma osmolality sufficiently to open the blood-brain barrier (BBB). The current investigation establishes the threshold of plasma osmolality that causes the opening of the BBB in euvolemic and dehydrated rabbits. Euvolemic rabbits were allowed food and water ad libitum. Dehydrated rabbits received 4.0 mg/kg of furosemide intramuscularly and were deprived of water for 72 hours. Meglumine/sodium diatrizoate 76% (n=28) or mannitol 20% (n=12) was administrated intravenously, at a rate of 25 mmol/kg body weihgt/hour for 2, 3 or 4 hours. Plasma osmolality, blood iodine concentration, blood pressure, heart rate and hematocrit were assessed at regular intervals. Evans blue and 99Tcm-DTPA were used simultaneously as tracers for BBB opening. Rating of BBB opening with 99Tcm-DTPA correlated well with Evans blue staining (r=0.863, p<0.001; n=42). BBB opening was related to plasma osmolality and was similar for both contrast media and mannitol. Widespread BBB opening occurred above 400 mmol/kg while focal BBB opening occurred above 370 mmol/kg. Dehydration per se increased plasma osmolality but did not reduce the threshold for BBB opening. (orig.)

  5. Energy harvesting from arterial blood pressure for powering embedded brain sensors

    Science.gov (United States)

    Nanda, Aditya; Karami, M. Amin

    2016-04-01

    This paper investigates energy harvesting from arterial blood pressure via the piezoelectric effect by using a novel streaked cylinder geometry for the purpose of powering embedded micro-sensors in the brain. Initially, we look at the energy harvested by a piezoelectric cylinder placed inside an artery acted upon by blood pressure. Such an arrangement would be tantamount to constructing a stent out of piezoelectric materials. A stent is a cylinder placed in veins and arteries to prevent obstruction in blood flow. The governing equations of a conductor coated piezoelectric cylinder are obtained using Hamilton's principle. Pressure acting in arteries is radially directed and this is used to simplify the modal analysis and obtain the transfer function relating pressure to the induced voltage across the surface of the harvester. The power harvested by the cylindrical harvester is obtained for different shunt resistances. Radially directed pressure occurs elsewhere and we also look at harvesting energy from oil flow in pipelines. Although the energy harvested by the cylindrical energy harvester is significant at resonance, the natural frequency of the system is found to be very high. To decrease the natural frequency, we propose a novel streaked stent design by cutting it along the length, transforming it to a curved plate and decreasing the natural frequency. The governing equations corresponding to the new geometry are derived using Hamilton's principle and modal analysis is used to obtain the transfer function.

  6. Therapeutic Potential of Umbilical Cord Blood Stem Cells on Brain Damage of a Model of Stroke

    Directory of Open Access Journals (Sweden)

    Mohammad Reza Nikravesh

    2011-11-01

    Full Text Available Introduction: Human cord blood-derived stem cells are a rich source of stem cells as well as precursors. With regard to the researchers have focused on the therapeutic potential of stem cell in the neurological disease such as stroke, the aim of this study was the investiga-tion of the therapeutic effects of human cord blood-derived stem cells in cerebral ischemia on rat. Methods: This study was carried out on young rats. Firstly, to create a laboratory model of ischemic stroke, carotid artery of animals was occluded for 30 minutes. Then, umbilical cord blood cells were isolated and labeled using bromodeoxyuridine and 2×105 cells were injected into the experimental group via the tail vein. Rats with hypoxic condi-tions were used as a sham group. A group of animals did not receive any injection or sur-geries were used as a control. Results: Obtained results were evaluated based on behavior-al responses and immunohistochemistry, with emphasis on areas of putamen and caudate nucleus in the control, sham and experimental groups. Our results indicated that behavioral recovery was observed in the experimental group compared to the either the sham or the control group. However, histological studies demonstrated a low percent of tissue injury in the experimental group in comparison with the sham group. Conclusion: Stem cell trans-plantation is beneficial for the brain tissue reparation after hypoxic ischemic cell death.

  7. DISSEMINATED CYSTICERCOSIS WITH HUGE MUSCLE HYPERTROPHY

    OpenAIRE

    Bandyopadhyay Debabrata; Sen Sumit

    2009-01-01

    Cysticercosis is caused by cysticercus cellulose, which is the larva of Taenia solium , the pork tapeworm. The larvae are carried in the blood stream after penetrating the walls of the alimentary tract and they lodge in different tissues like the skin, skeletal muscles, brain, fundus and heart, to cause disseminated cysticercosis. Cases of disseminated cysticercosis have rarely been reported in the literature. They may inhabit the muscles and cause muscular hypertrophy, which, at times, may ...

  8. Hyperthermic Laser Ablation of Recurrent Glioblastoma Leads to Temporary Disruption of the Peritumoral Blood Brain Barrier.

    Directory of Open Access Journals (Sweden)

    Eric C Leuthardt

    Full Text Available Poor central nervous system penetration of cytotoxic drugs due to the blood brain barrier (BBB is a major limiting factor in the treatment of brain tumors. Most recurrent glioblastomas (GBM occur within the peritumoral region. In this study, we describe a hyperthemic method to induce temporary disruption of the peritumoral BBB that can potentially be used to enhance drug delivery.Twenty patients with probable recurrent GBM were enrolled in this study. Fourteen patients were evaluable. MRI-guided laser interstitial thermal therapy was applied to achieve both tumor cytoreduction and disruption of the peritumoral BBB. To determine the degree and timing of peritumoral BBB disruption, dynamic contrast-enhancement brain MRI was used to calculate the vascular transfer constant (Ktrans in the peritumoral region as direct measures of BBB permeability before and after laser ablation. Serum levels of brain-specific enolase, also known as neuron-specific enolase, were also measured and used as an independent quantification of BBB disruption.In all 14 evaluable patients, Ktrans levels peaked immediately post laser ablation, followed by a gradual decline over the following 4 weeks. Serum BSE concentrations increased shortly after laser ablation and peaked in 1-3 weeks before decreasing to baseline by 6 weeks.The data from our pilot research support that disruption of the peritumoral BBB was induced by hyperthemia with the peak of high permeability occurring within 1-2 weeks after laser ablation and resolving by 4-6 weeks. This provides a therapeutic window of opportunity during which delivery of BBB-impermeant therapeutic agents may be enhanced.ClinicalTrials.gov NCT01851733.

  9. Blood-brain barrier transport kinetics of the neuromedin peptides NMU, NMN, NMB and NT.

    Science.gov (United States)

    Gevaert, Bert; Wynendaele, Evelien; Stalmans, Sofie; Bracke, Nathalie; D'Hondt, Matthias; Smolders, Ilse; van Eeckhaut, Ann; De Spiegeleer, Bart

    2016-08-01

    The neuromedin peptides are peripherally and centrally produced, but until now, it is generally believed that they only function as locally acting compounds without any quantitative knowledge about their blood-brain barrier (BBB) passage. Here, we characterize the transport kinetics of four neuromedins (NMU, NMN, NMB and NT) across the BBB, as well as their metabolization profile, and evaluate if they can act as endocrine hormones. Using the in vivo mouse model, multiple time regression (MTR), capillary depletion (CD) and brain efflux studies were performed. Data was fitted using linear (NMU, NT and NMB) or biphasic modeling (NMU and NMN). Three of the four investigated peptides, i.e. NMU, NT and NMN, showed a significant influx into the brain with unidirectional influx rate constants of 1.31 and 0.75 μL/(g × min) for NMU and NT respectively and initial influx constants (K1) of 72.14 and 7.55 μL/(g × min) and net influx constants (K) of 1.28 and 1.36 × 10(-16) μL/(g×min) for NMU and NMN respectively. The influx of NMB was negligible. Only NMN and NT showed a significant efflux out of the brain with an efflux constant (kout) of 0.042 min(-1) and 0.053 min(-1) respectively. Our results indicate that locally produced neuromedin peptides and/or fragments can be transported through the whole body, including passing the BBB, and taken up by different organs/tissues, supporting the idea that the neuromedins could have a much bigger role in the regulation of biological processes than currently assumed. PMID:27040796

  10. Identification of blood-brain barrier function following subarachnoid hemorrhage in rats at different stages

    Institute of Scientific and Technical Information of China (English)

    Zongyi Xie; Weiwei Shen; Ying Ma; Yuan Cheng

    2008-01-01

    BACKGROUND: Recent studies have indicated that blood-brain barrier (BBB) disruption following subarachnoid hemorrhage (SAH) significantly correlates with the development of brain injury and poor prognosis of patients subjected to SAH. OBJECTIVE: To investigate both functional and structural changes related to BBB in various phases after SAH in rats through quantitative and qualitative methods.DESIGN, TIME AND SETTING: This experiment, a completely randomized design and controlled experiment, was performed at the Department of Neurosurgery, the Second Affiliated Hospital of Chongqing University of Medical Sciences from June 2006 to March 2007.MATERIALS: A total of 128 female, healthy, Sprague-Dawley rats were selected for this study. Main reagents and instruments: Evans Blue dye (Sigma Company, USA), fluorescence spectrophotometer (Shimadzu Company, Japan), and transmission electron microscope (Olympus Company, Japan). MAIN OUTCOME MEASURES: Brain tissue water content was determined by the wet-dry method. BBB permeability in the cerebral cortex was determined by Evans Blue dye and fluorescent spectrophotometer. The ultrastructural changes in BBB were observed with transmission electron microscope.RESULTS: Compared with the sham-operated group, SAH induced a significant increase in brain water content between 24 and 60 hours (F = 888.32, P 0.05). Electron microscopy demonstrated only a mild perivascular edema at 24 hours after SAH. By 36 hours, a notable perivascular edema was associated with a collapse of the capillary. Astrocytic endfeet surrounding the capillary were prominently swollen in the edematous areas. The above-mentioned abnormal ultrastructural changes in the BBB were reversed by 72 hours after SAH. No obvious morphological changes in the BBB were detected in the sham-operated rats.CONCLUSION: These results directly suggest that SAH could induce rapid changes in BBB function and structure during the acute phases of BBB breakdown. Moreover, these dynamic

  11. Spatio-temporal analysis of molecular delivery through the blood-brain barrier using focused ultrasound

    International Nuclear Information System (INIS)

    The deposition of gadolinium through ultrasound-induced blood-brain barrier (BBB) openings in the murine hippocampus was investigated. First, wave propagation simulations through the intact mouse skull revealed minimal beam distortion while thermal deposition simulations, at the same sonication parameters used to induce BBB opening in vivo, revealed temperature increases lower than 0.5 0C. The simulation results were validated experimentally in ex vivo skulls (m = 6) and in vitro tissue specimens. Then, in vivo mice (n = 9) were injected with microbubbles (Optison(TM); 25-50 μl) and sonicated (frequency: 1.525 MHz, pressure amplitudes: 0.5-1.1 MPa, burst duration: 20 ms, duty cycle: 20%, durations: 2-4 shots, 30 s per shot, 30 s interval) at the left hippocampus, through intact skin and skull. Sequential, high-resolution, T1-weighted MRI (9.4 Tesla, in-plane resolution: 75 μm, scan time: 45-180 min) with gadolinium (Omniscan(TM); 0.5 ml) injected intraperitoneally revealed a threshold of the BBB opening at 0.67 MPa and BBB closing within 28 h from opening. The contrast-enhancement area and gadolinium deposition path were monitored over time and the influence of vessel density, size and location was determined. Sonicated arteries, or their immediate surroundings, depicted greater contrast enhancement than sonicated homogeneous brain tissue regions. In conclusion, gadolinium was delivered through a transiently opened BBB and contained to a specific brain region (i.e., the hippocampus) using a single-element focused ultrasound transducer. It was also found that the amount of gadolinium deposited in the hippocampal region increased with the acoustic pressure and that the spatial distribution of the BBB opening was determined not only by the ultrasound beam, but also by the vasculature of the targeted brain region

  12. Determination of endocrine disrupting compounds in fish liver, brain, and muscle using focused ultrasound solid-liquid extraction and dispersive solid phase extraction as clean-up strategy.

    Science.gov (United States)

    Ros, Oihana; Vallejo, Asier; Olivares, Maitane; Etxebarria, Nestor; Prieto, Ailette

    2016-08-01

    This study describes a new method for the simultaneous extraction of several endocrine disrupting compounds, including alkylphenols (APs), estrogen, bisphenol-A (BPA) and one phthalate metabolite (mono-2-ethylhexyl ester, MEHP) in fish liver, brain, and muscle. Parameters affecting the extraction (extraction solvent and temperature) and the clean-up (dispersive phase nature and amount) steps were evaluated. The extraction was performed by means of focused ultrasound solid-liquid extraction (FUSLE) using 10 mL of n-hexane:acetone (50:50, v/v) for 5 min at ~0 °C, and the clean-up was done by means of dispersive solid phase extraction (dSPE) using 100 mg of ENVI-CARB and 100 mg of MgSO4 for the cleaning of brain and muscle extracts together with 100 mg of PSA in the case of liver extracts. Good apparent recoveries were obtained in the case of liver (62-132 %), brain (66-120 %), and muscle (74-129 %), relative standard deviation (RSD%) was always below 26 %, and the method detection limits (MDLs) were at low ng/g level. The developed method was applied to fish captured in Urdaibai estuary (Bay of Biscay) in December 2015, and the concentrations obtained were in the range MDL-1115 ng/g in brain, MDL-962 ng/g in muscle, and MDL-672 ng/g in liver. In general, the highest concentrations were measured in liver, followed by brain and muscle. In addition, diethylstilbestrol was only detected in fish brain. Graphical Abstract MS method scheme for the/MS method scheme for the determination of EDCs in fish liver, brain and muscle. PMID:27342793

  13. Effect of X-irradiation on the pharmacokinetics of methotrexate in rats: alteration of the blood-brain barrier

    International Nuclear Information System (INIS)

    A study was designed to evaluate the effects of brain irradiation on the permeability of the blood-brain barrier for methotrexate (MTX). Female WAG/Rij rats were cranially irradiated with a single dose of 20 gy of 300 kV X-rays. At different times (1-15 days) after the exposure the rats were injected intravenously with MTX (25 mg/kg body wt). Irradiation had hardly any effect on the MTX concentrations in the plasma, heart and kidneys as determined by high-performance liquid chromatography. However, irradiation resulted in a significant increase of MTX (determined by 125I-radioimmunoassay) in brain tissue per gram wet weight (187.6 +- 17.9 pmol/g vs 46.4 +- 29.3 pmol/g in unirradiated brain). This change in permeability of the blood-brain barrier lasted for about 9 days. The MTX elimination from the irradiated brain was the same as that from the non-irradiated brain. This indicates that only the MTX uptake and not the elimination by the brain was affected by the irradiation treatment. (author)

  14. Melatonin Preserves Blood-Brain Barrier Integrity and Permeability via Matrix Metalloproteinase-9 Inhibition

    Science.gov (United States)

    Alluri, Himakarnika; Wilson, Rickesha L.; Anasooya Shaji, Chinchusha; Wiggins-Dohlvik, Katie; Patel, Savan; Liu, Yang; Peng, Xu; Beeram, Madhava R.; Davis, Matthew L.; Huang, Jason H.; Tharakan, Binu

    2016-01-01

    Microvascular hyperpermeability that occurs at the level of the blood-brain barrier (BBB) often leads to vasogenic brain edema and elevated intracranial pressure following traumatic brain injury (TBI). At a cellular level, tight junction proteins (TJPs) between neighboring endothelial cells maintain the integrity of the BBB via TJ associated proteins particularly, zonula occludens-1 (ZO-1) that binds to the transmembrane TJPs and actin cytoskeleton intracellularly. The pro-inflammatory cytokine, interleukin-1β (IL-1β) as well as the proteolytic enzymes, matrix metalloproteinase-9 (MMP-9) are key mediators of trauma-associated brain edema. Recent studies indicate that melatonin a pineal hormone directly binds to MMP-9 and also might act as its endogenous inhibitor. We hypothesized that melatonin treatment will provide protection against TBI-induced BBB hyperpermeability via MMP-9 inhibition. Rat brain microvascular endothelial cells grown as monolayers were used as an in vitro model of the BBB and a mouse model of TBI using a controlled cortical impactor was used for all in vivo studies. IL-1β (10 ng/mL; 2 hours)-induced endothelial monolayer hyperpermeability was significantly attenuated by melatonin (10 μg/mL; 1 hour), GM6001 (broad spectrum MMP inhibitor; 10 μM; 1 hour), MMP-9 inhibitor-1 (MMP-9 specific inhibitor; 5 nM; 1 hour) or MMP-9 siRNA transfection (48 hours) in vitro. Melatonin and MMP-9 inhibitor-1 pretreatment attenuated IL-1β-induced MMP-9 activity, loss of ZO-1 junctional integrity and f-actin stress fiber formation. IL-1β treatment neither affected ZO-1 protein or mRNA expression or cell viability. Acute melatonin treatment attenuated BBB hyperpermeability in a mouse controlled cortical impact model of TBI in vivo. In conclusion, one of the protective effects of melatonin against BBB hyperpermeability occurs due to enhanced BBB integrity via MMP-9 inhibition. In addition, acute melatonin treatment provides protection against BBB

  15. Expiratory muscle control during vomiting - Role of brain stem expiratory neurons

    Science.gov (United States)

    Miller, A. D.; Tan, L. K.

    1987-01-01

    The neural mechanisms controlling the muscles involved during vomiting were examined using decerebrated cats. In one experiment, the activity of the ventral respiratory group (VRG) expiratory (E) neurons was recorded during induced 'fictive vomiting' (i.e., a series of bursts of coactivation of abdominal and phrenic nerves that would be expected to produce expulsion in unparalyzed animals) and vomiting. In a second, abdominal muscle electromyographic and nerve activity were compared before and after sectioning the axons of descending VRG E neurons as they cross the midline between C1 and the obex (the procedure that is known to abolish expiratory modulation of internal intercostal muscle activity). The results of the study indicate that the abdominal muscles are controlled differently during respiration and vomiting.

  16. Blood Thinners

    Science.gov (United States)

    If you have some kinds of heart or blood vessel disease, or if you have poor blood flow to your brain, your doctor may recommend that you take a blood thinner. Blood thinners reduce the risk of heart ...

  17. Ischemic brain edema following occlusion of the middle cerebral artery in the rat. I: The time courses of the brain water, sodium and potassium contents and blood-brain barrier permeability to 125I-albumin

    International Nuclear Information System (INIS)

    The present study was undertaken to analyze the roles of brain cations and of the blood-brain barrier (BBB) to albumin in the development of ischemic brain edema. Using the rat middle cerebral artery (MCA) occlusion model, changes in the brain water, sodium, and potassium contents were followed for a period of seven days. The permeability of the BBB to proteins was also followed by 125I-albumin transfer from the blood into the brain. A significant edema developed as early as three hours after MCA occlusion. This progressed rapidly to reach a maximum on the third day, gradually regressing thereafter. The increase in the brain water contents showed a parallel time course to the increase in the sodium and decrease in the potassium contents. A significant increase in the BBB permeability to albumin occurred 72 hours after MCA occlusion. However, there was no correlation between the brain water content and BBB permeability to albumin in the hemispheres studied 72 hours after MCA occlusion. The correlation between the brain water and sodium contents was not clear during the first six hours, but became highly significant thereafter. The data suggest that an increase in the BBB permeability to sodium occurred 12-48 hours after MCA occlusion, which, together with an antecedent intracellular shift of sodium, resulted in a massive influx of water and sodium into the brain. The BBB permeability change to sodium, not to proteins, seems to play a predominant role in the pathogenesis underlying ischemic brain edema

  18. 7.0-T Magnetic Resonance Imaging Characterization of Acute Blood-Brain-Barrier Disruption Achieved with Intracranial Irreversible Electroporation

    OpenAIRE

    Garcia, Paulo A.; John H. Rossmeisl; Robertson, John L.; Olson, John D.; Johnson, Annette J.; Ellis, Thomas L; Davalos, Rafael V.

    2012-01-01

    The blood-brain-barrier (BBB) presents a significant obstacle to the delivery of systemically administered chemotherapeutics for the treatment of brain cancer. Irreversible electroporation (IRE) is an emerging technology that uses pulsed electric fields for the non-thermal ablation of tumors. We hypothesized that there is a minimal electric field at which BBB disruption occurs surrounding an IRE-induced zone of ablation and that this transient response can be measured using gadolinium (Gd) up...

  19. White matter cerebral blood flow is inversely correlated with structural and functional connectivity in the human brain

    OpenAIRE

    Aslan, Sina; Huang, Hao; Uh, Jinsoo; Mishra, Virendra; Xiao, Guanghua; van Osch, Matthias J.P.; Lu, Hanzhang

    2011-01-01

    White matter provides anatomic connections among brain regions and has received increasing attention in understanding brain intrinsic networks and neurological disorders. Despite significant progresses made in characterizing the white matter’s structural properties using post-mortem techniques and in vivo diffusion-tensor-imaging (DTI) methods, its physiology remains poorly understood. In the present study, cerebral blood flow (CBF) of the white matter was investigated on a fiber-tract-specif...

  20. Ultrasound-mediated blood-brain barrier disruption for targeted drug delivery in the central nervous system

    OpenAIRE

    Aryal, Muna; Arvanitis, Costas D.; Alexander, Phillip M.; McDannold, Nathan

    2014-01-01

    The physiology of the vasculature in the central nervous system (CNS), which includes the blood-brain barrier (BBB) and other factors, complicates the delivery of most drugs to the brain. Different methods have been used to bypass the BBB, but they have limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Focused ultrasound (FUS), when combined with circulating microbubbles, is a noninvasive method to locally and transiently disrupt the BBB at discrete t...

  1. Blood-brain barrier delivery of protein and non-viral gene therapeutics with molecular Trojan horses

    OpenAIRE

    Pardridge, William M

    2007-01-01

    The products of biotechnology, recombinant proteins, monoclonal antibodies, antisense, RNA interference, or non-viral gene transfer, cannot be developed as pharmaceuticals for the brain, unless these molecules are re-formulated to enable transport across the blood-brain barrier (BBB). Large molecule drugs, and plasmid DNA, can be delivered across the BBB with receptor-specific molecular Trojan horses. Trojan horse BBB delivery systems, coupled with one of 3 different technology platforms (fus...

  2. STAT1 signaling modulates HIV-1–induced inflammatory responses and leukocyte transmigration across the blood-brain barrier

    OpenAIRE

    Chaudhuri, Anathbandhu; Yang, Bo; Gendelman, Howard E; Persidsky, Yuri; Kanmogne, Georgette D.

    2008-01-01

    The relationship among neuroinflammation, blood-brain barrier (BBB) dysfunction, and progressive HIV-1 infection as they affect the onset and development of neuroAIDS is incompletely understood. One possible link is signal transducers and activators of transcription (STATs) pathways. These respond to proinflammatory and regulatory factors and could affect neuroinflammatory responses induced from infected cells and disease-affected brain tissue. Our previous works demonstrated that HIV-1 activ...

  3. Impact of standing wave effects on transcranial focused ultrasound disruption of the blood-brain barrier in a rat model

    OpenAIRE

    O’Reilly, Meaghan A.; Huang, Yuexi; Hynynen, Kullervo

    2010-01-01

    Microbubble mediated disruption of the blood brain barrier (BBB) for targeted drug delivery using focused ultrasound shows great potential as a therapy for a wide range of brain disorders. This technique is currently at the pre-clinical stage and important work is being conducted in animal models. Measurements of standing waves in ex vivo rat skulls were conducted using an optical hydrophone and a geometry dependence was identified. Standing waves could not be eliminated through the use of sw...

  4. Localized Down-regulation of P-glycoprotein by Focused Ultrasound and Microbubbles induced Blood-Brain Barrier Disruption in Rat Brain

    Science.gov (United States)

    Cho, HongSeok; Lee, Hwa-Youn; Han, Mun; Choi, Jong-ryul; Ahn, Sanghyun; Lee, Taekwan; Chang, Yongmin; Park, Juyoung

    2016-01-01

    Multi-drug resistant efflux transporters found in Blood-Brain Barrier (BBB) acts as a functional barrier, by pumping out most of the drugs into the blood. Previous studies showed focused ultrasound (FUS) induced microbubble oscillation can disrupt the BBB by loosening the tight junctions in the brain endothelial cells; however, no study was performed to investigate its impact on the functional barrier of the BBB. In this study, the BBB in rat brains were disrupted using the MRI guided FUS and microbubbles. The immunofluorescence study evaluated the expression of the P-glycoprotein (P-gp), the most dominant multi-drug resistant protein found in the BBB. Intensity of the P-gp expression at the BBB disruption (BBBD) regions was significantly reduced (63.2 ± 18.4%) compared to the control area. The magnitude of the BBBD and the level of the P-gp down-regulation were significantly correlated. Both the immunofluorescence and histologic analysis at the BBBD regions revealed no apparent damage in the brain endothelial cells. The results demonstrate that the FUS and microbubbles can induce a localized down-regulation of P-gp expression in rat brain. The study suggests a clinically translation of this method to treat neural diseases through targeted delivery of the wide ranges of brain disorder related drugs. PMID:27510760

  5. Permeability of ergot alkaloids across the blood-brain barrier in vitro and influence on the barrier integrity

    OpenAIRE

    Mulac, Dennis; Hüwel, Sabine; Galla, Hans-Joachim; Humpf, Hans-Ulrich

    2011-01-01

    Scope Ergot alkaloids are secondary metabolites of Claviceps spp. and they have been in the focus of research for many years. Experiments focusing on ergotamine as a former migraine drug referring to the ability to reach the brain revealed controversial results. The question to which extent ergot alkaloids are able to cross the blood-brain barrier is still not answered. Methods and results In order to answer this question we have studied the ability of ergot alkaloids to penetrate the blood-b...

  6. Analysis of Regional Cerebral Blood Flow Using 99mTc-HMPAO Brain SPECT in Senile Dementia of Alzheimer Type

    International Nuclear Information System (INIS)

    99mTc-HMPAO brain SPECT studies were performed in 11 patients with Alzheimer's disease, 7 patients with psychological depression and 12 normal controls. Changes of regional cerebral blood flow was semiquantitatively analyzed and the results were as follows. 1) In 11 patients with Alzheimer's disease, significant reduction of regional cerebral blood flow was found In both temporoparietal areas. 2) Relative perfusion between cerebral hemispheres was rather symmetrical in patient with Alzheimer's disease. 3) All patients with depression showed normal SPECT findings. As for conclusion, 99mTc-HMPAO brain SPECT seemed to be a valuable method for clinical assessment and management of patients with Alzheimer's disease.

  7. Acute supplementation of N-acetylcysteine does not affect muscle blood flow and oxygenation characteristics during handgrip exercise.

    Science.gov (United States)

    Smith, Joshua R; Broxterman, Ryan M; Ade, Carl J; Evans, Kara K; Kurti, Stephanie P; Hammer, Shane M; Barstow, Thomas J; Harms, Craig A

    2016-04-01

    N-acetylcysteine (NAC; antioxidant and thiol donor) supplementation has improved exercise performance and delayed fatigue, but the underlying mechanisms are unknown. One possibility isNACsupplementation increases limb blood flow during severe-intensity exercise. The purpose was to determine ifNACsupplementation affected exercising arm blood flow and muscle oxygenation characteristics. We hypothesized thatNACwould lead to higher limb blood flow and lower muscle deoxygenation characteristics during severe-intensity exercise. Eight healthy nonendurance trained men (21.8 ± 1.2 years) were recruited and completed two constant power handgrip exercise tests at 80% peak power until exhaustion. Subjects orally consumed either placebo (PLA) orNAC(70 mg/kg) 60 min prior to handgrip exercise. Immediately prior to exercise, venous blood samples were collected for determination of plasma redox balance. Brachial artery blood flow (BABF) was measured via Doppler ultrasound and flexor digitorum superficialis oxygenation characteristics were measured via near-infrared spectroscopy. FollowingNACsupplementaiton, plasma cysteine (NAC: 47.2 ± 20.3 μmol/L vs.PLA: 9.6 ± 1.2 μmol/L;P = 0.001) and total cysteine (NAC: 156.2 ± 33.9 μmol/L vs.PLA: 132.2 ± 16.3 μmol/L;P = 0.048) increased. Time to exhaustion was not significantly different (P = 0.55) betweenNAC(473.0 ± 62.1 sec) andPLA(438.7 ± 58.1 sec). RestingBABFwas not different (P = 0.79) withNAC(99.3 ± 31.1 mL/min) andPLA(108.3 ± 46.0 mL/min).BABFwas not different (P = 0.42) during exercise or at end-exercise (NAC: 413 ± 109 mL/min;PLA: 445 ± 147 mL/min). Deoxy-[hemoglobin+myoglobin] and total-[hemoglobin+myoglobin] were not significantly different (P = 0.73 andP = 0.54, respectively) at rest or during exercise between conditions. We conclude that acuteNACsupplementation does not alter oxygen delivery during exercise in men. PMID:27044854

  8. Influence of nutrient intake on antioxidant capacity, muscle damage and white blood cell count in female soccer players

    Directory of Open Access Journals (Sweden)

    Gravina Leyre

    2012-07-01

    Full Text Available Abstract Background Soccer is a form of exercise that induces inflammatory response, as well as an increase in free radicals potentially leading to muscle injury. Balanced nutritional intake provides important antioxidant vitamins, including vitamins A, C and E, which may assist in preventing exercise-related muscle damage. The purpose of the present study was to determine the effect of macro/micronutrient intake on markers of oxidative stress, muscle damage, inflammatory and immune response in female soccer players. Methods Twenty-eight female players belonging to two soccer teams of the same professional soccer club participated in this study after being informed about the aims and procedures and after delivering written consent. Each team completed an 8-day dietary record and played one competition match the same week. Participants were divided into two groups: the REC group (who complied with recommended intakes and the NO-REC group (who were not compliant. Laboratory blood tests were carried out to determine hematological, electrolytic and hormonal variables, as well as to monitor markers of cell damage and oxidative stress. Blood samples were obtained 24 h before, immediately after and 18 h after official soccer matches. Student t-test or Mann–Whitney U-test was used to compare both groups throughout the match. Results At rest, we observed that the REC group had higher levels of total antioxidant status (TAS, glutathione peroxidase (GPx, and lower levels of creatine kinase (CK and lactate dehydrogenase (LDH in comparison to the NO-REC group. Immediately after the match, levels of TAS, GPx, superoxide dismutase (SOD, LDH and % lymphocytes were higher and the % of neutrophils were lower in the REC group compared to the NO-REC group. These differences were also maintained 18 h post-match, only for TAS and GPx. Conclusions Our data reveal an association between nutritional intake and muscle damage, oxidative stress, immunity and inflammation

  9. Increased muscle blood supply and transendothelial nutrient and insulin transport induced by food intake and exercise: effect of obesity and ageing.

    Science.gov (United States)

    Wagenmakers, Anton J M; Strauss, Juliette A; Shepherd, Sam O; Keske, Michelle A; Cocks, Matthew

    2016-04-15

    This review concludes that a sedentary lifestyle, obesity and ageing impair the vasodilator response of the muscle microvasculature to insulin, exercise and VEGF-A and reduce microvascular density. Both impairments contribute to the development of insulin resistance, obesity and chronic age-related diseases. A physically active lifestyle keeps both the vasodilator response and microvascular density high. Intravital microscopy has shown that microvascular units (MVUs) are the smallest functional elements to adjust blood flow in response to physiological signals and metabolic demands on muscle fibres. The luminal diameter of a common terminal arteriole (TA) controls blood flow through up to 20 capillaries belonging to a single MVU. Increases in plasma insulin and exercise/muscle contraction lead to recruitment of additional MVUs. Insulin also increases arteriolar vasomotion. Both mechanisms increase the endothelial surface area and therefore transendothelial transport of glucose, fatty acids (FAs) and insulin by specific transporters, present in high concentrations in the capillary endothelium. Future studies should quantify transporter concentration differences between healthy and at risk populations as they may limit nutrient supply and oxidation in muscle and impair glucose and lipid homeostasis. An important recent discovery is that VEGF-B produced by skeletal muscle controls the expression of FA transporter proteins in the capillary endothelium and thus links endothelial FA uptake to the oxidative capacity of skeletal muscle, potentially preventing lipotoxic FA accumulation, the dominant cause of insulin resistance in muscle fibres. PMID:25627798

  10. The value of brain blood perfusion SPECT imaging in evaluation of the curative effect of hyperbaric oxygen in patients with ischemic brain injury

    International Nuclear Information System (INIS)

    Objective: Brain blood flow SPECT perfusion can detect changes in brain blood flow. The obiective of this study was to explore the clinical value of SPECT perfusion imaging in brain ischemic injury due to traumatic at before and after hyperbaric oxygen (HBO)treatment.Methods: Sixty-five cases of secondary ischemic brain injury patients were randomly divided into two groups. One was with HBO treatment group and the other was with conventional treatment. All had brain perfusion SPECT at before and after treatment. Computer region of interest (ROI)technology was applied in the cross-sectional images using lo-cat mirror ratio (Ra) method to determine cerebral ischemic lesions. The t-test was used to analyze the quantitative data. It would be considered as abnormal if the brain perfusion SPECT reduce Ra ≤ 0.9 aftertreatment. Results: In HBO treatment group.regional cerebral blood flow (rCBF) before and after treatment to reduce the district Ra values were 0.58 ± 0.1l and 0.82 ± 0.12 (t=7.327, P<0.01). In con-ventional treatment group. Rcbf before and after treatment to reduce the district Ra values were 0.6l ± 0.13 and 0.73 ± 0.12 (t=2.153. P=0.038). IncreaSed Rcbf at ischemic lesions in HBO treatment group was 0.24 ± 0.08 and was 0.12 ± 0.06 for conventional treatment group (t=2.571. P=0.015). Conclusions: Brain SPECT imaging could sensitively reflect the rCBF before and after treatment and was considered to be useful for therapeutic monitoring of HBO treatment efficacy. (authors)

  11. Increased efflux of amyloid-β peptides through the blood-brain barrier by muscarinic acetylcholine receptor inhibition reduces pathological phenotypes in mouse models of brain amyloidosis.

    Science.gov (United States)

    Paganetti, Paolo; Antoniello, Katia; Devraj, Kavi; Toni, Nicolas; Kieran, Dairin; Madani, Rime; Pihlgren, Maria; Adolfsson, Oskar; Froestl, Wolfgang; Schrattenholz, André; Liebner, Stefan; Havas, Daniel; Windisch, Manfred; Cirrito, John R; Pfeifer, Andrea; Muhs, Andreas

    2014-01-01

    The formation and accumulation of toxic amyloid-β peptides (Aβ) in the brain may drive the pathogenesis of Alzheimer's disease. Accordingly, disease-modifying therapies for Alzheimer's disease and related disorders could result from treatments regulating Aβ homeostasis. Examples are the inhibition of production, misfolding, and accumulation of Aβ or the enhancement of its clearance. Here we show that oral treatment with ACI-91 (Pirenzepine) dose-dependently reduced brain Aβ burden in AβPPPS1, hAβPPSL, and AβPP/PS1 transgenic mice. A possible mechanism of action of ACI-91 may occur through selective inhibition of muscarinic acetylcholine receptors (AChR) on endothelial cells of brain microvessels and enhanced Aβ peptide clearance across the blood-brain barrier. One month treatment with ACI-91 increased the clearance of intrathecally-injected Aβ in plaque-bearing mice. ACI-91 also accelerated the clearance of brain-injected Aβ in blood and peripheral tissues by favoring its urinal excretion. A single oral dose of ACI-91 reduced the half-life of interstitial Aβ peptide in pre-plaque mhAβPP/PS1d mice. By extending our studies to an in vitro model, we showed that muscarinic AChR inhibition by ACI-91 and Darifenacin augmented the capacity of differentiated endothelial monolayers for active transport of Aβ peptide. Finally, ACI-91 was found to consistently affect, in vitro and in vivo, the expression of endothelial cell genes involved in Aβ transport across the Blood Brain Brain (BBB). Thus increased Aβ clearance through the BBB may contribute to reduced Aβ burden and associated phenotypes. Inhibition of muscarinic AChR restricted to the periphery may present a therapeutic advantage as it avoids adverse central cholinergic effects. PMID:24072071

  12. Effect of insulin in combination with selenium on blood glucose and GLUT4 expression in skeletal muscle of streptozotocin-induced diabetic rats

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Objective To evaluate the effect of low-dose insulin [1 U/(kg·d)] in combination with selenium [180 g/(kg·d)] on general physiological parameters and glucose transporter (GLUT4) level in skeletal muscle of streptozotocin (STZ)-induced diabetic rats. Methods Diabetic rats were treated with insulin,selenium,and insulin and selenium in combination for four weeks. The level of blood glucose was determined using One Touch SureStep Blood Glucose meter and the level of GLUT4 in skeletal muscle was examined by immu...

  13. Developmental changes of protein, RNA, DNA, lipid, and glycogen in the liver, skeletal muscle, and brain of the piglet

    International Nuclear Information System (INIS)

    A scheme for the sequential quantitative separation and determination of protein, RNA, DNA, lipid, and glycogen from rat-liver homogenate is modified for application to frozen tissues of the piglet. The biochemical methods, including the biuret method, used in the present investigation are described and thoroughly checked. The effects of freezing and storage on the recovery of major tissue constituents are recorded. The modified scheme is applied to the determination of protein, RNA, DNA, lipid, and glycogen in the liver, skeletal muscle, and brain of the developing piglet. Developmental changes for these major tissue constituents, including the biuret protein, are described with special reference to protein synthesis and physiology of growth at the cellular level from 45 days of foetal age to 35-42 days of postnatal age for liver and skeletal muscle, and from birth to 31-40 days of postnatal age for the cerebrum and cerebellum. The uniformly labelled amino acid, 14C-L-leucine, is used to study protein synthesis. Developmental patterns of labelling of protein and lipid in the liver, skeletal muscle, cerebrum, and cerebellum of the piglet from birth up to the age of two weeks are described. The results of the methodological, developmental, and experimental studies are thoroughly discussed in the light of the relevant literature and compared with those obtained in developmental and experimental studies on rats and other mammal species. (author)

  14. Hypoxia tolerance in sculpins is associated with high anaerobic enzyme activity in brain but not in liver or muscle.

    Science.gov (United States)

    Mandic, Milica; Speers-Roesch, Ben; Richards, Jeffrey G

    2013-01-01

    We assessed hypoxia tolerance in 11 species of fish from the superfamily Cottoidea (commonly called sculpins) that are known to differ in their critical O(2) tensions (P(crit)) and examined whether hypoxia tolerance correlated with larger substrate stores and higher maximal activity of enzymes associated with anaerobic adenosine triphosphate production (especially glycolysis). Among the sculpins studied, there was large variation in time to loss of equilibrium (LOE(50)) at 6.4 ± 0.1 torr, with values ranging between 25 and 538 min, and the variation in LOE(50) was correlated with P(crit). Our measures of time to LOE(50) and P(crit) were regressed against maximal enzyme activities of lactate dehydrogenase (LDH), pyruvate kinase (PK), creatine phosphokinase (CPK), and citrate synthase (CS) as well as the concentrations of glycogen, glucose, and creatine phosphate in the brain, liver, and white muscle. In the brain, there was a phylogenetically independent relationship between P(crit) and tissue LDH, PK, CPK, and CS activities expressed relative to tissue mass. Hypoxia-tolerant sculpins (those with low P(crit) values) had higher levels of brain LDH, PK, CPK, and CS than did hypoxia-sensitive sculpins. Similarly, LOE(50) regressed against brain LDH, PK, and CPK activities expressed relative to tissue mass, with the more hypoxia-tolerant species (i.e., those with higher LOE(50)) having higher enzyme activities. However, when the phylogenetic relationship among our sculpins was taken into account, only the relationship between hypoxia tolerance and LDH activity remained significant. When enzyme activities were expressed relative to total soluble protein in the tissue, the only relationships that remained were between brain LDH activity and P(crit) and LOE(50). In liver and white muscle, there were no relationships between the measures of hypoxia tolerance and enzyme activity or metabolite content. Overall, our analysis suggests that hypoxia-tolerant sculpins maintain

  15. Blood-brain barrier permeability is increased in normal appearing white matter in patients with lacunar stroke and leukoaraiosis

    OpenAIRE

    Topakian, R; Barrick, T R; Howe, F. A.; Markus, H. S.

    2010-01-01

    Abstract Background and purpose: The pathogenesis of cerebral small vessel disease (SVD) is incompletely understood. Endothelial dysfunction has been implicated and may result in increased blood-brain barrier (BBB) permeability with leakage of blood constituents into the vessel wall and white matter. We used contrast enhanced magnetic resonance imaging (MRI) to determine whether there was evidence for BBB permeability in the white matter of patients with SVD, and whether this was p...

  16. Relations between blood supply of brain of students and condition of autonomic nervous system and risk factors

    OpenAIRE

    L. D. Korovina; T. M. Zaporozhets

    2015-01-01

    The purpose of our research was to estimate the brain blood supply level by rheoencephalography method in junior students of the Medical academy and to determine the blood supply links with the autonomic regulation state, behavioural and alimentary factors. Rheo-encephalographic study, research of the autonomic nervous system state, heart rate regulation and questioning of 17–29 year-old students have been conducted. Basic hemodynamic indices were normal in all surveyed students. Increase in ...

  17. Healthy Muscles Matter

    Science.gov (United States)

    ... body? These muscles help you move, lift things, pump blood through your body, and even help you breathe. ... is a specialized type of involuntary muscle. It pumps blood through your body, changing its speed to keep ...

  18. Molecular targets in radiation-induced blood-brain barrier disruption

    International Nuclear Information System (INIS)

    Disruption of the blood-brain barrier (BBB) is a key feature of radiation injury to the central nervous system. Studies suggest that endothelial cell apoptosis, gene expression changes, and alteration of the microenvironment are important in initiation and progression of injury. Although substantial effort has been directed at understanding the impact of radiation on endothelial cells and oligodendrocytes, growing evidence suggests that other cell types, including astrocytes, are important in responses that include induced gene expression and microenvironmental changes. Endothelial apoptosis is important in early BBB disruption. Hypoxia and oxidative stress in the later period that precedes tissue damage might lead to astrocytic responses that impact cell survival and cell interactions. Cell death, gene expression changes, and a toxic microenvironment can be viewed as interacting elements in a model of radiation-induced disruption of the BBB. These processes implicate particular genes and proteins as targets in potential strategies for neuroprotection

  19. Blood-brain barrier disruption by continuous-wave radio frequency radiation.

    Science.gov (United States)

    Sirav, Bahriye; Seyhan, Nesrin

    2009-01-01

    The increasing use of cellular phones and the increasing number of associated base stations are becoming a widespread source of non ionizing electromagnetic radiation. Some biological effects are likely to occur even at low-level EM fields. This study was designed to investigate the effects of 900 and 1,800 MHz Continuous Wave Radio Frequency Radiation (CW RFR) on the permeability of Blood Brain Barrier (BBB) of rats. Results have shown that 20 min RFR exposure of 900 and 1,800 MHz induces an effect and increases the permeability of BBB of male rats. There was no change in female rats. The scientific evidence on RFR safety or harm remains inconclusive. More studies are needed to demonstrate the effects of RFR on the permeability of BBB and the mechanisms of that breakdown. PMID:19811403

  20. Implications of MMP9 for Blood Brain Barrier Disruption And Hemorrhagic Transformation Following Ischemic Stroke

    Directory of Open Access Journals (Sweden)

    Renee Jade Turner

    2016-03-01

    Full Text Available Numerous studies have documented increases in matrix metalloproteinases (MMPs, specifically MMP-9 levels following stroke, with such perturbations associated with disruption of the blood brain barrier (BBB, increased risk of hemorrhagic complications and worsened outcome. Despite this, controversy remains as to which cells release MMP-9 at the normal and pathological BBB, with even less clarity in the context of stroke. This may be further complicated by the influence of tissue plasminogen activator (tPA treatment. The aim of the present review is to examine the relationship between neutrophils, MMP-9 and tPA following ischemic stroke to elucidate which cells are responsible for the increases in MMP-9 and resultant barrier changes and hemorrhage observed following stroke.

  1. Regional cerebral blood flow in various types of brain tumor. Effect of the space-occupying lesion on blood flow in brain tissue close to and remote from tumor site

    DEFF Research Database (Denmark)

    Kuroda, K; Skyhøj Olsen, T; Lassen, N A

    1982-01-01

    Regional cerebral blood flow (rCBF) was measured in 23 patients with brain tumors using the 133Xe intra-carotid injection method and a 254 channel gamma camera. The glioblastomas (4) and astrocytomas (4) all showed hyperemia in the tumor and tumor-near region. This was also seen in several...

  2. Oligodendrocyte precursor cells support blood-brain barrier integrity via TGF-β signaling.

    Directory of Open Access Journals (Sweden)

    Ji Hae Seo

    Full Text Available Trophic coupling between cerebral endothelium and their neighboring cells is required for the development and maintenance of blood-brain barrier (BBB function. Here we report that oligodendrocyte precursor cells (OPCs secrete soluble factor TGF-β1 to support BBB integrity. Firstly, we prepared conditioned media from OPC cultures and added them to cerebral endothelial cultures. Our pharmacological experiments showed that OPC-conditioned media increased expressions of tight-junction proteins and decreased in vitro BBB permeability by activating TGB-β-receptor-MEK/ERK signaling pathway. Secondly, our immuno-electron microscopic observation revealed that in neonatal mouse brains, OPCs attach to cerebral endothelial cells via basal lamina. And finally, we developed a novel transgenic mouse line that TGF-β1 is knocked down specifically in OPCs. Neonates of these OPC-specific TGF-β1 deficient mice (OPC-specific TGF-β1 partial KO mice: PdgfraCre/Tgfb1flox/wt mice or OPC-specific TGF-β1 total KO mice: PdgfraCre/Tgfb1flox/flox mice exhibited cerebral hemorrhage and loss of BBB function. Taken together, our current study demonstrates that OPCs increase BBB tightness by upregulating tight junction proteins via TGF-β signaling. Although astrocytes and pericytes are well-known regulators of BBB maturation and maintenance, these findings indicate that OPCs also play a pivotal role in promoting BBB integrity.

  3. Human umbilical cord blood cells restore brain damage induced changes in rat somatosensory cortex.

    Directory of Open Access Journals (Sweden)

    Maren Geissler

    Full Text Available Intraperitoneal transplantation of human umbilical cord blood (hUCB cells has been shown to reduce sensorimotor deficits after hypoxic ischemic brain injury in neonatal rats. However, the neuronal correlate of the functional recovery and how such a treatment enforces plastic remodelling at the level of neural processing remains elusive. Here we show by in-vivo recordings that hUCB cells have the capability of ameliorating the injury-related impairment of neural processing in primary somatosensory cortex. Intact cortical processing depends on a delicate balance of inhibitory and excitatory transmission, which is disturbed after injury. We found that the dimensions of cortical maps and receptive fields, which are significantly altered after injury, were largely restored. Additionally, the lesion induced hyperexcitability was no longer observed in hUCB treated animals as indicated by a paired-pulse behaviour resembling that observed in control animals. The beneficial effects on cortical processing were reflected in an almost complete recovery of sensorimotor behaviour. Our results demonstrate that hUCB cells reinstall the way central neurons process information by normalizing inhibitory and excitatory processes. We propose that the intermediate level of cortical processing will become relevant as a new stage to investigate efficacy and mechanisms of cell therapy in the treatment of brain injury.

  4. Biogenic amines, amino acids and regional blood flow in rat brain after prenatal irradiation

    International Nuclear Information System (INIS)

    Damage to nerve cells after prenatal irradiation could affect their later ability to function normally. The concentration of several biogenic amines and amino acids was therefore determined at different times after prenatal irradiation with 0.95 Gy on day 10, 12 or 15 of pregnancy. The offspring was sacrified 0.5, 1, 3 and 6 months after birth and the following structures were dissected: Cortex, hippocampus, striatum, thalamus, hypothalamus, cerebellum and medulla. Biogenic amines isolated by HPLC and detected electrochemically were: Dopamine, DOPA, DOPAC, epinephrine, norepinephrine, serotonin and hydroxyindolacetate. Amino acids converted to their dansyl derivatives and separated by HPLC were: Aspartate, glutamate, glutamine, gamma aminobutyrate and taurine. Many neurotransmitters were found increased in brain after prenatal irradiation, particularly on day 12 and 15 p.c. Marked changes were found for serotonin in several brain structures and for dopamin in striatum. An increase was also found in glutamate, glutamine and GABA. Studies on regional blood flow using injection of labelled 15 μ microspheres did not reveal significant alterations after prenatal irradiation. (orig.)

  5. Transport rankings of non-steroidal antiinflammatory drugs across blood-brain barrier in vitro models.

    Directory of Open Access Journals (Sweden)

    Iveta Novakova

    Full Text Available The aim of this work was to conduct a comprehensive study about the transport properties of NSAIDs across the blood-brain barrier (BBB in vitro. Transport studies with celecoxib, diclofenac, ibuprofen, meloxicam, piroxicam and tenoxicam were accomplished across Transwell models based on cell line PBMEC/C1-2, ECV304 or primary rat brain endothelial cells. Single as well as group substance studies were carried out. In group studies substance group compositions, transport medium and serum content were varied, transport inhibitors verapamil and probenecid were added. Resulted permeability coefficients were compared and normalized to internal standards diazepam and carboxyfluorescein. Transport rankings of NSAIDs across each model were obtained. Single substance studies showed similar rankings as corresponding group studies across PBMEC/C1-2 or ECV304 cell layers. Serum content, glioma conditioned medium and inhibitors probenecid and verapamil influenced resulted permeability significantly. Basic differences of transport properties of the investigated NSAIDs were similar comparing all three in vitro BBB models. Different substance combinations in the group studies and addition of probenecid and verapamil suggested that transporter proteins are involved in the transport of every tested NSAID. Results especially underlined the importance of same experimental conditions (transport medium, serum content, species origin, cell line for proper data comparison.

  6. Drug and gene delivery across the blood-brain barrier with focused ultrasound.

    Science.gov (United States)

    Timbie, Kelsie F; Mead, Brian P; Price, Richard J

    2015-12-10

    The blood-brain barrier (BBB) remains one of the most significant limitations to treatments of central nervous system (CNS) disorders including brain tumors, neurodegenerative diseases and psychiatric disorders. It is now well-established that focused ultrasound (FUS) in conjunction with contrast agent microbubbles may be used to non-invasively and temporarily disrupt the BBB, allowing localized delivery of systemically administered therapeutic agents as large as 100nm in size to the CNS. Importantly, recent technological advances now permit FUS application through the intact human skull, obviating the need for invasive and risky surgical procedures. When used in combination with magnetic resonance imaging, FUS may be applied precisely to pre-selected CNS targets. Indeed, FUS devices capable of sub-millimeter precision are currently in several clinical trials. FUS mediated BBB disruption has the potential to fundamentally change how CNS diseases are treated, unlocking potential for combinatorial treatments with nanotechnology, markedly increasing the efficacy of existing therapeutics that otherwise do not cross the BBB effectively, and permitting safe repeated treatments. This article comprehensively reviews recent studies on the targeted delivery of therapeutics into the CNS with FUS and offers perspectives on the future of this technology. PMID:26362698

  7. Peripheral injection of human umbilical cord blood stimulates neurogenesis in the aged rat brain

    Directory of Open Access Journals (Sweden)

    Sanberg Paul R

    2008-02-01

    Full Text Available Abstract Background Neurogenesis continues to occur throughout life but dramatically decreases with increasing age. This decrease is mostly related to a decline in proliferative activity as a result of an impoverishment of the microenvironment of the aged brain, including a reduction in trophic factors and increased inflammation. Results We determined that human umbilical cord blood mononuclear cells (UCBMC given peripherally, by an intravenous injection, could rejuvenate the proliferative activity of the aged neural stem/progenitor cells. This increase in proliferation lasted for at least 15 days after the delivery of the UCBMC. Along with the increase in proliferation following UCBMC treatment, an increase in neurogenesis was also found in the aged animals. The increase in neurogenesis as a result of UCBMC treatment seemed to be due to a decrease in inflammation, as a decrease in the number of activated microglia was found and this decrease correlated with the increase in neurogenesis. Conclusion The results demonstrate that a single intravenous injection of UCBMC in aged rats can significantly improve the microenvironment of the aged hippocampus and rejuvenate the aged neural stem/progenitor cells. Our results raise the possibility of a peripherally administered cell therapy as an effective approach to improve the microenvironment of the aged brain.

  8. Computational Prediction of Blood-Brain Barrier Permeability Using Decision Tree Induction

    Directory of Open Access Journals (Sweden)

    Jörg Huwyler

    2012-08-01

    Full Text Available Predicting blood-brain barrier (BBB permeability is essential to drug development, as a molecule cannot exhibit pharmacological activity within the brain parenchyma without first transiting this barrier. Understanding the process of permeation, however, is complicated by a combination of both limited passive diffusion and active transport. Our aim here was to establish predictive models for BBB drug permeation that include both active and passive transport. A database of 153 compounds was compiled using in vivo surface permeability product (logPS values in rats as a quantitative parameter for BBB permeability. The open source Chemical Development Kit (CDK was used to calculate physico-chemical properties and descriptors. Predictive computational models were implemented by machine learning paradigms (decision tree induction on both descriptor sets. Models with a corrected classification rate (CCR of 90% were established. Mechanistic insight into BBB transport was provided by an Ant Colony Optimization (ACO-based binary classifier analysis to identify the most predictive chemical substructures. Decision trees revealed descriptors of lipophilicity (aLogP and charge (polar surface area, which were also previously described in models of passive diffusion. However, measures of molecular geometry and connectivity were found to be related to an active drug transport component.

  9. Effects of GSM modulated radio-frequency electromagnetic radiation on permeability of blood-brain barrier in male & female rats.

    Science.gov (United States)

    Sırav, Bahriye; Seyhan, Nesrin

    2016-09-01

    With the increased use of mobile phones, their biological and health effects have become more important. Usage of mobile phones near the head increases the possibility of effects on brain tissue. This study was designed to investigate the possible effects of pulse modulated 900MHz and 1800MHz radio-frequency radiation on the permeability of blood-brain barrier of rats. Study was performed with 6 groups of young adult male and female wistar albino rats. The permeability of blood-brain barrier to intravenously injected evans blue dye was quantitatively examined for both control and radio-frequency radiarion exposed groups. For male groups; Evans blue content in the whole brain was found to be 0.08±0.01mg% in the control, 0.13±0.03mg% in 900MHz exposed and 0.26±0.05mg% in 1800MHz exposed animals. In both male radio-frequency radiation exposed groups, the permeability of blood-brain barrier found to be increased with respect to the controls (pmale animals (pfemale groups; dye contents in the whole brains were 0.14±0.01mg% in the control, 0.24±0.03mg% in 900MHz exposed and 0.14±0.02mg% in 1800MHz exposed animals. No statistical variance found between the control and 1800MHz exposed animals (p>0.01). However 900MHz pulse modulated radio-frequency exposure was found effective on the permeability of blood-brain barrier of female animals. Results have shown that 20min pulse modulated radio-frequency radiation exposure of 900MHz and 1800MHz induces an effect and increases the permeability of blood-brain barrier of male rats. For females, 900MHz was found effective and it could be concluded that this result may due to the physiological differences between female and male animals. The results of this study suggest that mobile phone radation could lead to increase the permeability of blood-brain barrier under non-thermal exposure levels. More studies are needed to demonstrate the mechanisms of that breakdown. PMID:26723545

  10. Effect of low-dose methylprednisolone on peripheral blood endothelial progenitor cells and its significance in rats after brain injury

    Directory of Open Access Journals (Sweden)

    Bin ZHANG

    2011-05-01

    Full Text Available Objective To explore the effects of low-dose methylprednisolone(MP treatment after traumatic brain injury(TBI in rats on the number of peripheral blood endothelial progenitor cells(EPCs and injury area of the brain.Methods One hundred and fifty-four adult male Wistar rats were involved in the present study,and they were randomly divided into normal control group(n=18,TBI control group(n=38,MP control group(n=30,MP+TBI group(n=30 and TBI+MP group(n=38.The TBI model was reproduced by fluid percussion injury(FPI.MP(5mg/kg was intraperitoneally administered once a day for 4 days.Peripheral venous blood samples were taken on day 1,3,7 and 14,and the counts of EPCs were determined by flow cytometry.The rats were sacrificed on day 1 and 3,brain edema was estimated by dry-wet weight method,and the blood-brain barrier(BBB permeability was determined by Evans-blue extravasation.Results The counts of peripheral blood EPCs were significantly higher in MP control group,MP+TBI group and TBI+MP group on day 1,3 and 7 than that in normal control and TBI control group,and it returned to the level of normal control group on day 14.The BBB permeability was improved and brain edema alleviated in MP+TBI and TBI+MP group on day 3.Conclusion The administration of low-dose MP may increase the count of peripheral blood EPCs in rats,decrease BBB damage,and alleviate brain edema.

  11. In vitro blood-brain barrier permeability predictions for GABAA receptor modulating piperine analogs.

    Science.gov (United States)

    Eigenmann, Daniela Elisabeth; Dürig, Carmen; Jähne, Evelyn Andrea; Smieško, Martin; Culot, Maxime; Gosselet, Fabien; Cecchelli, Romeo; Helms, Hans Christian Cederberg; Brodin, Birger; Wimmer, Laurin; Mihovilovic, Marko D; Hamburger, Matthias; Oufir, Mouhssin

    2016-06-01

    The alkaloid piperine from black pepper (Piper nigrum L.) and several synthetic piperine analogs were recently identified as positive allosteric modulators of γ-aminobutyric acid type A (GABAA) receptors. In order to reach their target sites of action, these compounds need to enter the brain by crossing the blood-brain barrier (BBB). We here evaluated piperine and five selected analogs (SCT-66, SCT-64, SCT-29, LAU397, and LAU399) regarding their BBB permeability. Data were obtained in three in vitro BBB models, namely a recently established human model with immortalized hBMEC cells, a human brain-like endothelial cells (BLEC) model, and a primary animal (bovine endothelial/rat astrocytes co-culture) model. For each compound, quantitative UHPLC-MS/MS methods in the range of 5.00-500ng/mL in the corresponding matrix were developed, and permeability coefficients in the three BBB models were determined. In vitro predictions from the two human BBB models were in good agreement, while permeability data from the animal model differed to some extent, possibly due to protein binding of the screened compounds. In all three BBB models, piperine and SCT-64 displayed the highest BBB permeation potential. This was corroborated by data from in silico prediction. For the other piperine analogs (SCT-66, SCT-29, LAU397, and LAU399), BBB permeability was low to moderate in the two human BBB models, and moderate to high in the animal BBB model. Efflux ratios (ER) calculated from bidirectional permeability experiments indicated that the compounds were likely not substrates of active efflux transporters. PMID:27018328

  12. Effects of two different dietary sources of long chain omega-3, highly unsaturated fatty acids on incorporation into the plasma, red blood cell, and skeletal muscle in horses.

    Science.gov (United States)

    Hess, T M; Rexford, J K; Hansen, D K; Harris, M; Schauermann, N; Ross, T; Engle, T E; Allen, K G D; Mulligan, C M

    2012-09-01

    The objective of this study was to examine the effects of different sources of dietary omega-3 (n-3) fatty acid supplementation on plasma, red blood cell, and skeletal muscle fatty acid compositions in horses. Twenty-one mares were blocked by age, BW, and BCS and assigned to 1 of 3 dietary treatments with 7 mares per treatment. Dietary treatments were: 1) control or no fatty acid supplement (CON), 2) 38 g of n-3 long chain, highly unsaturated fatty acid (LCHUFA) supplement/d provided by algae and fish oil (MARINE) containing alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and docosapentaenoic acid (DPA), and 3) 38 g of n-3 LCHUFA supplement/d provided by a flaxseed meal (FLAX) containing ALA. Each supplement was added to a basal diet consisting of hay and barley and was fed for 90 d. Blood samples and muscle middle gluteal biopsies were taken at d 0, 30, 60 and 90 of supplementation. Plasma, red blood cell and skeletal muscle fatty acid profiles were determined via gas chromatography. Plasma linoleic acid (LA) and ALA were at least 10 and 60% less (P < 0.01), respectively, in the MARINE compared with the FLAX and CON groups. Plasma EPA and DHA were only detected in the MARINE group, and EPA increased 40% (P < 0.001) from d 30 to 60, and DHA 19% (P < 0.01) from d 30 to 90. Red blood cell LA and ALA were not different among treatments. Red blood cell EPA and DHA were only detected in the MARINE group, where EPA increased 38% (P < 0.01) from d 30 to 60, and DHA increased 56% (P < 0.001) between d 30 and 90. Skeletal muscle LA was at least 17% less (P < 0.001) in the MARINE group compared with the other treatments. Skeletal muscle ALA was 15% less (P = 0.03) in the MARINE group compared with FLAX and CON groups. Skeletal muscle EPA was at least 25% greater (P < 0.001) in MARINE group compared with other treatments and increased (P < 0.001) by 71% from d 30 to 60. Skeletal muscle DHA was at least 57% greater (P < 0.001) in the MARINE

  13. Prolonged androgen deprivation may influence the autoregulation of estrogen receptors in the brain and pelvic floor muscles of male rats.

    Science.gov (United States)

    Wibowo, Erik; Calich, Hannah J; Currie, R William; Wassersug, Richard J

    2015-06-01

    Androgen deprivation in males has detrimental effects on various tissues and bodily functions, some of which can be restored by estradiol (E2) administration. We investigated how the duration of androgen deprivation affects the autoregulation of estrogen receptors (ERs) levels in core brain areas associated with sexual behavior and cognition, as well as in pelvic floor muscles (PFM). We also measured c-Fos levels in brain areas associated with sexual behavior shortly after the rats mated. Prolonged castration increases ERα levels in the preoptic area (POA) and E2 treatment reverses these effects. In the POA, c-Fos levels after mating are not affected by the duration of androgen deprivation and/or E2 treatment. ERβ levels in the POA as well as c-Fos levels in the POA and the core area of nucleus accumbens correlate with the mounting frequency for E2-treated Short-Term castrates. Additionally, ERβ levels in the medial amygdala are positively correlated with the mounting frequency of Long-Term castrates that received E2 treatment. In the hippocampus, ERs are downregulated only when E2 is administered early after castration, whereas downregulation of ERα in the prefrontal cortex only occurs with delayed E2 treatment. Early, but not delayed, E2 treatment after castration increases ERβ levels in the bulbocavernosus and ERα levels in the levator ani of male rats. Our data suggest that the duration of androgen deprivation may influence the autoregulation of ERs by E2 treatment in select brain areas and pelvic floor muscles of male rats. PMID:25746452

  14. Correlation of acetylcholinesterase activity in the brain and blood of wistar rats acutely infected with Trypanosoma congolense

    Institute of Scientific and Technical Information of China (English)

    Habila N; Inuwa HM; Aimola IA; Lasisi OI; Chechet DG; Okafor IA

    2012-01-01

    Objective: To investigate the neurotransmitter enzyme Acetylcholinesterase (AChE) activity in the brain and blood of rats infected with Trypanosoma congolense (T. congo). Methods: Presence and degree of parasitemia was determined daily for each rat by the rapid matching method. AChE activity was determined by preparing a reaction mixture of brain homogenate and whole blood with 5, 5-dithiobisnitrobenzioc acid (DTNB or Ellman’s reagent) and Acetylthiocholine (ATC). The increase in absorbance was recorded at 436 nm over 10 min at 2 min intervals. Trypanosome species identification (before inoculation and on day 10 post infection) was done by Polymerase chain reaction using specific primers. Results: The AChE activity in the brain and blood decreased significantly as compared with the uninfected control. The AChE activity dropped to 0.32 from 2.20 μmol ACTC min-1mg protein-1 in the brain and 4.57 to 0.76 μmol ACTC min-1mg protein-1 in the blood. The animals treated with Diminaveto at 3.5 mg/kg/d were observed to have recovered significantly from parasitemia and were able to regain AChE activity in the blood but not in the brain as compared to the control groups. We also observed, that progressive parasitemia resulted to alterations in PCV, Hb, RBC, WBC, neurophils, total protein, lymphocytes, monocytes and eosinophil in acute infections of T. congo. Polymerase chain reaction (PCR) of infected blood before inoculation and on day 10 post infection revealed 600 bp on agarose gel electrophoresis. Conclusions: This finding suggest that decrease in AChE activity increases acetylcholine concentration in the synaptic cleft resulting to neurological failures in impulse transfer in T. congo infection rats.

  15. Effect of floorball training on blood lipids, body composition, muscle strength, and functional capacity of elderly men

    DEFF Research Database (Denmark)

    Petersen, Jacob Vorup; Pedersen, Mogens Theisen; Melcher, Pia Grethe Sandfeld;

    2016-01-01

    effect of floorball training on blood lipids, muscle strength, body composition, and functional capacity of men aged 65-76 years. Thirty-nine recreational active men were randomized into a floorball group (FG; n = 22) or petanque group (PG; n = 17), in which training was performed 1 h twice a week for 12...... functional capacity tests were better (P < 0.05) after compared to before the training period. No changes were observed in PG. In conclusion, 12 weeks of floorball training resulted in a number of favorable effects important for health and functional capacity, suggesting that floorball training can be used......Floorball training consists of intense repeated exercise and may offer a motivating and social stimulating team activity in elderly individuals. However, the effect of floorball training in elderly adults on physiological adaptations important for health is not known. Thus, this study examined the...

  16. Effect of insulin on human skeletal muscle protein synthesis is modulated by insulin-induced changes in muscle blood flow and amino acid availability

    OpenAIRE

    Fujita, Satoshi; Rasmussen, Blake B.; Cadenas, Jerson G.; Grady, James J.; Volpi, Elena

    2006-01-01

    Insulin promotes muscle anabolism, but it is still unclear whether it stimulates muscle protein synthesis in humans. We hypothesized that insulin can increase muscle protein synthesis only if it increases muscle amino acid availability. We measured muscle protein and amino acid metabolism using stable-isotope methodologies in 19 young healthy subjects at baseline and during insulin infusion in one leg at low (LD, 0.05), intermediate (ID, 0.15), or high (HD, 0.30 mU·min−1·100 ml−1) doses. Insu...

  17. Anemia and Blood Transfusion in Patients with Isolated Traumatic Brain Injury

    Science.gov (United States)

    Al-Dorzi, Hasan M.; Al-Humaid, Waleed; Tamim, Hani M.; Haddad, Samir; Aljabbary, Ahmad; Arifi, Abdulaziz; Arabi, Yaseen M.

    2015-01-01

    Rationale. By reducing cerebral oxygen delivery, anemia may aggravate traumatic brain injury (TBI) secondary insult. This study evaluated the impact of anemia and blood transfusion on TBI outcomes. Methods. This was a retrospective cohort study of adult patients with isolated TBI at a tertiary-care intensive care unit from 1/1/2000 to 31/12/2011. Daily hemoglobin level and packed red blood cell (PRBC) transfusion were recorded. Patients with hemoglobin < 10 g/dL during ICU stay (anemic group) were compared with other patients. Results. Anemia was present on admission in two (2%) patients and developed in 48% during the first week with hemoglobin < 7 g/dL occurring in 3.0%. Anemic patients had higher admission Injury Severity Score and underwent more craniotomy (50% versus 13%, p < 0.001). Forty percent of them received PRBC transfusion (2.8 ± 1.5 units per patient, median pretransfusion hemoglobin = 8.8 g/dL). Higher hospital mortality was associated with anemia (25% versus 6% for nonanemic patients, p = 0.01) and PRBC transfusion (38% versus 9% for nontransfused patients, p = 0.003). On multivariate analysis, only PRBC transfusion independently predicted hospital mortality (odds ratio: 6.8; 95% confidence interval: 1.1–42.3). Conclusions. Anemia occurred frequently after isolated TBI, but only PRBC transfusion independently predicted mortality. PMID:26605080

  18. Heat stress redistributes blood flow in arteries of the brain during dynamic exercise.

    Science.gov (United States)

    Sato, Kohei; Oue, Anna; Yoneya, Marina; Sadamoto, Tomoko; Ogoh, Shigehiko

    2016-04-01

    We hypothesized that heat stress would decrease anterior and posterior cerebral blood flow (CBF) during exercise, and the reduction in anterior CBF would be partly associated with large increase in extracranial blood flow (BF). Nine subjects performed 40 min of semirecumbent cycling at 60% of the peak oxygen uptake in hot (35°C; Heat) and thermoneutral environments (25°C; Control). We evaluated BF and conductance (COND) in the external carotid artery (ECA), internal carotid artery (ICA), and vertebral artery (VA) using ultrasonography. During the Heat condition, ICA and VA BF were significantly increased 10 min after the start of exercise (PECA BF and COND at the end of Heat were both higher than levels in the Control condition (PECA BF during Heat was negatively correlated with a change in ICA BF (r= -0.75). Heat stress resulted in modification of the vascular response of head and brain arteries to exercise, which resulted in an alteration in the distribution of cardiac output. Moreover, a hyperthermia-induced increase in extracranial BF might compromise anterior CBF during exercise with heat stress. PMID:26846548

  19. Smooth Muscle Cell Alignment and Phenotype Control by Melt Spun Polycaprolactone Fibers for Seeding of Tissue Engineered Blood Vessels

    Directory of Open Access Journals (Sweden)

    Animesh Agrawal

    2015-01-01

    Full Text Available A method has been developed to induce and retain a contractile phenotype for vascular smooth muscle cells, as the first step towards the development of a biomimetic blood vessel construct with minimal compliance mismatch. Melt spun PCL fibers were deposited on a mandrel to form aligned fibers of 10 μm in diameter. The fibers were bonded into aligned arrangement through dip coating in chitosan solution. This formed a surface of parallel grooves, 10 μm deep by 10 μm across, presenting a surface layer of chitosan to promote cell surface interactions. The aligned fiber surface was used to culture cells present in the vascular wall, in particular fibroblasts and smooth muscle cells. This topography induced “surface guidance” over the orientation of the cells, which adopted an elongated spindle-like morphology, whereas cells on the unpatterned control surface did not show such orientation, assuming more rhomboid shapes. The preservation of VSMC contractile phenotype on the aligned scaffold was demonstrated by the retention of α-SMA expression after several days of culture. The effect was assessed on a prototype vascular graft prosthesis fabricated from polylactide caprolactone; VSMCs aligned longitudinally along a fiberless tube, whereas, for the aligned fiber coated tubes, the VSMCs aligned in the required circumferential orientation.

  20. Non-invasive laser Doppler perfusion measurements of large tissue volumes and human skeletal muscle blood RMS velocity

    International Nuclear Information System (INIS)

    This study proposes the implementation of an algorithm allowing one to derive absolute blood root-mean-square (RMS) velocity values from laser Doppler perfusion meter (LDP) data. The algorithm is based on the quasi-elastic light scattering theory and holds for multiple scattering. While standard LDP measurements are normally applicable to a small region of interest (∼1 mm2), the present method allows the analysis of both small and large tissue volumes with small and large interoptode spacings (e.g., 1.5 cm). The applicability and the limits of the method are demonstrated with measurements on human skeletal muscle using a custom-built near-infrared LDP meter. Human brachioradialis muscle RMS velocity values of 9.99 ± 0.01 and 5.58 ± 0.03 mm s-1 at 1.5 cm and of 5.18 ± 0.01 and 2.54 ± 0.09 mm s-1 at 2 cm were found when the arm was (a) at rest and (b) occluded, respectively. At very large optode spacings or very high moving particle densities, the theory developed here would need to be amended to take into account second-order effects