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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. A common pathway for regulation of nutritive blood flow to the brain: arterial muscle membrane potential and cytochrome P450 metabolites.

    Science.gov (United States)

    Harder, D R; Roman, R J; Gebremedhin, D; Birks, E K; Lange, A R

    1998-12-01

    Perfusion pressure to the brain must remain relatively constant to provide rapid and efficient distribution of blood to metabolically active neurones. Both of these processes are regulated by the level of activation and tone of cerebral arterioles. The active state of cerebral arterial muscle is regulated, to a large extent, by the level of membrane potential. At physiological levels of arterial pressure, cerebral arterial muscle is maintained in an active state owing to membrane depolarization, compared with zero pressure load. As arterial pressure changes, so does membrane potential. The membrane is maintained in a relatively depolarized state because of, in part, inhibition of K+ channel activity. The activity of K+ channels, especially the large conductance Ca(2+)-activated K+ channel (KCa) is dependent upon the level of 20-HETE produced by arterial muscle. As arterial pressure increases, so does cytochrome P450 (P4504A) activity. P4504A enzymes catalyse omega-hydroxylation of arachidonic acid and formation of 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE is a potent inhibitor of KCa which maintains membrane depolarization and muscle cell activation. Astrocytes also metabolize AA via P450 enzymes of the 2C11 gene family to produce epoxyeicosatrienoic acids (EETs). Epoxyeicosatrienoic acids are released from astrocytes by glutamate which 'spills over' during neuronal activity. These locally released EETs shunt blood to metabolically active neurones providing substrate to support neuronal function. This short paper will discuss the findings which support the above scenario, the purpose of which is to provide a basis for future studies on the molecular mechanisms through which cerebral blood flow matches metabolism.

  3. Society of cardiovascular anesthesiologists: the effect of blood pressure regulation during aortic coarctation repair on brain, kidney, and muscle oxygen saturation measured by near-infrared spectroscopy: a randomized, clinical trial

    NARCIS (Netherlands)

    Moerman, Annelies; Bové, Thierry; François, Katrien; Jacobs, Stefan; Deblaere, Isabel; Wouters, Patrick; de Hert, Stefan

    2013-01-01

    In this study, we compared the effects of 3 frequently used arterial blood pressure-regulating agents on brain (rScO2), renal (SrO2), and muscle (SmO2) oxygen saturation, during aortic coarctation repair in children. Based on the reported adverse effect of sodium nitroprusside (SNP) on left-sided

  4. Brain blood-flow changes during motion sickness. [thalamus vascular changes in dogs during swing tests

    Science.gov (United States)

    Johnson, W. H.; Hsuen, J.

    1973-01-01

    The possibility of diminished blood flow in the brain is studied as one of the factors resulting from an increase in skeletal muscle blood volume concomitant with other characteristics of motion sickness. Thermistors are implanted in the thalamus of dogs and blood flow changes are recorded while they are subjected to sinusoidal movement on a two pole swing. Results of these initial steps in a proposed long term exploration of different areas of the brain are presented.

  5. Relationship between blood glucose levels and muscle strength in ...

    African Journals Online (AJOL)

    The prevalence of diabetes is increasing worldwide. High blood glucose has been associated with loss of muscle strength and mass in the lower extremities. However, in African children, little is known about the association between handgrip strength, flexed arm hang or other measures of muscle strength with blood ...

  6. Human brain activity associated with painful mechanical stimulation to muscle and bone

    OpenAIRE

    Maeda, Lynn; Ono, Mayu; Koyama, Tetsuo; Oshiro, Yoshitetsu; Sumitani, Masahiko; Mashimo, Takashi; Shibata, Masahiko

    2011-01-01

    Purpose The purpose of this study was to elucidate the central processing of painful mechanical stimulation to muscle and bone by measuring blood oxygen level-dependent signal changes using functional magnetic resonance imaging (fMRI). Methods Twelve healthy volunteers were enrolled. Mechanical pressure on muscle and bone were applied at the right lower leg by an algometer. Intensities were adjusted to cause weak and strong pain sensation at either target site in preliminary testing. Brain ac...

  7. LEGS AND TRUNK MUSCLE HYPERTROPHY FOLLOWING WALK TRAINING WITH RESTRICTED LEG MUSCLE BLOOD FLOW

    Directory of Open Access Journals (Sweden)

    Mikako Sakamaki

    2011-06-01

    Full Text Available 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-measured upper (3.8%, P < 0.05 and lower leg (3.2%, P < 0. 05 muscle volume increased significantly, whereas the muscle volume of the gluteus maximus (-0.6% and iliopsoas (1.8% and the muscle CSA of the lumber L4-L5 (-1.0 did not change. There was no significant change in muscle volume in the walk training alone. Our results suggest that the combination of leg muscle blood flow restriction with slow walk training elicits hypertrophy only in the distal blood flow restricted leg muscles. Exercise intensity may be too low during BFR walk training to increase muscle mass in the non- blood flow restricted muscles (gluteus maximus and other trunk muscles.

  8. Rat muscle blood flows during high-speed locomotion

    International Nuclear Information System (INIS)

    Armstrong, R.B.; Laughlin, M.H.

    1985-01-01

    We previously studied blood flow distribution within and among rat muscles as a function of speed from walking (15 m/min) through galloping (75 m/min) on a motor-driven treadmill. The results showed that muscle blood flows continued to increase as a function of speed through 75 m/min. The purpose of the present study was to have rats run up to maximal treadmill speeds to determine if blood flows in the muscles reach a plateau as a function of running speed over the animals normal range of locomotory speeds. Muscle blood flows were measured with radiolabeled microspheres at 1 min of running at 75, 90, and 105 m/min in male Sprague-Dawley rats. The data indicate that even at these relatively high treadmill speeds there was still no clear evidence of a plateau in blood flow in most of the hindlimb muscles. Flows in most muscles continued to increase as a function of speed. These observed patterns of blood flow vs. running speed may have resulted from the rigorous selection of rats that were capable of performing the high-intensity exercise and thus only be representative of a highly specific population of animals. On the other hand, the data could be interpreted to indicate that the cardiovascular potential during exercise is considerably higher in laboratory rats than has normally been assumed and that inadequate blood flow delivery to the muscles does not serve as a major limitation to their locomotory performance

  9. Hormones and the blood-brain barrier.

    Science.gov (United States)

    Hampl, Richard; Bičíková, Marie; Sosvorová, Lucie

    2015-03-01

    Hormones exert many actions in the brain, and brain cells are also hormonally active. To reach their targets in brain structures, hormones must overcome the blood-brain barrier (BBB). The BBB is a unique device selecting desired/undesired molecules to reach or leave the brain, and it is composed of endothelial cells forming the brain vasculature. These cells differ from other endothelial cells in their almost impermeable tight junctions and in possessing several membrane structures such as receptors, transporters, and metabolically active molecules, ensuring their selection function. The main ways how compounds pass through the BBB are briefly outlined in this review. The main part concerns the transport of major classes of hormones: steroids, including neurosteroids, thyroid hormones, insulin, and other peptide hormones regulating energy homeostasis, growth hormone, and also various cytokines. Peptide transporters mediating the saturable transport of individual classes of hormones are reviewed. The last paragraph provides examples of how hormones affect the permeability and function of the BBB either at the level of tight junctions or by various transporters.

  10. 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...... 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 HRP in the mid twentieth-century was an important advance because its reaction product can be visualized at the electron microscopical level, but it also has limitations. Advantages and disadvantages of these markers will be discussed together with a critical evaluation of alternative approaches...

  11. Vasodilator interactions in skeletal muscle blood flow regulation

    DEFF Research Database (Denmark)

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

    2012-01-01

    of vasodilators have been shown to bring about this increase in blood flow and, importantly, interactions between these compounds seem to be essential for the precise regulation of blood flow. Two compounds stand out as central in these vasodilator interactions; nitric oxide (NO) and prostacyclin. These two...... that this remaining hyperemia may be explained by cAMP and cGMP independent smooth muscle relaxation, such as effects of endothelial derived hyperpolarization factors (EDHFs) or through metabolic modulation of sympathetic effects. The nature and role of EDHF as well as potential novel mechanisms in muscle blood flow...... regulation remain to be further explored to fully elucidate the regulation of exercise hyperemia....

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

    DEFF Research Database (Denmark)

    Asgari, Nasrin; Berg, Carsten Tue; Mørch, Marlene Thorsen

    2015-01-01

    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....

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

    DEFF Research Database (Denmark)

    Nyberg, Michael Permin; Hellsten, Ylva

    2016-01-01

    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......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....

  14. Metabolic control of muscle blood flow during exercise in humans

    DEFF Research Database (Denmark)

    Boushel, Robert Christopher

    2003-01-01

    that combined blockade of NOS and PGI2, and NOS and cytochrome P450, both attenuate exercise-induced hyperemia in humans. Combined vasodilator blockade studies offer the potential to uncover important interactions and compensatory vasodilator responses. The signaling pathways that link metabolic events evoked...... to exert control of muscle vasodilation. Adenosine, nitric oxide (NO), prostacyclin (PGI2), and endothelial-derived hyperpolarization factor (EDHF) are possible mediators of muscle vasodilation during exercise. In humans, adenosine has been shown to contribute to functional hyperemia as blood flow...... by muscle contraction to vasodilatory signals in the local vascular bed remains an important area of study....

  15. 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 ... forbrain (pyruvate and 3-hydroxybutyrate). Thus, long-term HF diet was associated with obesity, dyslipidemia, insulin resistance, andsignificantly altered mitochondrial function in skeletal muscle. Yet, brain mitochondria were unaffected. We suggest that therelative isolation of the brain due to the blood...

  16. An unusual presentation of muscle-eye-brain disease: severe eye abnormalities with mild muscle and brain involvement.

    Science.gov (United States)

    Demir, Ercan; Gucuyener, Kivilcim; Akturk, Aysima; Talim, Beril; Konus, Oznur; Del Bo, Roberto; Ghezzi, Serena; Comi, Giacomo P

    2009-10-01

    Muscle-eye-brain disease (MEB) is characterised by congenital muscular dystrophy, structural brain malformations and eye abnormalities. We report a MEB case whose presenting sign was congenital blindness. She was investigated primarily for eye abnormalities at onset. She had bilateral retinal detachment and microphthalmia. Mild axial hypotonia and motor retardation were attributed to cerebral disorder in another center. Muscle biopsy showed mild myopathic changes and significant alpha-dystroglycan deficiency. Analysis of the POMGnT1 showed a novel homozygous mutation 1814G>C, causing p.Arg605Pro change. This case expands the clinical spectrum of MEB with unusually severe eye abnormalities compared to mild skeletal muscle and brain involvement.

  17. 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.

  18. Human brain activity associated with painful mechanical stimulation to muscle and bone.

    Science.gov (United States)

    Maeda, Lynn; Ono, Mayu; Koyama, Tetsuo; Oshiro, Yoshitetsu; Sumitani, Masahiko; Mashimo, Takashi; Shibata, Masahiko

    2011-08-01

    The purpose of this study was to elucidate the central processing of painful mechanical stimulation to muscle and bone by measuring blood oxygen level-dependent signal changes using functional magnetic resonance imaging (fMRI). Twelve healthy volunteers were enrolled. Mechanical pressure on muscle and bone were applied at the right lower leg by an algometer. Intensities were adjusted to cause weak and strong pain sensation at either target site in preliminary testing. Brain activation in response to mechanical nociceptive stimulation targeting muscle and bone were measured by fMRI and analyzed. Painful mechanical stimulation targeting muscle and bone activated the common areas including bilateral insula, anterior cingulate cortex, posterior cingulate cortex, secondary somatosensory cortex (S2), inferior parietal lobe, and basal ganglia. The contralateral S2 was more activated by strong stimulation than by weak stimulation. Some areas in the basal ganglia (bilateral putamen and caudate nucleus) were more activated by muscle stimulation than by bone stimulation. The putamen and caudate nucleus may have a more significant role in brain processing of muscle pain compared with bone pain.

  19. Regulation of Blood Flow in Contracting Skeletal Muscle in Aging

    DEFF Research Database (Denmark)

    Piil, Peter Bergmann

    Oxygen delivery to skeletal muscle is regulated precisely to match the oxygen demand; however, with aging the regulation of oxygen delivery during exercise is impaired. The present thesis investigated mechanisms underlying the age-related impairment in regulation of blood flow and oxygen delivery...... to contracting skeletal muscle. Two studies, one acute exercise study and one large 8-week training intervention study, were conducted in young (18-28 years) and older (65-80 years) healthy, male subjects. In both studies, pharmacologic potentiation of the formation of cyclic guanosine monophosphate (c...... that improving sympatholytic capacity by training may be a slower process in older than in young men. In conclusion, this thesis provides new important knowledge related to the regulation of skeletal muscle blood flow in aging. Specifically, it demonstrates that changes in cGMP signaling is an underlying cause...

  20. 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...

  1. Ciliary muscle capillaries have blood-tissue barrier characteristics

    NARCIS (Netherlands)

    Schlingemann, R. O.; Hofman, P.; Klooster, J.; Blaauwgeers, H. G.; van der Gaag, R.; Vrensen, G. F.

    1998-01-01

    It was determined whether the capillaries in the ciliary muscle are of the blood-tissue barrier or of the permeable non-barrier type. Ciliary body and iris of normal human and animal eyes were examined by electron microscopy and by immunohistochemical staining with a panel of antibodies recognizing

  2. Repeated blood flow restriction induces muscle fiber hypertrophy.

    Science.gov (United States)

    Sudo, Mizuki; Ando, Soichi; Kano, Yutaka

    2017-02-01

    We recently developed an animal model to investigate the effects of eccentric contraction (ECC) and blood flow restriction (BFR) on muscle tissue at the cellular level. This study clarified the effects of repeated BFR, ECC, and BFR combined with ECC (BFR+ECC) on muscle fiber hypertrophy. Male Wistar rats were assigned to 3 groups: BFR, ECC, and BFR+ECC. The contralateral leg in the BFR group served as a control (CONT). Muscle fiber cross-sectional area (CSA) of the tibialis anterior was determined after the respective treatments for 6 weeks. CSA was greater in the BFR+ECC group than in the CONT (P hypertrophy at the cellular level. Muscle Nerve 55: 274-276, 2017. © 2016 Wiley Periodicals, Inc.

  3. Histopathology of gill, liver, muscle and brain of Cyprinus carpio ...

    African Journals Online (AJOL)

    Histological studies in organs like gill, liver, muscle and brain of Cyprinus carpio communis were made to assess tissue damage due to sublethal concentration of heavy metals lead and cadmium after 28 days of exposure. In lead treated gill, disintegration and fusion of primary lamellae, extensive vacuolization with ...

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

    International Nuclear Information System (INIS)

    Chatterjee, Somik; Yin, Hongshan; Nam, Deokhwa; Li, Yong; Ma, Ke

    2015-01-01

    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 −/− 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. 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.

  6. Brain pericytes from stress-susceptible pigs increase blood-brain barrier permeability in vitro

    Directory of Open Access Journals (Sweden)

    Vandenhaute Elodie

    2012-06-01

    Full Text Available Abstract Background The function of pericytes remains questionable but with improved cultured technique and the use of genetically modified animals, it has become increasingly clear that pericytes are an integral part of blood–brain barrier (BBB function, and the involvement of pericyte dysfunction in certain cerebrovascular diseases is now emerging. The porcine stress syndrome (PSS is the only confirmed, homologous model of malignant hyperthermia (MH in veterinary medicine. Affected animals can experience upon slaughter a range of symptoms, including skeletal muscle rigidity, metabolic acidosis, tachycardia and fever, similar to the human syndrome. Symptoms are due to an enhanced calcium release from intracellular stores. These conditions are associated with a point mutation in ryr1/hal gene, encoding the ryanodine receptor, a calcium channel. Important blood vessel wall muscle modifications have been described in PSS, but potential brain vessel changes have never been documented in this syndrome. Methods In the present work, histological and ultrastructural analyses of brain capillaries from wild type and ryr1 mutated pigs were conducted to investigate the potential impairment of pericytes, in this pathology. In addition, brain pericytes were isolated from the three porcine genotypes (wild-type NN pigs; Nn and nn pigs, bearing one or two (n mutant ryr1/hal alleles, respectively, and tested in vitro for their influence on the permeability of BBB endothelial monolayers. Results Enlarged perivascular spaces were observed in ryr1-mutant samples, corresponding to a partial or total detachment of the astrocytic endfeet. These spaces were electron lucent and sometimes filled with lipid deposits and swollen astrocytic feet. At the ultrastructural level, brain pericytes did not seem to be affected because they showed regular morphology and characteristics, so we aimed to check their ability to maintain BBB properties in vitro. Our results indicated

  7. Glial and neuronal control of brain blood flow

    DEFF Research Database (Denmark)

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

    2010-01-01

    recognized that neurotransmitter-mediated signalling has a key role in regulating cerebral blood flow, that much of this control is mediated by astrocytes, that oxygen modulates blood flow regulation, and that blood flow may be controlled by capillaries as well as by arterioles. These conceptual shifts......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...... in our understanding of cerebral blood flow control have important implications for the development of new therapeutic approaches....

  8. 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...

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

    DEFF Research Database (Denmark)

    Gjedde, Albert; Aanerud, Joel; Braendgaard, Hans

    2013-01-01

    -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...... with the observation that numerically, but insignificantly, unidirectional blood-brain clearances are lower and extraction fractions higher in the patients. The evidence of unchanged permeability-surface area products in the patients implies that blood flow changes can be deduced from the unidirectional blood......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...

  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. 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.

  12. Controlling ferrofluid permeability across the blood-brain barrier model

    Science.gov (United States)

    Shi, Di; Sun, Linlin; Mi, Gujie; Sheikh, Lubna; Bhattacharya, Soumya; Nayar, Suprabha; Webster, Thomas J.

    2014-02-01

    In the present study, an in vitro blood-brain barrier model was developed using murine brain endothelioma cells (b.End3 cells). Confirmation of the blood-brain barrier model was completed by examining the permeability of FITC-Dextran at increasing exposure times up to 96 h in serum-free medium and comparing such values with values from the literature. After such confirmation, the permeability of five novel ferrofluid (FF) nanoparticle samples, GGB (ferrofluids synthesized using glycine, glutamic acid and BSA), GGC (glycine, glutamic acid and collagen), GGP (glycine, glutamic acid and PVA), BPC (BSA, PEG and collagen) and CPB (collagen, PVA and BSA), was determined using this blood-brain barrier model. All of the five FF samples were characterized by zeta potential to determine their charge as well as TEM and dynamic light scattering for determining their hydrodynamic diameter. Results showed that FF coated with collagen passed more easily through the blood-brain barrier than FF coated with glycine and glutamic acid based on an increase of 4.5% in permeability. Through such experiments, diverse magnetic nanomaterials (such as FF) were identified for: (1) MRI use since they were less permeable to penetrate the blood-brain barrier to avoid neural tissue toxicity (e.g. GGB) or (2) brain drug delivery since they were more permeable to the blood-brain barrier (e.g. CPB).

  13. Barrier mechanisms in the Drosophila blood-brain barrier

    Directory of Open Access Journals (Sweden)

    Samantha Jane Hindle

    2014-12-01

    Full Text Available The invertebrate blood-brain barrier field is growing at a rapid pace and, in recent years, studies have shown a physiologic and molecular complexity that has begun to rival its vertebrate counterpart. Novel mechanisms of paracellular barrier maintenance through GPCR signaling were the first demonstrations of the complex adaptive mechanisms of barrier physiology. Building upon this work, the integrity of the invertebrate blood-brain barrier has recently been shown to require coordinated function of all layers of the compound barrier structure, analogous to signaling between the layers of the vertebrate neurovascular unit. These findings strengthen the notion that many blood-brain barrier mechanisms are conserved between vertebrates and invertebrates, and suggest that novel findings in invertebrate model organisms will have a significant impact on the understanding of vertebrate BBB functions. In this vein, important roles in coordinating localized and systemic signaling to dictate organism development and growth are beginning to show how the blood-brain barrier can govern whole animal physiologies. This includes novel functions of blood-brain barrier gap junctions in orchestrating synchronized neuroblast proliferation, and of blood-brain barrier secreted antagonists of insulin receptor signaling. These advancements and others are pushing the field forward in exciting new directions. In this review, we provide a synopsis of invertebrate blood-brain barrier anatomy and physiology, with a focus on insights from the past 5 years, and highlight important areas for future study.

  14. Anatomy and physiology of the blood-brain barrier.

    Science.gov (United States)

    Serlin, Yonatan; Shelef, Ilan; Knyazer, Boris; Friedman, Alon

    2015-02-01

    Essential requisite for the preservation of normal brain activity is to maintain a narrow and stable homeostatic control in the neuronal environment of the CNS. Blood flow alterations and altered vessel permeability are considered key determinants in the pathophysiology of brain injuries. We will review the present-day literature on the anatomy, development and physiological mechanisms of the blood-brain barrier, a distinctive and tightly regulated interface between the CNS and the peripheral circulation, playing a crucial role in the maintenance of the strict environment required for normal brain function. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. 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.

  16. Kinesthetic imagery training of forceful muscle contractions increases brain signal and muscle strength.

    Science.gov (United States)

    Yao, Wan X; Ranganathan, Vinoth K; Allexandre, Didier; Siemionow, Vlodek; Yue, Guang H

    2013-01-01

    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 IMI 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.

  17. Functional Imaging of Dolphin Brain Metabolism and Blood Flow

    National Research Council Canada - National Science Library

    Ridgway, Sam; Finneran, James; Carder, Don; Keogh, Mandy; Van Bonn, William; Smith, Cynthia; Scadeng, Miriam; Dubowitz, David; Mattrey, Robert; Hoh, Carl

    2006-01-01

    .... Diazepam has been shown to induce unihemispheric slow waves (USW), therefore we used functional imaging of dolphins with and without diazepam to observe hemispheric differences in brain metabolism and blood flow...

  18. Neural Contributions to Muscle Fatigue: From the Brain to the Muscle and Back Again.

    Science.gov (United States)

    Taylor, Janet L; Amann, Markus; Duchateau, Jacques; Meeusen, Romain; Rice, Charles L

    2016-11-01

    : During exercise, there is a progressive reduction in the ability to produce muscle force. Processes within the nervous system as well as within the muscles contribute to this fatigue. In addition to impaired function of the motor system, sensations associated with fatigue and impairment of homeostasis can contribute to the impairment of performance during exercise. This review discusses some of the neural changes that accompany exercise and the development of fatigue. The role of brain monoaminergic neurotransmitter systems in whole-body endurance performance is discussed, particularly with regard to exercise in hot environments. Next, fatigue-related alterations in the neuromuscular pathway are discussed in terms of changes in motor unit firing, motoneuron excitability, and motor cortical excitability. These changes have mostly been investigated during single-limb isometric contractions. Finally, the small-diameter muscle afferents that increase firing with exercise and fatigue are discussed. These afferents have roles in cardiovascular and respiratory responses to exercise, and in the impairment of exercise performance through interaction with the motor pathway, as well as in providing sensations of muscle discomfort. Thus, changes at all levels of the nervous system, including the brain, spinal cord, motor output, sensory input, and autonomic function, occur during exercise and fatigue. The mix of influences and the importance of their contribution vary with the type of exercise being performed.

  19. Neural Contributions to Muscle Fatigue: From the Brain to the Muscle and Back Again

    Science.gov (United States)

    Taylor, Janet L.; Amann, Markus; Duchateau, Jacques; Meeusen, Romain; Rice, Charles L.

    2016-01-01

    During exercise, there is a progressive reduction in the ability to produce muscle forces. Processes within the nervous system, as well as within the muscles contribute to this fatigue. In addition to impaired function of the motor system, sensations associated with fatigue, and impairment of homeostasis can contribute to impairment of performance during exercise. This review discusses some of the neural changes that accompany exercise and the development of fatigue. The role of brain monoaminergic neurotransmitter systems in whole-body endurance performance is discussed, particularly with regard to exercise in hot environments. Next, fatigue-related alterations in the neuromuscular pathway are discussed in terms of changes in motor unit firing, motoneuron excitability and motor cortical excitability. These changes have mostly been investigated during single-limb isometric contractions. Finally, the small-diameter muscle afferents that increase firing with exercise and fatigue are discussed. These afferents have roles in cardiovascular and respiratory responses to exercise, and in impairment of exercise performance through interaction with the motor pathway, as well as providing sensations of muscle discomfort. Thus, changes at all levels of the nervous system including the brain, spinal cord, motor output, sensory input and autonomic function occur during exercise and fatigue. The mix of influences and the importance of their contribution varies with the type of exercise being performed. PMID:27003703

  20. Glutamate Transporters in the Blood-Brain Barrier

    DEFF Research Database (Denmark)

    Helms, Hans Christian Cederberg; Nielsen, Carsten Uhd; Waagepetersen, Helle Sønderby

    2017-01-01

    The amino acid L-glutamate serves a number of roles in the central nervous system, being an excitatory neurotransmitter, metabolite, and building block in protein synthesis. During pathophysiological events, where L-glutamate homeostasis cannot be maintained, the increased brain interstitial fluid...... studies have demonstrated blood-to-brain transport of L-glutamate, at least during pathological events. A number of studies have shown that brain endothelial cells express excitatory amino acid transporters, which may account for abluminal concentrative uptake of L-glutamate into the capillary endothelial...... concentration of L-glutamate causes excitotoxicity. A tight control of the brain interstitial fluid L-glutamate levels is therefore imperative, in order to maintain optimal neurotransmission and to avoid such excitotoxicity. The blood-brain barrier, i.e., the endothelial lining of the brain capillaries...

  1. Increasing oxime efficacy by blood-brain barrier modulation

    NARCIS (Netherlands)

    Joosen, M.J.A.; Schans, M.J. van der; Dijk, C.G.M. van; Kuijpers, W.C.; Wortelboer, H.M.; Helden, H.P.M. van

    2011-01-01

    One of the shortcomings of current treatment of nerve agent poisoning is that oximes hardly penetrate the blood-brain barrier (BBB), whereas nerve agents easily do. Increasing the concentration of oximes in the brain, would therefore provide an attractive approach to improve medical countermeasures.

  2. Maintaining cerebral blood flow : From heart to brain

    NARCIS (Netherlands)

    Bronzwaer, A.-S.G.T.

    2017-01-01

    Brain function depends on a continuous provision of oxygen and nutrients. Interruption of blood supply to the brain for only a few seconds results already in loss of consciousness, emphasizing the need for tight regulation of CBF. Although CBF regulation by cerebrovascular control mechanisms (e.g.

  3. Contractures and involuntary muscle overactivity in severe brain injury.

    Science.gov (United States)

    Pohl, Marcus; Mehrholz, Jan; Rockstroh, Günter; Rückriem, Stefan; Koch, Rainer

    2007-04-01

    The aim of the present study was to evaluate the association of contractures with an increase or reduction of non-spastic muscle overactivity due to severe cerebral damage. Forty-five patients with tetraparesis after severe cerebral damage were investigated. Three groups were defined based on the presence of spasticity (revealed as resistance to passive stretch (= hypertonia)), and the presence of contracture of the relevant knee joint: Group(s) (17 patients with hypertonia without contracture), Group(s+c) (20 patients with hypertonia and contracture), and Group(c) (eight patients without hypertonia and with contracture). In all groups spontaneous involuntary muscle activity was assessed continuously over a 12-hour period through isometric measurement of knee joint flexion torque. A mathematical algorithm differentiated an hourly muscle activity spectrum (PI(h)). The frequency of peaks (peaks(h)) from the activity spectrum was determined. We revealed that Group(s) had higher PI(h) and more frequent peaks(h) compared with Group(s+c) and Group(c) (p0.05). The presence of contractures was associated with lower involuntary muscle overactivity in terms of lower PI(h) and less frequent peaks(h), indicating that contractures may be associated with reduced non-spastic positive features of the upper motor neurone syndrome in patients with severe brain damage.

  4. 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.

  5. Motor Evoked Potentials of Trunk Muscles in Traumatic Brain Injury Patients

    OpenAIRE

    Seo, Min-Ho; Park, Sung-Hee; Ko, Myoung-Hwan; Seo, Jeong-Hwan

    2011-01-01

    Objective To evaluate the motor innervation of trunk muscles in traumatic brain injury patients. Method Twenty patients (12 men and 8 women) with traumatic brain injury were enrolled in this study. Their mean age was 41 years. Motor evoked potentials (MEPs) were performed on the motor cortex. Electromyographic activities were recorded from the bilateral rectus abdominis muscles, the external oblique abdominal muscles, and the 4th and 9th thoracic erector spinae muscles. The onset latency and ...

  6. 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

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

    International Nuclear Information System (INIS)

    Ogawa, S.; Lee, T.M.; Kay, A.R.; Tank, D.W.

    1990-01-01

    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

  8. Blood-Brain Transfer of Pittsburgh Compound B in Humans

    Directory of Open Access Journals (Sweden)

    Albert eGjedde

    2013-11-01

    Full Text Available In the labeled form, the Pittsburgh compound B (2-(4’-{N-methyl-[11C]}methyl-aminophenyl-6-hydroxybenzothiazole,[11C]PiB, is used as a biomarker for positron emission tomography (PET of brain □-amyloiddeposition in Alzheimer’s disease (AD. The permeability of [11C]PiB in the blood-brain barrier is held tobe high but the permeability-surface area product and extraction fractions in patients or healthy volunteersare not known. We used PET to determine the clearance associated with the unidrectional blood-braintransfer of [11C]PiB and the corresponding cerebral blood flow rates in frontal lobe, whole cerebral cortex,and cerebellum of patients with Alzheimer’s disease and healthy volunteers. Regional cerebral blood flowrates differed significantly between the two groups, but regional and whole-brain permeability-surface areaproducts were identical, in agreement with the observation that numerically, but insignificantly, unidirectionalblood-brain clearances are lower and extraction fractions higher in the patients. The evidence of unchangedpermeability-surface area products in the patients implies that blood flow changes can be deduced from theunidirectional blood-brain clearances of [11C]PiB in the patients.

  9. Slow CCL2-dependent translocation of biopersistent particles from muscle to brain.

    Science.gov (United States)

    Khan, Zakir; Combadière, Christophe; Authier, François-Jérôme; Itier, Valérie; Lux, François; Exley, Christopher; Mahrouf-Yorgov, Meriem; Decrouy, Xavier; Moretto, Philippe; Tillement, Olivier; Gherardi, Romain K; Cadusseau, Josette

    2013-04-04

    Long-term biodistribution of nanomaterials used in medicine is largely unknown. This is the case for alum, the most widely used vaccine adjuvant, which is a nanocrystalline compound spontaneously forming micron/submicron-sized agglomerates. Although generally well tolerated, alum is occasionally detected within monocyte-lineage cells long after immunization in presumably susceptible individuals with systemic/neurologic manifestations or autoimmune (inflammatory) syndrome induced by adjuvants (ASIA). On the grounds of preliminary investigations in 252 patients with alum-associated ASIA showing both a selective increase of circulating CCL2, the major monocyte chemoattractant, and a variation in the CCL2 gene, we designed mouse experiments to assess biodistribution of vaccine-derived aluminum and of alum-particle fluorescent surrogates injected in muscle. Aluminum was detected in tissues by Morin stain and particle induced X-ray emission) (PIXE) Both 500 nm fluorescent latex beads and vaccine alum agglomerates-sized nanohybrids (Al-Rho) were used. Intramuscular injection of alum-containing vaccine was associated with the appearance of aluminum deposits in distant organs, such as spleen and brain where they were still detected one year after injection. Both fluorescent materials injected into muscle translocated to draining lymph nodes (DLNs) and thereafter were detected associated with phagocytes in blood and spleen. Particles linearly accumulated in the brain up to the six-month endpoint; they were first found in perivascular CD11b+ cells and then in microglia and other neural cells. DLN ablation dramatically reduced the biodistribution. Cerebral translocation was not observed after direct intravenous injection, but significantly increased in mice with chronically altered blood-brain-barrier. Loss/gain-of-function experiments consistently implicated CCL2 in systemic diffusion of Al-Rho particles captured by monocyte-lineage cells and in their subsequent neurodelivery

  10. 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-glutamate...

  11. Localized phosphorus STEAM MR spectroscopy of muscle, liver, and brain

    International Nuclear Information System (INIS)

    Frahm, J.; Merboldt, D.; Chien, D.; Haenicke, W.; Gyngell, M.L.; Bruhn, H.

    1989-01-01

    This paper reports on a study to acquire localized phosphorus MR spectra of human brain, muscle, and liver using STEAM sequences and to evaluate T1 and T2 relaxation times in vivo. Stimulated-echo (STEAM) localization sequences have been modified to allow echo times as short as 3 msec. In vivo phosphorus T1 and T2 relaxation times were determined by varying the repetition time and echo time, respectively, Investigations were performed at 2.0 T on a whole-body research system (Siemens Magnetom). With use of the water proton signal for localized shimming, excellent homogeneity over the volume of interest (VOI) was achieved, resulting in resolution of the homonuclear splitting of the adenosine triphosphate resonances without broadband proton decoupling. Typical acquisition parameters were 125-mL VOI, 256 accumulations, TE = 3 msec, and TR = 3,000 msec (muscle, brain). In some cases, T2-weighted spectra at TE = 10 msec show enhanced resolution in the phosphomonoester and phosphodiester regions due to differential T2 losses of the individual compounds

  12. Acid extrusion via blood-brain barrier causes brain alkalosis and seizures after neonatal asphyxia.

    Science.gov (United States)

    Helmy, Mohamed M; Ruusuvuori, Eva; Watkins, Paul V; Voipio, Juha; Kanold, Patrick O; Kaila, Kai

    2012-11-01

    Birth asphyxia is often associated with a high seizure burden that is predictive of poor neurodevelopmental outcome. The mechanisms underlying birth asphyxia seizures are unknown. Using an animal model of birth asphyxia based on 6-day-old rat pups, we have recently shown that the seizure burden is linked to an increase in brain extracellular pH that consists of the recovery from the asphyxia-induced acidosis, and of a subsequent plateau level well above normal extracellular pH. In the present study, two-photon imaging of intracellular pH in neocortical neurons in vivo showed that pH changes also underwent a biphasic acid-alkaline response, resulting in an alkaline plateau level. The mean alkaline overshoot was strongly suppressed by a graded restoration of normocapnia after asphyxia. The parallel post-asphyxia increase in extra- and intracellular pH levels indicated a net loss of acid equivalents from brain tissue that was not attributable to a disruption of the blood-brain barrier, as demonstrated by a lack of increased sodium fluorescein extravasation into the brain, and by the electrophysiological characteristics of the blood-brain barrier. Indeed, electrode recordings of pH in the brain and trunk demonstrated a net efflux of acid equivalents from the brain across the blood-brain barrier, which was abolished by the Na/H exchange inhibitor, N-methyl-isobutyl amiloride. Pharmacological inhibition of Na/H exchange also suppressed the seizure activity associated with the brain-specific alkalosis. Our findings show that the post-asphyxia seizures are attributable to an enhanced Na/H exchange-dependent net extrusion of acid equivalents across the blood-brain barrier and to consequent brain alkalosis. These results suggest targeting of blood-brain barrier-mediated pH regulation as a novel approach in the prevention and therapy of neonatal seizures.

  13. Regional cerebral blood flow in the patient with brain tumor

    Energy Technology Data Exchange (ETDEWEB)

    Tsuchida, Shohei (Okayama Univ. (Japan). School of Medicine)

    1993-06-01

    Regional cerebral blood flow (rCBF) was measured with xenon-enhanced CT (Xe-CT) in 21 cases of intracranial tumors (13 meningiomas, 5 gliomas, 3 metastatic brain tumors). Peritumoral edema was graded as mild, moderate or severe based on the extent of edema on CT and MRI. According to intratumoral blood flow distribution patterns, three patterns were classified as central type with relatively high blood flow at the center of the tumor, homogeneous type with an almost homogeneous blood flow distribution, and marginal type with relatively high blood flow at the periphery of the tumor. High grade astrocytoma and metastatic brain tumor showed marginal type blood flow and moderate or severe edema except in one case. Five meningiomas with severe peritumoral edema revealed marginal type blood flow and four with mild peritumoral edema showed central type blood flow, except for one case. No correlation was found between the extent of peritumoral edema and histological subtype, tumor size, location, duration of clinical history, vascularization on angiogram, and mean blood flow in the tumor. These results suggest that blood flow distribution patterns within the tumor may affect the extension of peritumoral edema. Pre- and postoperative rCBFs were evaluated with Xe-CT and IMP-SPECT in 7 cases, mean rCBF of peritumoral edema was 6.2 ml/100 g/min preoperatively, and discrepancy between rCBF on Xe-CT and that on IMP-SPECT was shown in the remote cortical region ipsilateral to the tumor. Postoperative rCBF revealed an improved blood flow in both adjacent and remote areas, suggesting that the decreased blood flow associated with brain tumors might be relieved after surgery. (author) 53 refs.

  14. Regional cerebral blood flow in the patient with brain tumor

    International Nuclear Information System (INIS)

    Tsuchida, Shohei

    1993-01-01

    Regional cerebral blood flow (rCBF) was measured with xenon-enhanced CT (Xe-CT) in 21 cases of intracranial tumors (13 meningiomas, 5 gliomas, 3 metastatic brain tumors). Peritumoral edema was graded as mild, moderate or severe based on the extent of edema on CT and MRI. According to intratumoral blood flow distribution patterns, three patterns were classified as central type with relatively high blood flow at the center of the tumor, homogeneous type with an almost homogeneous blood flow distribution, and marginal type with relatively high blood flow at the periphery of the tumor. High grade astrocytoma and metastatic brain tumor showed marginal type blood flow and moderate or severe edema except in one case. Five meningiomas with severe peritumoral edema revealed marginal type blood flow and four with mild peritumoral edema showed central type blood flow, except for one case. No correlation was found between the extent of peritumoral edema and histological subtype, tumor size, location, duration of clinical history, vascularization on angiogram, and mean blood flow in the tumor. These results suggest that blood flow distribution patterns within the tumor may affect the extension of peritumoral edema. Pre- and postoperative rCBFs were evaluated with Xe-CT and IMP-SPECT in 7 cases, mean rCBF of peritumoral edema was 6.2 ml/100 g/min preoperatively, and discrepancy between rCBF on Xe-CT and that on IMP-SPECT was shown in the remote cortical region ipsilateral to the tumor. Postoperative rCBF revealed an improved blood flow in both adjacent and remote areas, suggesting that the decreased blood flow associated with brain tumors might be relieved after surgery. (author) 53 refs

  15. Monitoring of blood oxygenation in brain by resonance Raman spectroscopy

    DEFF Research Database (Denmark)

    Brazhe, Nadezda A; Thomsen, Kirsten; Lønstrup, Micael

    2018-01-01

    Blood oxygenation in cerebral vessels is an essential parameter to evaluate brain function and to investigate the coupling between local blood flow and neuronal activity. We apply resonance Raman spectroscopy in vivo to study hemoglobin oxygenation in cortex vessels of anesthetized ventilated mice...... of oxyhemoglobin in venules, arterioles, and capillaries. In vivo measurements of blood oxygenation in the cortex of mice ventilated with inspiratory gas mixtures containing different amounts of oxygen - normoxia, hyperoxia and hypoxia - validate the proposed approach. Our method allows to visualize blood...

  16. Charting the course across the blood-brain barrier

    OpenAIRE

    Nathanson, David; Mischel, Paul S.

    2010-01-01

    The blood-brain barrier (BBB) presents a significant obstacle to delivery of targeted therapies to brain tumors. In this issue of the JCI, Staquicini and colleagues apply an in vivo phage-displayed library of random peptides to identify differentially expressed peptides that can be used to transport targeted agents across the intact BBB. The authors uncover a non-canonical, peptide-mediated iron-mimicry mechanism to induce transport of the transferrin/transferrin receptor complex across the B...

  17. Iron uptake and transport at the blood-brain barrier

    DEFF Research Database (Denmark)

    Larsen, Annette Burkhart; Thomsen, Louiza Bohn; Moos, Torben

    The mechanism by which iron is transported across the blood-brain barrier (BBB) remains controversial, and in this study we aimed to further clarify mechanisms by which iron is transported into the brain. We analyzed and compared the mRNA and protein expression of a variety of proteins involved...... space on its non-toxic ferric form to become accessible for iron uptake by neurons and glia....

  18. The Effect of Ovariectomy and Estrogen on Penetrating Brain Arterioles and Blood-Brain Barrier Permeability

    NARCIS (Netherlands)

    Cipolla, Marilyn J.; Godfrey, Julie A.; Wiegman, Marchien J.

    2009-01-01

    Objective: We investigated the effect of estrogen replacement on the structure and function of penetrating brain arterioles (PA) and blood-brain barrier (BBB) permeability. Materials and Methods: Female ovariectomized Sprague-Dawley rats were replaced with estradiol (E-2) and estriol (E-3) (OVX + E;

  19. Blood-Brain Glucose Transfer in Alzheimer's disease

    DEFF Research Database (Denmark)

    Gejl, Michael; Brock, Birgitte; Egefjord, Lærke

    2017-01-01

    There are fewer than normal glucose transporters at the blood-brain barrier (BBB) in Alzheimer's disease (AD). When reduced expression of transporters aggravates the symptoms of AD, the transporters become a potential target of therapy. The incretin hormone GLP-1 prevents the decline of cerebral...... metabolic rate for glucose (CMRglc) in AD, and GLP-1 may serve to raise transporter numbers. We hypothesized that the GLP-1 analog liraglutide would prevent the decline of CMRglc in AD by raising blood-brain glucose transfer, depending on the duration of disease. We randomized 38 patients with AD...

  20. Exercise intensity and muscle hypertrophy in blood flow-restricted limbs and non-restricted muscles: a brief review.

    Science.gov (United States)

    Abe, Takashi; Loenneke, Jeremy P; Fahs, Christopher A; Rossow, Lindy M; Thiebaud, Robert S; Bemben, Michael G

    2012-07-01

    Although evidence for high-intensity resistance training-induced muscle hypertrophy has accumulated over the last several decades, the basic concept of the training can be traced back to ancient Greece: Milo of Croton lifted a bull-calf daily until it was fully grown, which would be known today as progressive overload. Now, in the 21st century, different types of training are being tested and studied, such as low-intensity exercise combined with arterial as well as venous blood flow restriction (BFR) to/from the working muscles. Because BFR training requires the use of a cuff that is placed at the proximal ends of the arms and/or legs, the BFR is only applicable to limb muscles. Consequently, most previous BFR training studies have focused on the physiological adaptations of BFR limb muscles. Muscle adaptations in non-BFR muscles of the hip and trunk are lesser known. Recent studies that have reported both limb and trunk muscle adaptations following BFR exercise training suggest that low-intensity (20-30% of 1RM) resistance training combined with BFR elicits muscle hypertrophy in both BFR limb and non-BFR muscles. However, the combination of leg muscle BFR with walk training elicits muscle hypertrophy only in the BFR leg muscles. In contrast to resistance exercise with BFR, the exercise intensity may be too low during BFR walk training to cause muscle hypertrophy in the non-BFR gluteus maximus and other trunk muscles. Other mechanisms including hypoxia, local and systemic growth factors and muscle cell swelling may also potentially affect the hypertrophic response of non-BFR muscles to BFR resistance exercise. © 2012 The Authors Clinical Physiology and Functional Imaging © 2012 Scandinavian Society of Clinical Physiology and Nuclear Medicine.

  1. Regulation of Increased Blood Flow (Hyperemia) to Muscles During Exercise: A Hierarchy of Competing Physiological Needs

    Science.gov (United States)

    Joyner, Michael J.; Casey, Darren P.

    2015-01-01

    This review focuses on how blood flow to contracting skeletal muscles is regulated during exercise in humans. The idea is that blood flow to the contracting muscles links oxygen in the atmosphere with the contracting muscles where it is consumed. In this context, we take a top down approach and review the basics of oxygen consumption at rest and during exercise in humans, how these values change with training, and the systemic hemodynamic adaptations that support them. We highlight the very high muscle blood flow responses to exercise discovered in the 1980s. We also discuss the vasodilating factors in the contracting muscles responsible for these very high flows. Finally, the competition between demand for blood flow by contracting muscles and maximum systemic cardiac output is discussed as a potential challenge to blood pressure regulation during heavy large muscle mass or whole body exercise in humans. At this time, no one dominant dilator mechanism accounts for exercise hyperemia. Additionally, complex interactions between the sympathetic nervous system and the microcirculation facilitate high levels of systemic oxygen extraction and permit just enough sympathetic control of blood flow to contracting muscles to regulate blood pressure during large muscle mass exercise in humans. PMID:25834232

  2. 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

    2013-01-01

    During skeletal muscle contractions, the concentration of ATP increases in muscle interstitial fluid as measured by microdialysis probes. This increase is associated with the magnitude of blood flow, suggesting that interstitial ATP may be important for contraction-induced vasodilation. However...... studied. The rat gluteus maximus skeletal muscle model was used to study changes in local skeletal muscle hemodynamics. Superfused ATP at concentrations found during muscle contractions (1-10 µM) increased blood flow by up to 400%. In this model, the underlying mechanism was also examined by inhibition...... in interstitial ATP concentrations increases muscle blood flow, indicating that the contraction-induced increase in skeletal muscle interstitial [ATP] is important for exercise hyperemia. The vasodilator effect of ATP application is mediated by NO and prostanoid formation....

  3. How the Brain May Have Shaped Muscle Anatomy and Physiology: A Preliminary Study.

    Science.gov (United States)

    Muchlinski, Magdalena N; Hemingway, Holden W; Pastor, Juan; Omstead, Kailey M; Burrows, Anne M

    2018-03-01

    Skeletal muscle fibers are often used to evaluate functional differences in locomotion. However, because there are energetic differences among muscle fiber cells, muscle fiber composition could be used to address evolutionary questions about energetics. Skeletal muscle is composed of two main types of fibers: Type I and II. The difference between the two can be reduced to how these muscle cells use oxygen and glucose. Type I fibers convert glucose to ATP using oxygen, while Type II fibers rely primarily on anaerobic metabolic processes. The expensive tissue hypothesis (ETH) proposes that the energetic demands imposed on the body by the brain result in a reduction in other expensive tissues (e.g., gastrointestinal tract). The original ETH dismisses the energetic demands of skeletal muscle, despite skeletal muscle being (1) an expensive tissue when active and (2) in direct competition for glucose with the brain. Based on these observations we hypothesize that larger brained primates will have relatively less muscle mass and a decrease in Type I fibers. As part of a larger study to test this hypothesis, we present data from 10 species of primates. We collected body mass, muscle mass, and biopsied four muscles from each specimen for histological procedures. We collected endocranial volumes from the literature. Using immunohistochemistry, a muscle fiber composition profile was created for each species sampled. Results show that larger brained primates have less muscle and fewer Type I fibers than primates with smaller brains. Results clarify the relationship between muscle mass and brain mass and illustrate how muscle mass could be used to address energetic questions. Anat Rec, 301:528-537, 2018. © 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

  4. Transport of thyroxine across the blood-brain barrier is directed primarily from brain to blood in the mouse

    International Nuclear Information System (INIS)

    Banks, W.A.; Kastin, A.J.; Michals, E.A.

    1985-01-01

    The role of the blood-brain barrier (BBB) in the transport of thyroxine was examined in mice. Radioiodinated (hot thyroxine (hT 4 ) administered icv had a half-time disappearance from the brain of 30 min. This increased to 60 min (p 4 ). The Km for this inhibition of hT 4 transport out of the brain by cT 4 was 9.66 pmole/brain. Unlabeled 3,3',5 triiodothyronine (cT 3 ) was unable to inhibit transport of hT 4 out of the brain, although both cT 3 (p 4 (p 3 ) to a small degree. Entry of hT 4 into the brain after peripheral administration was negligible and was not affected by either cT 4 nor cT 3 . By contrast, the entry of hT 3 into the brain after peripheral administration was inhibited by cT 3 (p 4 (p < 0.01). The levels of the unlabeled thyroid hormones administered centrally in these studies did not affect bulk flow, as assessed by labeled red blood cells (/sup 99m/Tc-RBC), or the carrier mediated transport of iodide out of the brain. Likewise, the vascular space of the brain and body, as assessed by /sup 99m/Tc-RBC, was unchanged by the levels of peripherally administered unlabeled thyroid hormones. Therefore, the results of these studies are not due to generalized effects of thyroid hormones on BBB transport. The results indicate that in the mouse the major carrier-mediated system for thyroxine in the BBB transports thyroxine out of the brain, while the major system for triiodothyronine transports hormone into the brain. 14 references, 3 figures, 2 tables

  5. Functional imaging of dolphin brain metabolism and blood flow.

    Science.gov (United States)

    Ridgway, Sam; Houser, Dorian; Finneran, James; Carder, Don; Keogh, Mandy; Van Bonn, William; Smith, Cynthia; Scadeng, Miriam; Dubowitz, David; Mattrey, Robert; Hoh, Carl

    2006-08-01

    This report documents the first use of magnetic resonance images (MRIs) of living dolphins to register functional brain scans, allowing for the exploration of potential mechanisms of unihemispheric sleep. Diazepam has been shown to induce unihemispheric slow waves (USW), therefore we used functional imaging of dolphins with and without diazepam to observe hemispheric differences in brain metabolism and blood flow. MRIs were used to register functional brain scans with single photon emission computed tomography (SPECT) and positron emission tomography (PET) in trained dolphins. Scans using SPECT revealed unihemispheric blood flow reduction following diazepam doses greater than 0.55 mg kg(-1) for these 180-200 kg animals. Scans using PET revealed hemispheric differences in brain glucose consumption when scans with and without diazepam were compared. The findings suggest that unihemispheric reduction in blood flow and glucose metabolism in the hemisphere showing USW are important features of unihemispheric sleep. Functional scans may also help to elucidate the degree of hemispheric laterality of sensory and motor systems as well as in neurotransmitter or molecular mechanisms of unihemispheric sleep in delphinoid cetaceans. The findings also demonstrate the potential value of functional scans to explore other aspects of dolphin brain physiology as well as pathology.

  6. 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...... conscious sheep....

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

    DEFF Research Database (Denmark)

    Aanerud, Joel; Borghammer, Per; Chakravarty, M Mallar

    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...

  8. 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.

  9. 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…

  10. Vascular Cell Senescence Contributes to Blood-Brain Barrier Breakdown

    NARCIS (Netherlands)

    Yamazaki, Y.; Baker, D.J.; Tachibana, M.; Liu, C.C.; Deursen, J.M.A. van; Brott, T.G.; Bu, G.; Kanekiyo, T.

    2016-01-01

    BACKGROUND AND PURPOSE: Age-related changes in the cerebrovasculature, including blood-brain barrier (BBB) disruption, are emerging as potential risks for diverse neurological conditions. Because the accumulation of senescent cells in tissues is increasingly recognized as a critical step leading to

  11. Blood-Brain Glucose Transfer in Alzheimer's disease

    DEFF Research Database (Denmark)

    Gejl, Michael; Brock, Birgitte; Egefjord, Lærke

    2017-01-01

    There are fewer than normal glucose transporters at the blood-brain barrier (BBB) in Alzheimer's disease (AD). When reduced expression of transporters aggravates the symptoms of AD, the transporters become a potential target of therapy. The incretin hormone GLP-1 prevents the decline of cerebral...

  12. Effects of Electromagnetic Fields on the Blood Brain Barrier

    National Research Council Canada - National Science Library

    Persson, Rolf

    2000-01-01

    ...) in the 91 5-2450 MHz range on the permeability of the blood brain barrier (BBB) in rats. Male and female Fischer rats were exposed to continuous wave or pulse-modulated EMF, with different pulse powers and times up to 960 minutes...

  13. Mercury in muscle and brain of catfish from the Madeira river, Amazon, Brazil.

    Science.gov (United States)

    Bastos, Wanderley R; Dórea, José G; Bernardi, José Vicente E; Lauthartte, Leidiane C; Mussy, Marilia H; Hauser, Marília; Dória, Carolina Rodrigues da C; Malm, Olaf

    2015-08-01

    The central nervous system is a critical target for Hg toxicity in all living organisms. Total Hg (THg) was determined in brain and muscle samples of 165 specimens of eight species of catfish (Brachyplatystoma filamentosum; Brachyplatystoma platynemum; Brachyplatystoma rousseauxii; Brachyplatystoma vaillantii; Phractocephalus hemiliopterus; Pseudoplatystoma punctifer; Pseudoplatystoma tigrinum; Zungaro zungaro) from the Madeira River, Brazilian Amazon. Despite the narrow range of Fishbase trophic level (4.2-4.6) the median THg concentrations ranged from 0.39 to 1.99mg/kg and from 0.03 to 0.29mg/kg respectively in muscle and brain from the studied species. Overall, the median concentration for all samples analyzed was 0.93mg/kg and 0.16mg/kg respectively in muscle and brain; most samples (76%) showed muscle Hg concentrations >0.5mg/kg. There were statistically significant THg differences between sex (female>males). The correlation between THg concentrations in muscle and brain was statistically significant (r=0.9170; p<0.0001). In the studied specimens, fish total length was significantly correlated with muscle (r=0.3163; p=0.0001) and brain (r=0.3039; p=0.0003) THg; however, fish age was negatively and significantly correlated (r=-0.2991; p=0.0012) with THg in muscle but not with THg in brain (r=-0.0190; p=0.8492). Amazonian catfish accumulate high levels of Hg in muscle and brain; however, brain-THg concentrations can be predicted from muscle-THg. Muscle-Hg in catfish can be a tool to detect brain-Hg concentrations associated with environmental Hg. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. 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.

  15. 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.

  16. Relationship between muscle oxygenation by NIRS and blood lactate

    International Nuclear Information System (INIS)

    Xu Guodong; Mao Zongzhen; Ye Yanjie; Lv Kunru

    2011-01-01

    The aim of the study was to investigate the relationship of muscle oxygenation in term of oxy-hemoglobin concentration change (ΔHbO 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 ΔHbO 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, ΔHbO 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 ΔHbO 2 and the concurrency of crucial turning points between ΔHbO 2 and BLA was revealed. This relationship between ΔHbO 2 and BLA presented in the increasing load training suggested that ΔHbO 2 might be capable for taking the place of the invasively measured parameter BLA. Considering that ΔHbO 2 can be noninvasively measured by NIRS, ΔHbO 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.

  17. A systematic review of the evidence that brain structure is related to muscle structure and their relationship to brain and muscle function in humans over the lifecourse.

    Science.gov (United States)

    Kilgour, Alixe H M; Todd, Oliver M; Starr, John M

    2014-07-10

    An association between cognition and physical function has been shown to exist but the roles of muscle and brain structure in this relationship are not fully understood. A greater understanding of these relationships may lead to identification of the underlying mechanisms in this important area of research. This systematic review examines the evidence for whether: a) brain structure is related to muscle structure; b) brain structure is related to muscle function; and c) brain function is related to muscle structure in healthy children and adults. Medline, Embase, CINAHL and PsycINFO were searched on March 6th 2014. A grey literature search was performed using Google and Google Scholar. Hand searching through citations and references of relevant articles was also undertaken. 53 articles were included in the review; mean age of the subjects ranged from 8.8 to 85.5 years old. There is evidence of a positive association between both whole brain volume and white matter (WM) volume and muscle size. Total grey matter (GM) volume was not associated with muscle size but some areas of regional GM volume were associated with muscle size (right temporal pole and bilateral ventromedial prefrontal cortex). No evidence was found of a relationship between grip strength and whole brain volume however there was some evidence of a positive association with WM volume. Conversely, there is evidence that gait speed is positively associated with whole brain volume; this relationship may be driven by total WM volume or regional GM volumes, specifically the hippocampus. Markers of brain ageing, that is brain atrophy and greater accumulation of white matter hyperintensities (WMH), were associated with grip strength and gait speed. The location of WMH is important for gait speed; periventricular hyperintensities and brainstem WMH are associated with gait speed but subcortical WMH play less of a role. Cognitive function does not appear to be associated with muscle size. There is evidence

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

    International Nuclear Information System (INIS)

    Lucchesi, K.J.

    1987-01-01

    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 3 H-inulin and 14 C-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

  19. Migration of African trypanosomes across the blood-brain barrier.

    Science.gov (United States)

    Masocha, Willias; Rottenberg, Martin E; Kristensson, Krister

    2007-09-10

    Subspecies of the extracellular parasite, Trypanosoma brucei, which are spread by the tsetse fly in sub-Saharan Africa, cause in humans Sleeping Sickness. In experimental rodent models the parasite can at a certain stage of disease pass through the blood-brain barrier across or between the endothelial cells and the vessel basement membranes. The laminin composition of the basement membranes determines whether they are permissive to parasite penetration. One cytokine, interferon-gamma, plays an important role in regulating the trypanosome trafficking into the brain. Treatment strategies aim at developing drugs that can impede penetration of trypanosomes into the brain and/or that can eliminate trypanosomes once they are inside the brain parenchyma, but have lower toxicity than the ones presently in use.

  20. Efflux transporters in blood-brain interfaces of the developing brain

    Directory of Open Access Journals (Sweden)

    Nathalie eStrazielle

    2015-02-01

    Full Text Available The cerebral microvessel endothelium forming the blood-brain barrier (BBB and the epithelium of the choroid plexuses forming the blood-CSF barrier (BCSFB operate as gatekeepers for the CNS. Exposure of the vulnerable developing brain to chemical insults can have dramatic consequences for brain maturation and lead to life-long neurological diseases. The ability of blood-brain interfaces (BBIs to efficiently protect the immature brain is therefore an important pathophysiological issue. This is also key to our understanding of drug entry into the brain of neonatal and pediatric patients. Nonspecific paracellular diffusion through BBIs is restricted early during development, but other neuroprotective properties of these interfaces differ between the developing and adult brains. This review focuses on the developmental expression and function of multispecific efflux transporters of the ABCB, ABCC, ABCG, SLC21, SLC22, and SLC15 families. These transporters play a key role in preventing brain entry of blood-borne molecules such as drugs, environmental toxicants, and endogenous metabolites, or else in increasing the clearance of potentially harmful organic ions from the brain. The limited data available for laboratory animals and human highlight transporter-specific developmental patterns of expression and function, which differ between BBIs. The BCSFB achieves an adult phenotype earlier than the BBB. Efflux transporters at the BBB appear to be regulated by various factors subsequently secreted by neural progenitors, and astrocytes during development. Their expression is also modulated by oxidative stress, inflammation, and exposure to xenobiotic inducers. A better understanding of these regulatory pathways during development, in particular the signaling pathways triggered by oxidative stress and xenobiotics, may open new opportunities to therapeutic manipulation in view to improve or restore neuroprotective functions of the BBIs in the context of

  1. Estimation of Pork Quality Traits Using Exsanguination Blood and Postmortem Muscle Metabolites

    Directory of Open Access Journals (Sweden)

    J. H. Choe

    2015-06-01

    Full Text Available The current study was designed to estimate the pork quality traits using metabolites from exsanguination blood and postmortem muscle simultaneously under the Korean standard pre- and post-slaughter conditions. A total of 111 Yorkshire (pure breed and castrated male pigs were evaluated under the Korean standard conditions. Measurements were taken of the levels of blood glucose and lactate at exsanguination, and muscle glycogen and lactate content at 45 min and 24 h postmortem. Certain pork quality traits were also evaluated. Correlation analysis and multiple regression analysis including stepwise regression were performed. Exsanguination blood glucose and lactate levels were positively correlated with each other, negatively related to postmortem muscle glycogen content and positively associated with postmortem muscle lactate content. A rapid and extended postmortem glycolysis was associated with high levels of blood glucose and lactate, with high muscle lactate content, and with low muscle glycogen content during postmortem. In addition, these were also correlated with paler meat color and reduced water holding capacity. The results of multiple regression analyses also showed that metabolites in exsanguination blood and postmortem muscle explained variations in pork quality traits. Especially, levels of blood glucose and lactate and content of muscle glycogen at early postmortem were significantly associated with an elevated early glycolytic rate. Furthermore, muscle lactate content at 24 h postmortem alone accounted for a considerable portion of the variation in pork quality traits. Based on these results, the current study confirmed that the main factor influencing pork quality traits is the ultimate lactate content in muscle via postmortem glycolysis, and that levels of blood glucose and lactate at exsanguination and contents of muscle glycogen and lactate at postmortem can explain a large portion of the variation in pork quality even under

  2. Impacts of Blood-Brain Barrier in Drug Delivery and Targeting of Brain Tumors

    Directory of Open Access Journals (Sweden)

    Yadollah Omidi

    2012-02-01

    Full Text Available Introduction: Entry of blood circulating agents into the brain is highly selectively controlled by specific transport machineries at the blood brain barrier (BBB, whose excellent barrier restrictiveness make brain drug delivery and targeting very challenging. Methods: Essential information on BBB cellular microenvironment were reviewed and discussed towards impacts of BBB on brain drug delivery and targeting. Results: Brain capillary endothelial cells (BCECs form unique biological structure and architecture in association with astrocytes and pericytes, in which microenvironment the BCECs express restrictive tight junctional complexes that block the paracellular inward/outward traverse of biomolecules/compounds. These cells selectively/specifically control the transportation process through carrier and/or receptor mediated transport machineries that can also be exploited for the delivery of pharmaceuticals into the brain. Intelligent molecular therapies should be designed using such transport machineries for the efficient delivery of designated drugs into the brain. For better clinical outcomes, these smart pharmaceuticals should be engineered as seamless nanosystems to provide simultaneous imaging and therapy (multimodal theranostics. Conclusion: The exceptional functional presence of BBB selectively controls inward and outward transportation mechanisms, thus advanced smart multifunctional nanomedicines are needed for the effective brain drug delivery and targeting. Fully understanding the biofunctions of BBB appears to be a central step for engineering of intelligent seamless therapeutics consisting of homing device for targeting, imaging moiety for detecting, and stimuli responsive device for on-demand liberation of therapeutic agent.

  3. 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...... 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 tissue......, and (2) whether blood flow is coupled to oxidative metabolism. 2. Seven individuals performed dynamic plantar flexion from 1 to 9 W. Radial artery and popliteal venous blood were sampled for O2, peritendinous blood flow was determined by 133Xe-washout, calf blood flow by plethysmography, cardiac output...

  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......, and (2) whether blood flow is coupled to oxidative metabolism. 2. Seven individuals performed dynamic plantar flexion from 1 to 9 W. Radial artery and popliteal venous blood were sampled for O2, peritendinous blood flow was determined by 133Xe-washout, calf blood flow by plethysmography, cardiac output...

  5. Charting the course across the blood-brain barrier

    Science.gov (United States)

    Nathanson, David; Mischel, Paul S.

    2010-01-01

    The blood-brain barrier (BBB) presents a significant obstacle to delivery of targeted therapies to brain tumors. In this issue of the JCI, Staquicini and colleagues apply an in vivo phage-displayed library of random peptides to identify differentially expressed peptides that can be used to transport targeted agents across the intact BBB. The authors uncover a non-canonical, peptide-mediated iron-mimicry mechanism to induce transport of the transferrin/transferrin receptor complex across the BBB. They then demonstrate the ability of phage-targeting approaches to deliver therapeutic cargo and molecular imaging reporters across the BBB in an intracranial glioblastoma mouse model. PMID:21183784

  6. Optical measurement of blood flow in exercising skeletal muscle: a pilot study

    Science.gov (United States)

    Wang, Detian; Baker, Wesley B.; Parthasarathy, Ashwin B.; Zhu, Liguo; Li, Zeren; Yodh, Arjun G.

    2017-07-01

    Blood flow monitoring during rhythm exercising is very important for sports medicine and muscle dieases. Diffuse correlation spectroscopy(DCS) is a relative new invasive way to monitor blood flow but suffering from muscle fiber motion. In this study we focus on how to remove exercise driven artifacts and obtain accurate estimates of the increase in blood flow from exercise. Using a novel fast software correlator, we measured blood flow in forearm flexor muscles of N=2 healthy adults during handgrip exercise, at a sampling rate of 20 Hz. Combining the blood flow and acceleration data, we resolved the motion artifact in the DCS signal induced by muscle fiber motion, and isolated the blood flow component of the signal from the motion artifact. The results show that muscle fiber motion strongly affects the DCS signal, and if not accounted for, will result in an overestimate of blood flow more than 1000%. Our measurements indicate rapid dilation of arterioles following exercise onset, which enabled blood flow to increase to a plateau of 200% in 10s. The blood flow also rapidly recovered to baseline following exercise in 10s. Finally, preliminary results on the dependence of blood flow from exercise intensity changes will be discussed.

  7. Blood flow distribution in dog gastrocnemius muscle at rest and during stimulation

    International Nuclear Information System (INIS)

    Piiper, J.; Pendergast, D.R.; Marconi, C.; Meyer, M.; Heisler, N.; Cerretelli, P.

    1985-01-01

    The distribution of blood flow within the isolated perfused dog gastrocnemius muscle (weight 100-240 g) was studied by intra-arterial injection of radioactively labeled microspheres (diameter 15 micron) at rest and during supramaximal stimulation to rhythmic isotonic tetanic contractions of varied frequency against varied loads. After the experiment the muscle was cut into 180-250 pieces of approximately 0.75 g each, and the blood flow to each muscle piece was determined from its radioactivity. The inhomogeneity of blood flow was represented as the frequency distribution of the ratios of regional specific blood flow, i.e., blood flow per unit tissue weight of the piece, QR, to the overall specific blood flow of the muscle, Q. The QR/Q values for the individual pieces of a muscle were found to vary widely both at rest and during stimulation. With rising work load the frequency distribution had a tendency to broaden and flatten, indicating increasing perfusion inhomogeneity. On the average of the experiments, there was no significant difference in specific blood flow between the three anatomic components of the gastrocnemius (lateral and medial heads of gastrocnemius and flexor digitorum superficialis) nor between the superficial and deep portions within these anatomic components, only the distal third of the muscle was relatively less perfused compared with the proximal two-thirds. The considerable inhomogeneity of blood flow as revealed by microsphere embolization and by other methods is expected to exert important limiting effects on local O 2 supply, particularly during exercise

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

    International Nuclear Information System (INIS)

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

    1988-01-01

    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

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    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......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...

  10. In vitro models of the blood-brain barrier

    DEFF Research Database (Denmark)

    Helms, Hans Christian Cederberg; Abbott, N Joan; Burek, Malgorzata

    2016-01-01

    The endothelial cells lining the brain capillaries separate the blood from the brain parenchyma. The endothelial monolayer of the brain capillaries serves both as a crucial interface for exchange of nutrients, gases, and metabolites between blood and brain, and as a barrier for neurotoxic compone...

  11. Neuron-Glial Interactions in Blood-Brain Barrier Formation

    OpenAIRE

    Banerjee, Swati; Bhat, Manzoor A.

    2007-01-01

    The blood brain barrier (BBB) evolved to preserve the microenvironment of the highly excitable neuronal cells to allow for action potential generation and propagation. Intricate molecular interactions between two main cell types, the neurons and the glial cells, form the underlying basis of the critical functioning of the nervous system across species. In invertebrates, interactions between neurons and glial cells are central in establishing a functional BBB. However, in vertebrates, the BBB ...

  12. Nanotechnologies: a strategy to overcome blood-brain barrier.

    Science.gov (United States)

    De Rosa, Giuseppe; Salzano, Giuseppina; Caraglia, Michele; Abbruzzese, Alberto

    2012-01-01

    The possibility to treat central nervous system (CNS) disorders is strongly limited by the poor access of many therapeutic agent to the target tissues. This is mainly due to the presence of the blood-brain barrier (BBB), formed by a complex interplay of endothelial cells, astrocyte and pericytes, through which only selected molecules can passively diffuse to reach CNS. Drug pharmacokinetics and biodistribution can be changed by using nanotechnology, in order to improve drug accumulation into the action site and to limit the drug release in the healthy tissues. When the CNS diseases are characterised by BBB altered permeability, an enhanced drug delivery into the brain can be achieved by using nanocarriers. Moreover, modification of nanocarrier surface with specific endogenous or exogenous ligands can promote enhanced BBB crossing, also in case of unaltered endothelium. This review summarizes the most meaningful advances in the field of nanotechnology for brain delivery of therapeutics.

  13. Cathepsin D deficiency induces oxidative damage in brain pericytes and impairs the blood-brain barrier.

    Science.gov (United States)

    Okada, Ryo; Wu, Zhou; Zhu, Aiqin; Ni, Junjun; Zhang, Jingqi; Yoshimine, Yoshito; Peters, Christoph; Saftig, Paul; Nakanishi, Hiroshi

    2015-01-01

    Recent evidence suggests that peripheral blood mononuclear cells (PBMCs) contribute to the pathogenesis of neuropathological changes in patients with neuronal ceroid lipofuscinosis (NCL) and lysosomal storage diseases. In order to examine the possible increase in the permeability of the blood-brain-barrier (BBB) and resultant infiltration of PBMCs due to cathepsin D (CatD) deficiency, a process underlying the onset of congenital NCL, we examined structural changes in brain vessels in CatD-/- mice. Consequently, the mean diameter of the brain vessels in the cerebral cortex on postnatal day 24 (P24) was significantly larger in CatD-/- mice than in wild-type mice. Furthermore, the mean number of brain pericytes in CatD-/- mice began to decline significantly on P16 and almost disappeared on P24, and oxidative DNA damage was first detected in brain pericytes on P12. Examinations with electron microscopy revealed that brain pericytes were laden with dense granular bodies, cytoplasmic vacuoles and lipid droplets. The infiltration of PBMCs characterized by segmented nucleus laden with dense granular bodies was also noted in the cerebral cortex of CatD-/- mice. When primary cultured microglia prepared from enhanced green fluorescent protein (GFP)-expressing transgenic rats were injected into the common carotid artery, GFP-positive microglia were detected in the brain parenchyma of CatD-/-, but not wild-type, mice. Moreover, pepstatin A, a specific aspartic protease inhibitor, induced mitochondria-derived reactive oxygen species (ROS) production in the isolated brain pericytes, which decreased the cell viability. These observations suggest that increased lysosomal storage due to CatD deficiency causes oxidative damage in brain pericytes, subsequently resulting in an increased vessel diameter, enhanced permeability of the BBB and the infiltration of PBMCs. Therefore, protecting brain pericytes against lysosomal storage-induced oxidative stress may represent an alternative

  14. Oral delivery of bioencapsulated proteins across blood-brain and blood-retinal barriers.

    Science.gov (United States)

    Kohli, Neha; Westerveld, Donevan R; Ayache, Alexandra C; Verma, Amrisha; Shil, Pollob; Prasad, Tuhina; Zhu, Ping; Chan, Sic L; Li, Qiuhong; Daniell, Henry

    2014-03-01

    Delivering neurotherapeutics to target brain-associated diseases is a major challenge. Therefore, we investigated oral delivery of green fluorescence protein (GFP) or myelin basic protein (MBP) fused with the transmucosal carrier cholera toxin B subunit (CTB), expressed in chloroplasts (bioencapsulated within plant cells) to the brain and retinae of triple transgenic Alzheimer's disease (3×TgAD) mice, across the blood-brain barriers (BBB) and blood-retinal barriers (BRB). Human neuroblastoma cells internalized GFP when incubated with CTB-GFP but not with GFP alone. Oral delivery of CTB-MBP in healthy and 3×TgAD mice shows increased MBP levels in different regions of the brain, crossing intact BBB. Thioflavin S-stained amyloid plaque intensity was reduced up to 60% by CTB-MBP incubation with human AD and 3×TgAD mice brain sections ex vivo. Amyloid loads were reduced in vivo by 70% in hippocampus and cortex brain regions of 3×TgAD mice fed with bioencapsulated CTB-MBP, along with reduction in the ratio of insoluble amyloid β 42 (Aβ42) to soluble fractions. CTB-MBP oral delivery reduced Aβ42 accumulation in retinae and prevented loss of retinal ganglion cells in 3×TgAD mice. Lyophilization of leaves increased CTB-MBP concentration by 17-fold and stabilized it during long-term storage in capsules, facilitating low-cost oral delivery of therapeutic proteins across the BBB and BRB.

  15. 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)....

  16. Quorum Sensing Peptides Selectively Penetrate the Blood-Brain Barrier.

    Science.gov (United States)

    Wynendaele, Evelien; Verbeke, Frederick; Stalmans, Sofie; Gevaert, Bert; Janssens, Yorick; Van De Wiele, Christophe; Peremans, Kathelijne; Burvenich, Christian; De Spiegeleer, Bart

    2015-01-01

    Bacteria communicate with each other by the use of signaling molecules, a process called 'quorum sensing'. One group of quorum sensing molecules includes the oligopeptides, which are mainly produced by Gram-positive bacteria. Recently, these quorum sensing peptides were found to biologically influence mammalian cells, promoting i.a. metastasis of cancer cells. Moreover, it was found that bacteria can influence different central nervous system related disorders as well, e.g. anxiety, depression and autism. Research currently focuses on the role of bacterial metabolites in this bacteria-brain interaction, with the role of the quorum sensing peptides not yet known. Here, three chemically diverse quorum sensing peptides were investigated for their brain influx (multiple time regression technique) and efflux properties in an in vivo mouse model (ICR-CD-1) to determine blood-brain transfer properties: PhrCACET1 demonstrated comparatively a very high initial influx into the mouse brain (Kin = 20.87 μl/(g×min)), while brain penetrabilities of BIP-2 and PhrANTH2 were found to be low (Kin = 2.68 μl/(g×min)) and very low (Kin = 0.18 μl/(g×min)), respectively. All three quorum sensing peptides were metabolically stable in plasma (in vitro) during the experimental time frame and no significant brain efflux was observed. Initial tissue distribution data showed remarkably high liver accumulation of BIP-2 as well. Our results thus support the potential role of some quorum sensing peptides in different neurological disorders, thereby enlarging our knowledge about the microbiome-brain axis.

  17. Targeted liposomes for drug delivery across the blood-brain barrier

    NARCIS (Netherlands)

    van Rooy, I.

    2011-01-01

    Our brain is protected by the blood-brain barrier (BBB). This barrier is formed by specialized endothelial cells of the brain vasculature and prevents toxic substances from entering the brain. The downside of this barrier is that many drugs that have been developed to cure brain diseases cannot

  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. Interventions for managing skeletal muscle spasticity following traumatic brain injury.

    Science.gov (United States)

    Synnot, Anneliese; Chau, Marisa; Pitt, Veronica; O'Connor, Denise; Gruen, Russell L; Wasiak, Jason; Clavisi, Ornella; Pattuwage, Loyal; Phillips, Kate

    2017-11-22

    Skeletal muscle spasticity is a major physical complication resulting from traumatic brain injury (TBI), which can lead to muscle contracture, joint stiffness, reduced range of movement, broken skin and pain. Treatments for spasticity include a range of pharmacological and non-pharmacological interventions, often used in combination. Management of spasticity following TBI varies from other clinical populations because of the added complexity of behavioural and cognitive issues associated with TBI. To assess the effects of interventions for managing skeletal muscle spasticity in people with TBI. In June 2017, we searched key databases including the Cochrane Injuries Group Specialised Register, CENTRAL, MEDLINE (Ovid), Embase (Ovid) and others, in addition to clinical trials registries and the reference lists of included studies. We included randomised controlled trials (RCTs) and cross-over RCTs evaluating any intervention for the management of spasticity in TBI. Only studies where at least 50% of participants had a TBI (or for whom separate data for participants with TBI were available) were included. The primary outcomes were spasticity and adverse effects. Secondary outcome measures were classified according to the World Health Organization International Classification of Functioning, Disability and Health including body functions (sensory, pain, neuromusculoskeletal and movement-related functions) and activities and participation (general tasks and demands; mobility; self-care; domestic life; major life areas; community, social and civic life). We used standard methodological procedures expected by Cochrane. Data were synthesised narratively; meta-analysis was precluded due to the paucity and heterogeneity of data. We included nine studies in this review which involved 134 participants with TBI. Only five studies reported between-group differences, yielding outcome data for 105 participants with TBI. These five studies assessed the effects of a range of

  20. 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......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......, respectively (P important synergistic role of NO and PG for skeletal muscle vasodilatation and hyperaemia during muscular contraction....

  1. 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.

  2. Motor evoked potentials of trunk muscles in traumatic brain injury patients.

    Science.gov (United States)

    Seo, Min-Ho; Park, Sung-Hee; Ko, Myoung-Hwan; Seo, Jeong-Hwan

    2011-08-01

    To evaluate the motor innervation of trunk muscles in traumatic brain injury patients. Twenty patients (12 men and 8 women) with traumatic brain injury were enrolled in this study. Their mean age was 41 years. Motor evoked potentials (MEPs) were performed on the motor cortex. Electromyographic activities were recorded from the bilateral rectus abdominis muscles, the external oblique abdominal muscles, and the 4th and 9th thoracic erector spinae muscles. The onset latency and amplitude of contralateral and ipsilateral MEPs were measured. All patients were assessed by the Korean version of the Berg Balance Scale (K-BBS) to investigate the relationship between the frequency of MEPs in trunk muscles and gait ability. The mean frequency of ipsilateral MEPs was 23.8% with more damaged hemisphere stimulation, while the contralateral MEPs showed a mean frequency of 47.5% with more damaged hemisphere stimulation in traumatic brain injury patients. The latencies and amplitudes of MEPs obtained from the more damaged hemisphere were not significantly different from those of the less damaged hemisphere. There was no correlation between the manifestation of MEPs in trunk muscles and gait ability. The ipsilateral and contralateral corticospinal pathways to trunk muscles are less likely to be activated in traumatic brain injury patients because of direct injury of the descending corticospinal motor tract or decreased excitability of the corticospinal tract from prefrontal contusion.

  3. Characterization of smooth muscle-like cells in circulating human peripheral blood.

    Science.gov (United States)

    Sugiyama, Seigo; Kugiyama, Kiyotaka; Nakamura, Shinichi; Kataoka, Keiichiro; Aikawa, Masanori; Shimizu, Koichi; Koide, Shunichi; Mitchell, Richard N; Ogawa, Hisao; Libby, Peter

    2006-08-01

    Smooth muscle cells play an important role in human vascular diseases. Several lines of evidence demonstrate that circulating smooth muscle precursor cells contribute to intimal hyperplasia in animal models. We obtained large spindle cells expressing alpha-smooth muscle actin (alpha-SMA), denoted here as "smooth muscle-like cells" (SMLC), from human peripheral blood mononuclear cells (PBMC). SMLC derived from human PBMC proliferated readily and expressed pro-inflammatory genes during early culture. After long-term culture, SMLC could contract and express characteristic smooth muscle cell markers. We found peripheral blood mononuclear cell expressing alpha-smooth muscle actin in the circulating blood that bore CD14 and CD105. Sorted CD14/CD105 double-positive PBMC could differentiate into SMLC. The number of CD14-CD105-bearing PBMC increased significantly in patients with coronary artery disease compared to patients without coronary artery disease. These results support the novel concept that smooth muscle precursor cells exist in circulating human blood and may contribute to the pathogenesis of vascular diseases.

  4. 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. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. 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

    The breakdown of DNA and RNA in decomposing human tissue represents a major obstacle for postmortem forensic molecular analysis. This study investigated the feasibility of performing PCR-based molecular analysis of blood and muscle tissue from 45 autopsy cases with defined postmortem intervals...... ranging from one to more than 14 days. It was not possible to collect blood from 38 % of the autopsy cases due to severe coagulation and hemolysis, whereas muscle tissue was available for all cases. PCR-amplifiable DNA could be extracted from 96 % of the frozen muscle specimens and from 93...... % of the 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...

  6. 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.

  7. 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.

  8. 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.

  9. Sleep restriction impairs blood-brain barrier function.

    Science.gov (United States)

    He, Junyun; Hsuchou, Hung; He, Yi; Kastin, Abba J; Wang, Yuping; Pan, Weihong

    2014-10-29

    The blood-brain barrier (BBB) is a large regulatory and exchange interface between the brain and peripheral circulation. We propose that changes of the BBB contribute to many pathophysiological processes in the brain of subjects with chronic sleep restriction (CSR). To achieve CSR that mimics a common pattern of human sleep loss, we quantified a new procedure of sleep disruption in mice by a week of consecutive sleep recording. We then tested the hypothesis that CSR compromises microvascular function. CSR not only diminished endothelial and inducible nitric oxide synthase, endothelin1, and glucose transporter expression in cerebral microvessels of the BBB, but it also decreased 2-deoxy-glucose uptake by the brain. The expression of several tight junction proteins also was decreased, whereas the level of cyclooxygenase-2 increased. This coincided with an increase of paracellular permeability of the BBB to the small tracers sodium fluorescein and biotin. CSR for 6 d was sufficient to impair BBB structure and function, although the increase of paracellular permeability returned to baseline after 24 h of recovery sleep. This merits attention not only in neuroscience research but also in public health policy and clinical practice. Copyright © 2014 the authors 0270-6474/14/3414697-10$15.00/0.

  10. Sorting Tubules Regulate Blood-Brain Barrier Transcytosis

    Directory of Open Access Journals (Sweden)

    Roberto Villaseñor

    2017-12-01

    Full Text Available Transcytosis across the blood-brain barrier (BBB regulates key processes of the brain, but the intracellular sorting mechanisms that determine successful receptor-mediated transcytosis in brain endothelial cells (BECs remain unidentified. Here, we used Transferrin receptor-based Brain Shuttle constructs to investigate intracellular transport in BECs, and we uncovered a pathway for the regulation of receptor-mediated transcytosis. By combining live-cell imaging and mathematical modeling in vitro with super-resolution microscopy of the BBB, we show that intracellular tubules promote transcytosis across the BBB. A monovalent construct (sFab sorted for transcytosis was localized to intracellular tubules, whereas a bivalent construct (dFab sorted for degradation formed clusters with impaired transport along tubules. Manipulating tubule biogenesis by overexpressing the small GTPase Rab17 increased dFab transport into tubules and induced its transcytosis in BECs. We propose that sorting tubules regulate transcytosis in BECs and may be a general mechanism for receptor-mediated transport across the BBB.

  11. Gut–Brain Axis in Regulation of Blood Pressure

    Directory of Open Access Journals (Sweden)

    Tao Yang

    2017-10-01

    Full Text Available Hypertension (HTN is an escalating health issue worldwide. It is estimated that 1.56 billion people will suffer from high blood pressure (BP by 2025. Recent studies reported an association between gut dysbiosis and HTN, thus proposing interesting avenues for novel treatments of this condition. The sympathetic nervous system (SNS and the immune system (IS play a recognized role in the onset and progression of HTN, while reciprocal communication between gut microbiota and the brain can regulate BP by modulating the interplay between the IS and SNS. This review presents the current state of the science implicating brain-gut connection in HTN, highlighting potential pathways of their interaction in control of BP.

  12. Physical insights into the blood-brain barrier translocation mechanisms

    Science.gov (United States)

    Theodorakis, Panagiotis E.; Müller, Erich A.; Craster, Richard V.; Matar, Omar K.

    2017-08-01

    The number of individuals suffering from diseases of the central nervous system (CNS) is growing with an aging population. While candidate drugs for many of these diseases are available, most of these pharmaceutical agents cannot reach the brain rendering most of the drug therapies that target the CNS inefficient. The reason is the blood-brain barrier (BBB), a complex and dynamic interface that controls the influx and efflux of substances through a number of different translocation mechanisms. Here, we present these mechanisms providing, also, the necessary background related to the morphology and various characteristics of the BBB. Moreover, we discuss various numerical and simulation approaches used to study the BBB, and possible future directions based on multi-scale methods. We anticipate that this review will motivate multi-disciplinary research on the BBB aiming at the design of effective drug therapies.

  13. Gut–Brain Axis in Regulation of Blood Pressure

    Science.gov (United States)

    Yang, Tao; Zubcevic, Jasenka

    2017-01-01

    Hypertension (HTN) is an escalating health issue worldwide. It is estimated that 1.56 billion people will suffer from high blood pressure (BP) by 2025. Recent studies reported an association between gut dysbiosis and HTN, thus proposing interesting avenues for novel treatments of this condition. The sympathetic nervous system (SNS) and the immune system (IS) play a recognized role in the onset and progression of HTN, while reciprocal communication between gut microbiota and the brain can regulate BP by modulating the interplay between the IS and SNS. This review presents the current state of the science implicating brain-gut connection in HTN, highlighting potential pathways of their interaction in control of BP. PMID:29118721

  14. Blood flow response to electrically induced twitch and tetanic lower-limb muscle contractions.

    NARCIS (Netherlands)

    Janssen, T.W.; Hopman, M.T.E.

    2003-01-01

    OBJECTIVES: To compare the effect of electric stimulation (ES)-induced twitch with tetanic leg muscle contractions on blood flow responses and to assess blood flow responses in the contralateral inactive leg. DESIGN: Intervention with within-subject comparisons. SETTING: University research

  15. Middle cerebral artery blood velocity depends on cardiac output during exercise with a large muscle mass

    NARCIS (Netherlands)

    Ide, K.; Pott, F.; van Lieshout, J. J.; Secher, N. H.

    1998-01-01

    We tested the hypothesis that pharmacological reduction of the increase in cardiac output during dynamic exercise with a large muscle mass would influence the cerebral blood velocity/perfusion. We studied the relationship between changes in cerebral blood velocity (transcranial Doppler), rectus

  16. Blood flow response to electrically induced twitch and tetanic lower-limb muscle contractions

    NARCIS (Netherlands)

    Janssen, T.W.J.; Hopman, M.T.E.

    2003-01-01

    Objectives: To compare the effect of electric stimulation (ES)-induced twitch with tetanic leg muscle contractions on blood flow responses and to assess blood flow responses in the contralateral inactive leg. Design: Intervention with within-subject comparisons. Setting: University research

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

    DEFF Research Database (Denmark)

    Nyberg, Michael Permin

    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...

  18. 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.

  19. Whole-Body Vibration and Blood Flow and Muscle Oxygenation: A Meta-Analysis

    Science.gov (United States)

    Games, Kenneth E.; Sefton, JoEllen M.; Wilson, Alan E.

    2015-01-01

    Context: The use and popularity of whole-body vibration (WBV) has increased in recent years, but there is a lack of consensus in the literature about the effectiveness of the treatment. Objective: To quantitatively examine the effects of WBV on muscle oxygenation and peripheral blood flow in healthy adults. Data Sources: We searched Web of Science and PubMed databases and reference lists from relevant articles using the key terms whole body vibration, whole-body vibration, WBV, blood flow, peripheral blood flow, oxygenation, muscle oxygenation, circulation, circulatory, near infrared spectroscopy, NIRS, and power Doppler. Key terms were searched using single word and combination searches. No date range was specified. Study Selection: Criteria for inclusion were (1) use of a commercially available WBV device, (2) a human research model, (3) a pre-WBV condition and at least 1 WBV experimental condition, and (4) reporting of unstandardized means and standard deviations of muscle oxygenation or peripheral blood flow. Data Extraction: Means, standard deviations, and sample sizes were extracted from the text, tables, and figures of included studies. A total of 35 and 90 data points were extracted for the muscle-oxygenation and blood-flow meta-analyses, respectively. Data for each meta-analysis were combined and analyzed using meta-analysis software. Weighted, random-effects meta-analyses using the Hedges g metric were completed for muscle oxygenation and blood flow. We then conducted follow-up analyses using the moderator variables of vibration type, vibration time, vibration frequency, measurement location, and sample type. Data Synthesis: We found 18 potential articles. Further examination yielded 10 studies meeting the inclusion criteria. Whole-body vibration was shown to positively influence peripheral blood flow. Additionally, the moderators of vibration type and frequency altered the influence of WBV on blood flow. Overall, WBV did not alter muscle oxygenation

  20. Whole-body vibration and blood flow and muscle oxygenation: a meta-analysis.

    Science.gov (United States)

    Games, Kenneth E; Sefton, JoEllen M; Wilson, Alan E

    2015-05-01

    The use and popularity of whole-body vibration (WBV) has increased in recent years, but there is a lack of consensus in the literature about the effectiveness of the treatment. To quantitatively examine the effects of WBV on muscle oxygenation and peripheral blood flow in healthy adults. We searched Web of Science and PubMed databases and reference lists from relevant articles using the key terms whole body vibration, whole-body vibration, WBV, blood flow, peripheral blood flow, oxygenation, muscle oxygenation, circulation, circulatory, near infrared spectroscopy, NIRS, and power Doppler. Key terms were searched using single word and combination searches. No date range was specified. Criteria for inclusion were (1) use of a commercially available WBV device, (2) a human research model, (3) a pre-WBV condition and at least 1 WBV experimental condition, and (4) reporting of unstandardized means and standard deviations of muscle oxygenation or peripheral blood flow. Means, standard deviations, and sample sizes were extracted from the text, tables, and figures of included studies. A total of 35 and 90 data points were extracted for the muscle-oxygenation and blood-flow meta-analyses, respectively. Data for each meta-analysis were combined and analyzed using meta-analysis software. Weighted, random-effects meta-analyses using the Hedges g metric were completed for muscle oxygenation and blood flow. We then conducted follow-up analyses using the moderator variables of vibration type, vibration time, vibration frequency, measurement location, and sample type. We found 18 potential articles. Further examination yielded 10 studies meeting the inclusion criteria. Whole-body vibration was shown to positively influence peripheral blood flow. Additionally, the moderators of vibration type and frequency altered the influence of WBV on blood flow. Overall, WBV did not alter muscle oxygenation; however, when the measurement site was considered, muscle oxygenation increased or

  1. Delivery of antihuman African trypanosomiasis drugs across the blood-brain and blood-CSF barriers.

    Science.gov (United States)

    Sekhar, Gayathri N; Watson, Christopher P; Fidanboylu, Mehmet; Sanderson, Lisa; Thomas, Sarah A

    2014-01-01

    Human African trypanosomiasis (HAT or sleeping sickness) is a potentially fatal disease caused by the parasite, Trypanosoma brucei sp. The parasites are transmitted by the bite of insect vectors belonging to the genus Glossina (tsetse flies) and display a life cycle strategy that is equally spread between human and insect hosts. T.b. gambiense is found in western and central Africa whereas, T.b. rhodesiense is found in eastern and southern Africa. The disease has two clinical stages: a blood stage after the bite of an infected tsetse fly, followed by a central nervous system (CNS) stage where the parasite penetrates the brain; causing death if left untreated. The blood-brain barrier (BBB) makes the CNS stage difficult to treat because it prevents 98% of all known compounds from entering the brain, including some anti-HAT drugs. Those that do enter the brain are toxic compounds in their own right and have serious side effects. There are only a few drugs available to treat HAT and those that do are stage specific. This review summarizes the incidence, diagnosis, and treatment of HAT and provides a close examination of the BBB transport of anti-HAT drugs and an overview of the latest drugs in development. © 2014 Elsevier Inc. All rights reserved.

  2. Novel models for studying the blood-brain and blood-eye barriers in Drosophila.

    Science.gov (United States)

    Pinsonneault, Robert L; Mayer, Nasima; Mayer, Fahima; Tegegn, Nebiyu; Bainton, Roland J

    2011-01-01

    In species as varied as humans and flies, humoral/central nervous system barrier structures are a major obstacle to the passive penetration of small molecules including endogenous compounds, environmental toxins, and drugs. In vivo measurement of blood-brain physiologic function in vertebrate animal models is difficult and current ex vivo models for more rapid experimentation using, for example, cultured brain endothelial cells, only partially reconstitute the anatomy and physiology of a fully intact blood-brain barrier (BBB). To address these problems, we and others continue to develop in vivo assays for studying the complex physiologic function of central nervous system (CNS) barriers using the fruit fly Drosophila melanogaster (Dm). These methods involve the introduction of small molecule reporters of BBB physiology into the fly humoral compartment by direct injection. Since these reporters must cross the Dm BBB in order to be visible in the eye, we can directly assess genetic or chemical modulators of BBB function by monitoring retinal fluorescence. This assay has the advantage of utilizing a physiologically intact BBB in a model organism that is economical and highly amenable to genetic manipulation. In combination with other approaches outlined here, such as brain dissection and behavioral assessment, one can produce a fuller picture of BBB biology and physiology. In this chapter, we provide detailed methods for examining BBB biology in the fly, including a Dm visual assay to screen for novel modulators of the BBB.

  3. Blood-ocular and blood-brain barrier function in streptozocin-induced diabetes in rats

    International Nuclear Information System (INIS)

    Maeepea, O.; Karlsson, C.; Alm, A.

    1984-01-01

    Edetic acid labeled with chromium 51 was injected intravenously in normal rats and in rats with streptozocin-induced diabetes. One hour after the injection the animals were killed and the concentrations of edetic acid 51Cr in vitreous body, retina, and brain were determined. No significant difference was observed between the two groups for either tissue. In a second series, a mixture of tritiated 1-glucose and aminohippuric acid tagged with carbon 14 was injected instead of edetic acid. A substantial accumulation of aminohippuric acid 14C compared with tritiated 1-glucose was observed in the vitreous body and the brain of diabetic rats in comparison with the control group. It is concluded that untreated streptozocin-induced diabetes in rats for one to two weeks will not cause a generalized increase in the permeability of the blood-ocular or the blood-brain barriers, but organic acids may accumulate in the vitreous body as well as in the brain as a consequence of reduced outward transport through these barriers

  4. The motor cortical representation of a muscle is not homogeneous in brain connectivity.

    Science.gov (United States)

    Smith, Jo Armour; Albishi, Alaa; Babikian, Sarine; Asavasopon, Skulpan; Fisher, Beth E; Kutch, Jason J

    2017-09-01

    Functional connectivity patterns of the motor cortical representational area of single muscles have not been extensively mapped in humans, particularly for the axial musculature. Functional connectivity may provide a neural substrate for adaptation of muscle activity in axial muscles that have both voluntary and postural functions. The purpose of this study was to combine brain stimulation and neuroimaging to both map the cortical representation of the external oblique (EO) in primary motor cortex (M1) and supplementary motor area (SMA), and to establish the resting-state functional connectivity associated with this representation. Motor-evoked potentials were elicited from the EO muscle in stimulation locations encompassing M1 and SMA. The coordinates of locations with the largest motor-evoked potentials were confirmed with task-based fMRI imaging during EO activation. The M1 and SMA components of the EO representation demonstrated significantly different resting-state functional connectivity with other brain regions: the SMA representation of the EO muscle was significantly more connected to the putamen and cerebellum, and the M1 representation of the EO muscle was significantly more connected to somatosensory cortex and the superior parietal lobule. This study confirms the representation of a human axial muscle in M1 and SMA, and demonstrates for the first time that different parts of the cortical representation of a human axial muscle have resting-state functional connectivity with distinct brain regions. Future studies can use the brain regions of interest we have identified here to test the association between resting-state functional connectivity and control of the axial muscles.

  5. 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...

  6. Blood-brain barrier-supported neurogenesis in healthy and diseased brain.

    Science.gov (United States)

    Pozhilenkova, Elena A; Lopatina, Olga L; Komleva, Yulia K; Salmin, Vladimir V; Salmina, Alla B

    2017-05-24

    Adult neurogenesis is one of the most important mechanisms contributing to brain development, learning, and memory. Alterations in neurogenesis underlie a wide spectrum of brain diseases. Neurogenesis takes place in highly specialized neurogenic niches. The concept of neurogenic niches is becoming widely accepted due to growing evidence of the important role of the microenvironment established in the close vicinity to stem cells in order to provide adequate control of cell proliferation, differentiation, and apoptosis. Neurogenic niches represent the platform for tight integration of neurogenesis and angiogenesis supported by specific properties of cerebral microvessel endothelial cells contributing to establishment of partially compromised blood-brain barrier (BBB) for the adjustment of local conditions to the current metabolic needs of stem and progenitor cells. Here, we review up-to-date data on microvascular dynamics in activity-dependent neurogenesis, specific properties of BBB in neurogenic niches, endothelial-driven mechanisms of clonogenic activity, and future perspectives for reconstructing the neurogenic niches in vitro.

  7. 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.

  8. Multidimensional control using a mobile-phone based brain-muscle-computer interface.

    Science.gov (United States)

    Vernon, Scott; Joshi, Sanjay S

    2011-01-01

    Many well-known brain-computer interfaces measure signals at the brain, and then rely on the brain's ability to learn via operant conditioning in order to control objects in the environment. In our lab, we have been developing brain-muscle-computer interfaces, which measure signals at a single muscle and then rely on the brain's ability to learn neuromuscular skills via operant conditioning. Here, we report a new mobile-phone based brain-muscle-computer interface prototype for severely paralyzed persons, based on previous results from our group showing that humans may actively create specified power levels in two separate frequency bands of a single sEMG signal. Electromyographic activity on the surface of a single face muscle (Auricularis superior) is recorded with a standard electrode. This analog electrical signal is imported into an Android-based mobile phone. User-modulated power in two separate frequency band serves as two separate and simultaneous control channels for machine control. After signal processing, the Android phone sends commands to external devices via Bluetooth. Users are trained to use the device via biofeedback, with simple cursor-to-target activities on the phone screen.

  9. Locating abnormalities in brain blood vessels using parallel computing architecture.

    Science.gov (United States)

    Adeshina, A M; Hashim, R; Khalid, N E A; Abidin, S Z Z

    2012-09-01

    CT and MRI scans are widely used in medical diagnosis procedures, but they only produce 2-D images. However, the human anatomical structure, the abnormalities, tumors, tissues and organs are in 3-D. 2-D images from these devices are difficult to interpret because they only show cross-sectional views of the human structure. Consequently, such circumstances require doctors to use their expert experiences in the interpretation of the possible location, size or shape of the abnormalities, even for large datasets of enormous amount of slices. Previously, the concept of reconstructing 2-D images to 3-D was introduced. However, such reconstruction model requires high performance computation, may either be time-consuming or costly. Furthermore, detecting the internal features of human anatomical structure, such as the imaging of the blood vessels, is still an open topic in the computer-aided diagnosis of disorders and pathologies. This paper proposes a volume visualization framework using Compute Unified Device Architecture (CUDA), augmenting the widely proven ray casting technique in terms of superior qualities of images but with slow speed. Considering the rapid development of technology in the medical community, our framework is implemented on Microsoft.NET environment for easy interoperability with other emerging revolutionary tools. The framework was evaluated with brain datasets from the department of Surgery, University of North Carolina, United States, containing around 109 MRA datasets. Uniquely, at a reasonably cheaper cost, our framework achieves immediate reconstruction and obvious mappings of the internal features of human brain, reliable enough for instantaneous locations of possible blockages in the brain blood vessels.

  10. Blood-Brain Barrier P-Glycoprotein Function in Neurodegenerative Disease

    NARCIS (Netherlands)

    Bartels, A. L.

    Protection of the brain is strengthened by active transport and ABC transporters. P-glycoprotein (P-gp) at the blood-brain barrier (BBB) functions as an active efflux pump by extruding a substrate from the brain, which is important for maintaining loco-regional homeostasis in the brain and

  11. 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.

  12. Partial neuromuscular blockade in humans enhances muscle blood flow during exercise independently of muscle oxygen uptake and acetylcholine receptor blockade

    DEFF Research Database (Denmark)

    Hellsten, Ylva; Krustrup, Peter; Iaia, F Marcello

    2009-01-01

    This study examined the role of acetylcholine for skeletal muscle blood flow during exercise by use of the competitive neuromuscular blocking agent cisatracurium in combination with the acetylcholine receptor blocker glycopyrrone. Nine healthy male subjects performed a 10-min bout of one...... conductance during exercise, events that are not associated with either acetylcholine or an increased oxygen demand. The results do not support an essential role for acetylcholine, released form the neuromuscular junction, in exercise hyperaemia or for the enhanced blood flow during neuromuscular blockade...

  13. Global cerebral blood flow changes measured by brain perfusion SPECT immediately after whole brain irradiation

    International Nuclear Information System (INIS)

    Ohtawa, Nobuyuki; Machida, Kikuo; Honda, Norinari; Hosono, Makoto; Takahashi, Takeo

    2003-01-01

    Whole brain irradiation (WBI) is still a major treatment option for patients with metastatic brain tumor despite recent advances in chemotherapy and newer techniques of radiation therapy. Cerebral blood flow (CBF) of changes induced by whole brain radiation is not fully investigated, and the aim of the study was to measure CBF changes non-invasively with brain perfusion SPECT to correlate with treatment effect or prognosis. Total of 106 patients underwent WBI during April 1998 to March 2002. Both brain MRI and brain perfusion SPECT could be performed before (less than 1 week before or less than 10 Gy of WBI) and immediately after (between 1 week before and 2 weeks after the completion of WBI) the therapy in 17 of these patients. They, 10 men and 7 women, all had metastatic brain tumor with age range of 45 to 87 (mean of 61.4) years. Tc-99m brain perfusion agent (HMPAO in 4, ECD in 13) was rapidly administered in a 740-MBq dose to measure global and regional CBF according to Matsuda's method, which based on both Patlak plot and Lassens' linearity correction. Brain MRI was used to measure therapeutic response according to World Health Organization (WHO) classification as complete remission (CR), partial response (PR), no change (NC), and progressive disease (PD). Survival period was measured from the completion of WBI. Mean global CBF was 40.6 and 41.5 ml/100 g/min before and immediately after the WBI, respectively. Four patients increased (greater than 10%) their global mean CBF, 10 unchanged (less than 10% increase or decrease), and 3 decreased after the WBI. The WBI achieved CR in none, PR in 8, NC in 6, and PD in 3 on brain MRI. Change in global mean CBF (mean±SD) was significantly larger in PR (4.3±2.0 ml/100 g/min, p=0.002) and in NC (-0.1±4.5) than in PD (-3.9±6.4, P=0.002, P=0.016, respectively). Survival was not significantly (p>0.05) different among the patients with CR (20 weeks), NC (48 weeks), and PD (21 weeks). Change in global CBF and survival was

  14. 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

    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...... 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...... and quadriceps muscle blood flow (IMBF and QMBF, respectively) were measured by near-infrared spectroscopy over the left 7th intercostal space and the left vastus lateralis muscle, respectively, using indocyanine green dye. The mean pressure time product of the diaphragm and the work of breathing did not differ...

  15. Brain edema and blood-brain barrier permeability following quantitative cerebral microembolism

    International Nuclear Information System (INIS)

    Bralet, A.M.; Bdley, A.; Beley, P.; Bralet, J.

    1979-01-01

    Cerebral microemboli were formed in rats by injecting 4000 carbonized microspheres, 50 +- 10 mu in diameter, labelled with 85 Sr, into the internal carotid artery. The use of radioactive microspheres as embolic agents enabled the number of microspheres to be determined in each cerebral hemisphere. The microspheres were mainly distributed in the cerebral hemisphere on the side of the injection. In 61 rats this hemisphere contained 582 +- 20 microspheres against 99 +- 9 in the contralateral hemisphere. Brain edema was assessed by measuring brain content of water, sodium and potassium. Blood-brain barrier (BBB) permeability was determined by brain accumulation of 125 I-albumin. In the ipsilateral hemisphere brain edema and an increase in BBB permeability appeared 6 hours after embolization and progressed up to 48 hours. Twenty-four hours after embolization, significant correlations were observed between the microsphere content of the cerebral hemispheres and (1) increases in water and sodium levels, (2) the decrease in potassium level, (3) the increase in BBB permeability. The study of these correlations should make it possible to ignore the poor reproducibility of embolizations and to analyze with increased accuracy the results of various experiments

  16. 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

    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...... positive correlation between frontal cortex and hippocampal BDNF levels in mice (r2=0.81, p=0.0139). Our data support the view that measures of blood and plasma BDNF levels reflect brain-tissue BDNF levels....

  17. Impact of drug permeability of blood-brain barrier after whole brain conventional fractionation irradiation

    International Nuclear Information System (INIS)

    Zhang Longzhen; Cao Yuandong; Chen Yong; Yu Changzhou; Zhuang Ming

    2006-01-01

    Objective: To explore the effect of drug permeability in rat blood-brain barrier(BBB) after different doses of whole brain conventional fractionation irradiation in rats and provide the experimental basis for the optimum time of clinical chemotherapy. Methods: According to different irradiation doses, 100 adult Sprague-Dowley rats were divided randomly into 5 groups: the normal control group(0 Gy); 10 Gy; 20 Gy; 30 Gy; and 40 Gy group. All rats were exposed to conventional fractionation(2 Gy/d, 5 d/w) with 60 Co γ-ray. MTX(25 mg/kg) was injected through the tail mainline 16 hours after whole brain irradiation. Cerebrospinal fluid(CSF) and blood were collected 2 hours later. Those samples were used to assay MTX concentration using RP-HPLC. Results: MTX mean concentrations in CSF was 0.07, 0.08, 0.12, 0.24, 0.23 mg/L in the control, 10 Gy, 20 Gy, 30 Gy, 40 Gy groups, respectively. All the data was analyzed with rank test of transform. MTX concentration of CSF was significantly different except the control and 10 Gy, 30 Gy and 40 Gy group. MTX concentration of blood was not significantly different in all groups (P>0.05). Conclusions: Irradiation can directly damage the function of BBB. BBB would be opened gradually following the increase of irradiation dose. It could be considered as the optimum time of chemotherapy when the whole brain irradiation ranges from 20 Gy to 30 Gy. (authors)

  18. Upper Limb Muscle and Brain Activity in Light Assembly Task on Different Load Levels

    Science.gov (United States)

    Zadry, Hilma Raimona; Dawal, Siti Zawiah Md.; Taha, Zahari

    2010-10-01

    A study was conducted to investigate the effect of load on upper limb muscles and brain activities in light assembly task. The task was conducted at two levels of load (Low and high). Surface electromyography (EMG) was used to measure upper limb muscle activities of twenty subjects. Electroencephalography (EEG) was simultaneously recorded with EMG to record brain activities from Fz, Pz, O1 and O2 channels. The EMG Mean Power Frequency (MPF) of the right brachioradialis and the left upper trapezius activities were higher on the high-load task compared to low-load task. The EMG MPF values also decrease as time increases, that reflects muscle fatigue. Mean power of the EEG alpha bands for the Fz-Pz channels were found to be higher on the high-load task compared to low-load task, while for the O1-O2 channels, they were higher on the low-load task than on the high-load task. These results indicated that the load levels effect the upper limb muscle and brain activities. The high-load task will increase muscle activities on the right brachioradialis and the left upper tapezius muscles, and will increase the awareness and motivation of the subjects. Whilst the low-load task can generate drowsiness earlier. It signified that the longer the time and the more heavy of the task, the subjects will be more fatigue physically and mentally.

  19. Overtraining is associated with DNA damage in blood and skeletal muscle cells of Swiss mice.

    Science.gov (United States)

    Pereira, Bruno Cesar; Pauli, José Rodrigo; Antunes, Lusânia Maria Greggi; de Freitas, Ellen Cristini; de Almeida, Mara Ribeiro; de Paula Venâncio, Vinícius; Ropelle, Eduardo Rochete; de Souza, Claudio Teodoro; Cintra, Dennys Esper; Papoti, Marcelo; da Silva, Adelino Sanchez Ramos

    2013-10-08

    The alkaline version of the single-cell gel (comet) assay is a useful method for quantifying DNA damage. Although some studies on chronic and acute effects of exercise on DNA damage measured by the comet assay have been performed, it is unknown if an aerobic training protocol with intensity, volume, and load clearly defined will improve performance without leading to peripheral blood cell DNA damage. In addition, the effects of overtraining on DNA damage are unknown. Therefore, this study aimed to examine the effects of aerobic training and overtraining on DNA damage in peripheral blood and skeletal muscle cells in Swiss mice. To examine possible changes in these parameters with oxidative stress, we measured reduced glutathione (GSH) levels in total blood, and GSH levels and lipid peroxidation in muscle samples. Performance evaluations (i.e., incremental load and exhaustive tests) showed significant intra and inter-group differences. The overtrained (OTR) group showed a significant increase in the percentage of DNA in the tail compared with the control (C) and trained (TR) groups. GSH levels were significantly lower in the OTR group than in the C and TR groups. The OTR group had significantly higher lipid peroxidation levels compared with the C and TR groups. Aerobic and anaerobic performance parameters can be improved in training at maximal lactate steady state during 8 weeks without leading to DNA damage in peripheral blood and skeletal muscle cells or to oxidative stress in skeletal muscle cells. However, overtraining induced by downhill running training sessions is associated with DNA damage in peripheral blood and skeletal muscle cells, and with oxidative stress in skeletal muscle cells and total blood.

  20. Cerebral blood flow, blood volume, and brain tissue hematocrit during isovolemic hemodilution with hetastarch in rats.

    Science.gov (United States)

    Todd, M M; Weeks, J B; Warner, D S

    1992-07-01

    The influence of isovolemic hemodilution with 6% hetastarch [hematocrits (Hct) ranging from 43 to 20%] on cerebral blood flow (CBF), cerebral red blood cell and plasma volumes, total cerebral blood volume (CBV), and cerebral Hct was examined in normothermic, normocarbic, halothane-anesthetized Sprague-Dawley rats. CBF was measured via the indicator-fractionation method ([3H]nicotine), red blood cell volume was measured using 99mTc-labeled red blood cells, while plasma volume was measured using [14C]dextran. Brain tissue was fixed in situ by microwave irradiation. All data plots (e.g., CBF vs. Hct) were fitted by linear regression methods. Hemodilution was associated with a progressive increase in forebrain CBF (from a fitted value of 78 ml.100 g-1.min-1 at Hct = 43%, to 171 ml.100 g-1.min-1 at 20%). Cerebral plasma volume also rose, while red blood cell volume decreased. Total CBV (i.e., the sum of red blood cell and plasma volumes) increased in parallel with CBF (from 2.51 ml/100 g at Hct = 43 to 4.94 ml/100 g at Hct = 20%). This increase is larger than can be explained by a simple increase in the diameter of arterial/arteriolar resistance vessels and may be due to either capillary recruitment or to an increase in the volume of postarteriolar structures. Calculated cerebral tissue hematocrit decreased. The magnitude of this decrease was larger than the reduction in arterial Hct; the ratio of cerebral to arterial Hct decreased from 0.780 at an arterial Hct equaling 43% to 0.458 at Hct equaling 20%.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. 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.

  2. Camphor induces cold and warm sensations with increases in skin and muscle blood flow in human.

    Science.gov (United States)

    Kotaka, Tomohiko; Kimura, Shoji; Kashiwayanagi, Makoto; Iwamoto, Jun

    2014-01-01

    Application of camphor to the skin has been empirically thought to improve blood circulation. However, camphor's effects on blood circulation to the skin and on thermal sensation have not been well elucidated. In this study, we examined its effects on the quality of sensation as well as on skin and muscle blood flow in human. Nine adults (average age 37±9.4 years) participated in the study. Petroleum jelly containing 5%, 10%, 20% camphor, or 2% menthol was separately applied to the skin on the medial side of one forearm of each subject. Just after the application, camphor at each concentration induced a cold sensation in a dose-dependent manner. Within 10 min, each subject reported that the cold sensation had faded, after which it was replaced by a warm sensation. As reported previously, a cold sensation was induced by application of 2% menthol, but the subjects did not adapt to that sensation. In addition, menthol did not induce a warm sensation at all. Application of menthol has been shown to increase blood flow in the skin. Finally, we measured blood flow in skin and muscle after the application of camphor or menthol. Application of camphor or menthol separately induced increases in local blood flow in the skin and muscle. The present results indicate that camphor induces both cold and warm sensations and improves blood circulation.

  3. 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

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

    NARCIS (Netherlands)

    Heijer, T.; Skoog, I.; Oudkerk, M.; Leeuw, H.F. de; Groot, J.C. de; Hofman, A.W.I.M.; Breteler, M.H.M.

    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

  5. Contraction-induced muscle fiber damage is increased in soleus muscle of streptozotocin-diabetic rats and is associated with elevated expression of brain-derived neurotrophic factor mRNA in muscle fibers and activated satellite cells

    NARCIS (Netherlands)

    Copray, S; Liem, R; Brouwer, N; Greenhaff, P; Habens, F; Fernyhough, P

    The expression of brain-derived neurotrophic factor (BDNF) is elevated in the soleus muscle of streptozotocin-diabetic rats. To determine whether this diabetes-induced elevation was associated with or enhanced by muscle activity we have induced high-intensity muscle contraction by electrically

  6. 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.

  7. Postmortem Brain and Blood Reference Concentrations of Alprazolam, Bromazepam, Chlordiazepoxide, Diazepam, and their Metabolites and a Review of the Literature

    DEFF Research Database (Denmark)

    Skov, Louise; Holm, Karen Marie Dollerup; Johansen, Sys Stybe

    2016-01-01

    -metabolite ratios were similar in brain and blood for most compounds. Duplicate measurements of brain samples showed that the pre-analytical variation in brain (5.9%) was relatively low, supporting the notion that brain tissue is a suitable postmortem specimen. The reported concentrations in both brain and blood...

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

    Science.gov (United States)

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

    2012-05-17

    Patients with spinal cord injury lack the connections between brain and spinal cord circuits that are 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 movements and to achieve a greater measure of independence in daily activities. In existing clinical systems, the patient uses residual proximal limb movements to trigger pre-programmed stimulation that causes the paralysed muscles to contract, allowing use of one or two basic grasps. Instead, we have developed an FES system in primates that is controlled by recordings made from microelectrodes permanently implanted in the brain. We simulated some of the effects of the paralysis caused by C5 or C6 spinal cord injury by injecting rhesus monkeys with a local anaesthetic to block the median and ulnar nerves at the elbow. Then, using recordings from approximately 100 neurons in the motor cortex, we predicted the intended activity of several of the paralysed muscles, and used these predictions to control the intensity of stimulation of the same muscles. This process essentially bypassed the spinal cord, restoring to the monkeys voluntary control of their paralysed muscles. This achievement is a major advance towards similar restoration of hand function in human patients through brain-controlled FES. We anticipate that in human patients, this neuroprosthesis would allow much more flexible and dexterous use of the hand than is possible with existing FES systems.

  9. MR-Guided Unfocused Ultrasound Disruption of the Rat Blood-Brain Barrier

    Science.gov (United States)

    Townsend, Kelly A.; King, Randy L.; Zaharchuk, Greg; Pauly, Kim Butts

    2011-09-01

    Therapeutic ultrasound with microbubbles can temporarily disrupt the blood-brain barrier (BBB) for drug delivery. Contrast-enhanced MRI (CE-MRI) can visualize gadolinium passage into the brain, indicating BBB opening. Previous studies used focused ultrasound, which is appropriate for the targeted delivery of drugs. The purpose of this study was to investigate unfocused ultrasound for BBB opening across the whole brain. In 10 rats, gadolinium-based MR contrast agent (Gd; 0.25 ml) was administered concurrent with ultrasound microbubbles (Optison, 0.25 ml) and circulated for 20 sec before sonication. A 753 kHz planar PZT transducer, diameter 1.8 cm, sonicated each rat brain with supplied voltage of 300, 400, or 500 mVpp for 10 sec in continuous wave mode, or at 500 mVpp at 20% duty cycle at 10 Hz for 30-300 sec. After sonication, coronal T1-weighted FSE CE-MRI images were acquired with a 3in surface coil. The imaging protocol was repeated 3-5 times after treatment. One control animal was given Gd and microbubbles, but not sonicated, and the other was given Gd and sonicated without microbubbles. Signal change in ROIs over the muscle, mesencephalon/ventricles, and the cortex/striatum were measured at 3-5 time points up to 36 min after sonication. Signal intensity was converted to % signal change compared to the initial image. In the controls, CE-MRI showed brightening of surrounding structures, but not the brain. In the continuous wave subjects, cortex/striatum signal did not increase, but ventricle/mesenchephalon signal did. Those that received pulsed sonications showed signal increases in both the cortex/striatum and ventricles/mesenchephalon. In conclusion, after pulsed unfocused ultrasound sonication, the BBB is disrupted across the whole brain, including cortex and deep grey matter, while continuous wave sonication affects only the ventricles and possibly deeper structures, without opening the cortex BBB. As time passes, the timeline of Gd passage into the brain

  10. Effects of intracarotid ioxaglate on the normal blood-brain barrier

    International Nuclear Information System (INIS)

    Wilcox, J.; Sage, M.R.

    1985-01-01

    Using two different models, the effect on the blood-brain barrier of intracarotid injections of sodium/meglumine ioxaglate at similar iodine concentrations (280 mgI/ml) was investigated. In both models the degree of blood-brain barrier damage was assessed visually using Evans' Blue stain. Quantitative assessment of blood-brain barrier disruption was made by contrast enhancement as measured by CT of the dog brain, and by 99m Tc-pertechnetate uptake by the brain in the rabbit model. No Evans' Blue staining was observed in any study using the canine/CT model. Slight staining was observed in two studies with ioxaglate using the rabbit/pertechnetate model. Statistical analysis of results from the canine/CT model did not detect any damage to the blood-brain barrier with either ioxaglate or saline control studies (P>0.1). However, in the rabbit/pertechnetate model a slight increase in disruption of the blood-brain barrier was observed with ioxaglate compared with control studies, but this was only significant at the 0.1 level. The results suggest that the rabbit/pertechnetate model is a more sensitive measure of blood-brain barrier disruption than the canine/CT model. This study also demonstrates that blood-brain barrier disruption following intracarotid injection of ioxaglate is minimal. (orig.)

  11. Muscle-Eye-Brain Disease; a Rare Form of Syndromic Congenital Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Gosal Gurinder S

    2011-03-01

    Full Text Available Congenital muscular dystrophy (CMD is a heterogeneous group of disorders characterized by muscular hypotonia since birth and the histologic features of muscular dystrophy. Syndromic congenital muscular dystrophies are clinically similar autosomal recessive disorders characterized by congenital muscular dystrophy, lissencephaly, and eye anomalies. We present a case of a rare form of syndromic congenital muscular dystrophy in an eight year old girl, born of first- degree consanguinity. She had: global developmental delay; a seizure disorder; hypotonia; progressive muscle contractures including bilateral symmetrical flexion contractures of hips, knees, equinus contracture and thoracolumbar scoliosis; diminished deep tendon reflexes: bilateral premature cataract; pseudophakia; and nystagmus. The patient was also highly myopic. Based on clinical features, muscle biopsy and MRI of the brain, a diagnosis of muscle- eye- brain disease was made. Identification of these patients may help to prevent this crippling disorder in the future siblings of probands by utilizing genetic counselling and mutation analysis.

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

    International Nuclear Information System (INIS)

    Baumbach, G.L.; Mayhan, W.G.; Heistad, D.D.

    1986-01-01

    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 125 I-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

  13. Blood flow restriction prevents muscle damage but not protein synthesis signaling following eccentric contractions

    Science.gov (United States)

    Sudo, Mizuki; Ando, Soichi; Poole, David C; Kano, Yutaka

    2015-01-01

    There is a growing body of evidence to suggest that resistance training exercise combined with blood flow restriction (BFR) increases muscle size and strength in humans. Eccentric contraction (ECC) frequently induces severe muscle damage. However, it is not known whether and to what extent muscle damage occurs following ECC + BFR due to the difficulty of conducting definitive invasive studies. The purpose of this study was to examine muscle fiber damage following ECC + BFR at the cellular level. High-intensity ECC was purposefully selected to maximize the opportunity for muscle damage and hypertrophic signaling in our novel in vivo animal model. Male Wistar rats were assigned randomly to the following groups: ECC and ECC + BFR at varying levels of occlusion pressure (140, 160, and 200 Torr). In all conditions, electrical stimulation was applied to the dorsiflexor muscles simultaneously with electromotor-induced plantar flexion. We observed severe histochemical muscle fiber damage (area of damaged fibers/total fiber area analyzed) following ECC (26.4 ± 4.0%). Surprisingly, however, muscle damage was negligible following ECC + BFR140 (2.6 ± 1.2%), ECC+BFR160 (3.0 ± 0.5%), and ECC + BFR200 (0.2 ± 0.1%). Ribosomal S6 kinase 1 (S6K1) phosphorylation, a downstream target of rapamycin (mTOR)-phosphorylation kinase, increased following ECC + BFR200 as well as ECC. In contrast, S6K1 phosphorylation was not altered by BFR alone. The present findings suggest that ECC combined with BFR, even at high exercise intensities, may enhance muscle protein synthesis without appreciable muscle fiber damage. PMID:26149281

  14. Reducing body fat with altitude hypoxia training in swimmers: role of blood perfusion to skeletal muscles.

    Science.gov (United States)

    Chia, Michael; Liao, Chin-An; Huang, Chih-Yang; Lee, Wen-Chih; Hou, Chien-Wen; Yu, Szu-Hsien; Harris, M Brennan; Hsu, Tung-Shiung; Lee, Shin-Da; Kuo, Chia-Hua

    2013-02-28

    Swimmers tend to have greater body fat than athletes from other sports. The purpose of the study was to examine changes in body composition after altitude hypoxia exposure and the role of blood distribution to the skeletal muscle in swimmers. With a constant training volume of 12.3 km/day, young male swimmers (N = 10, 14.8 ± 0.5 years) moved from sea-level to a higher altitude of 2,300 meters. Body composition was measured before and after translocation to altitude using dual-energy X-ray absorptiometry (DXA) along with 8 control male subjects who resided at sea level for the same period of time. To determine the effects of hypoxia on muscle blood perfusion, total hemoglobin concentration (THC) was traced by near-infrared spectroscopy (NIRS) in the triceps and quadriceps muscles under glucose-ingested and insulin-secreted conditions during hypoxia exposure (16% O2) after training. While no change in body composition was found in the control group, subjects who trained at altitude had unequivocally decreased fat mass (-1.7 ± 0.3 kg, -11.4%) with increased lean mass (+0.8 ± 0.2 kg, +1.5%). Arterial oxygen saturation significantly decreased with increased plasma lactate during hypoxia recovery mimicking 2,300 meters at altitude (~93% versus ~97%). Intriguingly, hypoxia resulted in elevated muscle THC, and sympathetic nervous activities occurred in parallel with greater-percent oxygen saturation in both muscle groups. In conclusion, the present study provides evidence that increased blood distribution to the skeletal muscle under postprandial condition may contribute to the reciprocally increased muscle mass and decreased body mass after a 3-week altitude exposure in swimmers.

  15. Paving the way towards complex blood-brain barrier models using pluripotent stem cells

    DEFF Research Database (Denmark)

    Lauschke, Karin; Frederiksen, Lise; Hall, Vanessa Jane

    2017-01-01

    to the unique tightness and selective permeability of the BBB and has been shown to be disrupted in many diseases and brain disorders, such as, vascular dementia, stroke, multiple sclerosis and Alzheimer's disease. Given the progress that pluripotent stem cells (PSCs) have made in the last two decades......A tissue with great need to be modelled in vitro is the blood-brain barrier (BBB). The BBB is a tight barrier that covers all blood vessels in the brain and separates the brain microenvironment from the blood system. It consists of three cell types (neurovascular unit (NVU)) that contribute...

  16. Blood-brain barrier disruption in CCL2 transgenic mice during pertussis toxin-induced brain inflammation

    DEFF Research Database (Denmark)

    Schellenberg, Angela E; Buist, Richard; Del Bigio, Marc R

    2012-01-01

    infiltrate into the brain parenchyma following the administration of pertussis toxin (PTx). METHODS: This study uses contrast-enhanced magnetic resonance imaging (MRI) to quantify the extent of blood-brain barrier (BBB) disruption in this model pre- and post-PTx administration compared to wild type mice...

  17. Transcriptional profiling of rat skeletal muscle hypertrophy under restriction of blood flow.

    Science.gov (United States)

    Xu, Shouyu; Liu, Xueyun; Chen, Zhenhuang; Li, Gaoquan; Chen, Qin; Zhou, Guoqing; Ma, Ruijie; Yao, Xinmiao; Huang, Xiao

    2016-12-15

    Blood flow restriction (BFR) under low-intensity resistance training (LIRT) can produce similar effects upon muscles to that of high-intensity resistance training (HIRT) while overcoming many of the restrictions to HIRT that occurs in a clinical setting. However, the potential molecular mechanisms of BFR induced muscle hypertrophy remain largely unknown. Here, using a BFR rat model, we aim to better elucidate the mechanisms regulating muscle hypertrophy as induced by BFR and reveal possible clinical therapeutic targets for atrophy cases. We performed genome wide screening with microarray analysis to identify unique differentially expressed genes during rat muscle hypertrophy. We then successfully separated the differentially expressed genes from BRF treated soleus samples by comparing the Affymetrix rat Genome U34 2.0 array with the control. Using qRT-PCR and immunohistochemistry (IHC) we also analyzed other related differentially expressed genes. Results suggested that muscle hypertrophy induced by BFR is essentially regulated by the rate of protein turnover. Specifically, PI3K/AKT and MAPK pathways act as positive regulators in controlling protein synthesis where ubiquitin-proteasome acts as a negative regulator. This represents the first general genome wide level investigation of the gene expression profile in the rat soleus after BFR treatment. This may aid our understanding of the molecular mechanisms regulating and controlling muscle hypertrophy and provide support to the BFR strategies aiming to prevent muscle atrophy in a clinical setting. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Control of abdominal muscles by brain stem respiratory neurons in the cat

    Science.gov (United States)

    Miller, Alan D.; Ezure, Kazuhisa; Suzuki, Ichiro

    1985-01-01

    The nature of the control of abdominal muscles by the brain stem respiratory neurons was investigated in decerebrate unanesthetized cats. First, it was determined which of the brain stem respiratory neurons project to the lumbar cord (from which the abdominal muscles receive part of their innervation), by stimulating the neurons monopolarly. In a second part of the study, it was determined if lumbar-projecting respiratory neurons make monosynaptic connections with abdominal motoneurons; in these experiments, discriminate spontaneous spikes of antidromically acivated expiratory (E) neurons were used to trigger activity from both L1 and L2 nerves. A large projection was observed from E neurons in the caudal ventral respiratory group to the contralateral upper lumber cord. However, cross-correlation experiments found only two (out of 47 neuron pairs tested) strong monosynaptic connections between brain stem neurons and abdominal motoneurons.

  19. Blood-Feeding Induces Reversible Functional Changes in Flight Muscle Mitochondria of Aedes aegypti Mosquito

    Science.gov (United States)

    Gonçalves, Renata L. S.; Machado, Ana Carolina L.; Paiva-Silva, Gabriela O.; Sorgine, Marcos H. F.; Momoli, Marisa M.; Oliveira, Jose Henrique M.; Vannier-Santos, Marcos A.; Galina, Antonio; Oliveira, Pedro L.; Oliveira, Marcus F.

    2009-01-01

    Background Hematophagy poses a challenge to blood-feeding organisms since products of blood digestion can exert cellular deleterious effects. Mitochondria perform multiple roles in cell biology acting as the site of aerobic energy-transducing pathways, and also an important source of reactive oxygen species (ROS), modulating redox metabolism. Therefore, regulation of mitochondrial function should be relevant for hematophagous arthropods. Here, we investigated the effects of blood-feeding on flight muscle (FM) mitochondria from the mosquito Aedes aegypti, a vector of dengue and yellow fever. Methodology/Principal Findings Blood-feeding caused a reversible reduction in mitochondrial oxygen consumption, an event that was parallel to blood digestion. These changes were most intense at 24 h after blood meal (ABM), the peak of blood digestion, when oxygen consumption was inhibited by 68%. Cytochromes c and a+a 3 levels and cytochrome c oxidase activity of the electron transport chain were all reduced at 24 h ABM. Ultrastructural and molecular analyses of FM revealed that mitochondria fuse upon blood meal, a condition related to reduced ROS generation. Consistently, BF induced a reversible decrease in mitochondrial H2O2 formation during blood digestion, reaching their lowest values at 24 h ABM where a reduction of 51% was observed. Conclusion Blood-feeding triggers functional and structural changes in hematophagous insect mitochondria, which may represent an important adaptation to blood feeding. PMID:19924237

  20. [Measurement of the blood flow in various areas of the rat brain by means of microspheres].

    Science.gov (United States)

    Deroo, J; Gerber, G B

    1976-01-01

    A method is described to measure regional blood flow in different structures of the rat brain. Microspheres (15 micron) are injected, the brain is sectioned, stained for myeline, radioautographs are prepared and the microspheres in the different structures are counted. The values obtained for different brain structures are counted. The values obtained for different brain regions (cortex, corpus callosum, thalamus hipocampus, hypothalamic region, colliculi, cerebellum, pons, medulla) compare well with those published by others on larger animals. In rats fed 1% of lead from birth, higher blood flow is found in the cortex and a lower one in the interior part of the brain compared to controls.

  1. 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 Drug Administration-approved tissue plasminogen activator for treatment of acute ischemic stroke being the most prominent example. A large number of potential drug candidates for treatment of ischemic brain tissue have been developed and subsequently failed in clinical trials. A deeper understanding...... of 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-brain...

  2. 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.

  3. Pathological changes in the structures of the blood-brain barrier in acute cerebral circulatory disorders

    Directory of Open Access Journals (Sweden)

    S.І. Tertyshny

    2012-04-01

    Full Text Available Morphological changes of the blood-brain barrier were investigated in case of an acute brain disturbed circulation. Autocontrol of vessels with their dilatation and formation of aggregation from formal elements were shown from the onset of the disease. Distructive changes of the endothelium, basement membranes, pericytes, asrtocytosal processes are marked in the microvessels with formation of the perivascular edema. Increase permeability of the blood-brain barrier promotes hemorrhagic transformation and lymphomicrophagical infi ltration of the perivascular zones.

  4. Brain and arterial blood temperatures of free-ranging oryx ( Oryx gazella).

    Science.gov (United States)

    Maloney, Shane K; Fuller, Andrea; Mitchell, Graham; Mitchell, Duncan

    2002-01-01

    We used implanted miniature data loggers to measure brain and arterial blood temperatures every 5 min for up to 15 days in four free-ranging oryx ( Oryx gazella) in their natural habitat. Globe temperatures exceeded 45 degrees C and average peak radiant heat load was 800 W.m(-2). Arterial blood temperature exhibited a moderate amplitude nychthemeral rhythm of 1.8+/-0.3 degrees C (mean +/-SD). The amplitude of the nychthemeral rhythm was not influenced by variations in ambient heat load. Average brain temperature exceeded carotid arterial blood temperature by 0.29 degrees C but there was a range of body temperatures over which the brain could be up to 0.4 degrees C cooler or 0.5 degrees C warmer than arterial blood. At high body temperatures (>39.5 degrees C) at rest, three of the animals tended to maintain the brain cooler than arterial blood. During exercise the brain was always warmer than arterial blood. The slope of the regression line relating brain temperature to carotid blood temperature was less than one. At short time scales of 5-20 min, brain temperature varied significantly more than did carotid blood temperature. We attribute part of the variability in brain temperature to transient stress responses and the influence of sympathetic activation attenuating selective brain cooling. We conclude that, contrary to the widely cited postulate, the carotid rete does not protect the brain during hyperthermia. Oryx also do not show adaptive heterothermy and, over short time intervals, have a brain temperature more variable than carotid blood temperature.

  5. The effect of ovariectomy and estrogen on penetrating brain arterioles and blood-brain barrier permeability.

    Science.gov (United States)

    Cipolla, Marilyn J; Godfrey, Julie A; Wiegman, Marchien J

    2009-11-01

    We investigated the effect of estrogen replacement on the structure and function of penetrating brain arterioles (PA) and blood-brain barrier (BBB) permeability. Female ovariectomized Sprague-Dawley rats were replaced with estradiol (E(2)) and estriol (E(3)) (OVX + E; N=13) and compared to ovariectomized animals without replacement (OVX; N=14) and intact controls (CTL, proestrous; N=13). Passive and active diameters, percent tone, and passive distensibility of pressurized PA were compared. In addition, BBB permeability to Lucifer Yellow, a marker of transcellular transport, was compared in cerebral arteries. Ovariectomy increased myogenic tone in PA, compared to CTL, that was not ameliorated by estrogen treatment. Percent tone at 75 mmHg for CTL vs. OVX and OVX + E was 44+/-3% vs. 51+/-1% and 54+/-3% (PLucifer Yellow for CTL, OVX, and OVX + E was (ng/mL): 3.4+/-1.2, 20.2+/-5.3 (P<0.01 vs. CTL), and 6.15+/-1.2 (n.s.). These results suggest that estrogen replacement may not be beneficial for small-vessel disease in the brain, but may limit BBB disruption and edema under conditions that cause it.

  6. Sex-specific divergence of antioxidant pathways in fetal brain, liver, and skeletal muscles.

    Science.gov (United States)

    Al-Gubory, Kaïs H; Garrel, Catherine

    2016-01-01

    The sex-specific divergence of antioxidant pathways in fetal organs of opposite-sex twin is unknown and remains urgently in need of investigation. Such study faces many challenges, mainly the ethical impossibility of obtaining human fetal organs. Opposite-sex sheep twins represent a unique model for studying a sex dimorphism for antioxidant systems. The activity of total superoxide dismutase (SOD), SOD1, SOD2, glutathione peroxidase (GPX), glutathione reductase (GR) and catalase (CAT), the content of total glutathione, reduced glutathione (GSH), and oxidized glutathione (GSSG) were measured in brain, lung, liver, kidney, and skeletal muscles of female and male fetuses collected from sheep twin pregnancies at day 65 of gestation. Lipid peroxidation was assessed by measuring melondialdehyde (MDA) tissue content. Male brain has greater total SOD and SOD1 activities than female brain. Female liver has greater SOD2 activity than male liver. Male liver has greater GR activity than female liver. Male liver has higher total GSH and GSSG content than female liver. Male skeletal muscles have higher total GSH, GSH, and GSSG content than female skeletal muscles. Female brain and liver have higher MDA content than male brain and liver. This is the first report of a sex dimorphism for fetal organ antioxidative pathways. Brain, liver, and skeletal muscles of male and female fetuses display distinct antioxidant pathways. Such sexually dimorphic responses to early life oxidative stress might be involved in the sex-related difference in fetal development that may have a long-term effect on offspring. Our study urges researchers to take into consideration the importance of sex as a biologic variable in their investigations.

  7. Endocannabinoids modulate human blood-brain barrier permeability in vitro.

    Science.gov (United States)

    Hind, William H; Tufarelli, Cristina; Neophytou, Maria; Anderson, Susan I; England, Timothy J; O'Sullivan, Saoirse E

    2015-06-01

    Endocannabinoids alter permeability at various epithelial barriers, and cannabinoid receptors and endocannabinoid levels are elevated by stroke, with potential neuroprotective effects. We therefore explored the role of endocannabinoids in modulating blood-brain barrier (BBB) permeability in normal conditions and in an ischaemia/reperfusion model. Human brain microvascular endothelial cell and astrocyte co-cultures modelled the BBB. Ischaemia was modelled by oxygen-glucose deprivation (OGD) and permeability was measured by transepithelial electrical resistance. Endocannabinoids or endocannabinoid-like compounds were assessed for their ability to modulate baseline permeability or OGD-induced hyperpermeability. Target sites of action were investigated using receptor antagonists and subsequently identified with real-time PCR. Anandamide (10 μM) and oleoylethanolamide (OEA, 10 μM) decreased BBB permeability (i.e. increased resistance). This was mediated by cannabinoid CB2 receptors, transient receptor potential vanilloid 1 (TRPV1) channels, calcitonin gene-regulated peptide (CGRP) receptor (anandamide only) and PPARα (OEA only). Application of OEA, palmitoylethanolamide (both PPARα mediated) or virodhamine (all 10 μM) decreased the OGD-induced increase in permeability during reperfusion. 2-Arachidonoyl glycerol, noladin ether and oleamide did not affect BBB permeability in normal or OGD conditions. N-arachidonoyl-dopamine increased permeability through a cytotoxic mechanism. PPARα and γ, CB1 receptors, TRPV1 channels and CGRP receptors were expressed in both cell types, but mRNA for CB2 receptors was only present in astrocytes. The endocannabinoids may play an important modulatory role in normal BBB physiology, and also afford protection to the BBB during ischaemic stroke, through a number of target sites. © 2015 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

  8. Methamphetamine Effects on Blood-Brain Barrier Structure and Function

    Directory of Open Access Journals (Sweden)

    Nicole Alia Northrop

    2015-03-01

    Full Text Available Methamphetamine (Meth is a widely abuse psychostimulant. Traditionally, studies have focused on the neurotoxic effects of Meth on monoaminergic neurotransmitter terminals. Recently, both in vitro and in vivo studies have investigated the effects of Meth on the BBB and found that Meth produces a decrease in BBB structural proteins and an increase in BBB permeability to various molecules. Moreover, preclinical studies are validated by clinical studies in which human Meth users have increased concentrations of toxins in the brain. Therefore, this review will focus on the structural and functional disruption of the BBB caused by Meth and the mechanisms that contribute to Meth-induced BBB disruption. The review will reveal that the mechanisms by which Meth damages dopamine and serotonin terminals are similar to the mechanisms by which the blood-brain barrier (BBB is damaged. Furthermore, this review will cover the factors that are known to potentiate the effects of Meth on the BBB, such as stress and HIV, both of which are co-morbid conditions associated with Meth abuse. Overall, the goal of this review is to demonstrate that the scope of damage produced by Meth goes beyond damage to monoaminergic neurotransmitter systems to include BBB disruption as well as provide a rationale for investigating therapeutics to treat Meth-induced BBB disruption. Since a breach of the BBB can have a multitude of consequences, therapies directed towards the treatment of BBB disruption may help to ameliorate the long-term neurodegeneration and cognitive deficits produced by Meth and possibly even Meth addiction.

  9. 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.

  10. 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

    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......, they support the hypothesis that cerebral perfusion during exercise reflects an increase in brain activation that is independent of MAP, central command, and muscle metaboreceptors but is likely to depend on influence of mechanoreceptors.......," 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...

  11. Chronic impairment of leg muscle blood flow following cardiac catheterization in childhood

    International Nuclear Information System (INIS)

    Skovranek, J.; Samanek, M.

    1979-01-01

    In 99 patients with congenital heart defects or chronic respiratory disease without clinical symptoms of disturbances in peripheral circulation, resting and maximal blood flow in the anterior tibial muscle of both extremities were investigated 2.7 yrs (average) after cardiac catheterization. The method used involved 133 Xe clearance. Resting blood flow was normal and no difference could be demonstrated between the extremity originally used for catheterization and the contralateral control extremity. No disturbance in maximal blood flow could be proved in the extremity used for catheterization by the venous route only. Maximal blood flow was significantly lower in that extremity where the femoral artery had been catheterized or cannulated for pressure measurement and blood sampling. The disturbance in maximal flow was shown regardless of whether the arterial catheterization involved the Seldinger percutaneous technique, arteriotomy, or mere cannulation of the femoral artery. The values in the involved extremity did not differ significantly from the values in a healthy population

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

    Directory of Open Access Journals (Sweden)

    Ong John M

    2007-03-01

    Full Text Available Abstract 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 permeability in brain tumors, but not in normal brain. Iberiotoxin, a KCa channel antagonist, significantly attenuated NS1619-induced BTB permeability increase. We found KCa channels and bradykinin type 2 receptors (B2R expressed in cultured human metastatic brain tumor cells (CRL-5904, non-small cell lung cancer, metastasized to brain, human brain microvessel endothelial cells (HBMEC and human lung cancer brain metastasis tissues. Potentiometric assays demonstrated the activity of KCa channels in metastatic brain tumor cells and HBMEC. Furthermore, we detected higher expression of KCa channels in the metastatic brain tumor tissue and tumor capillary endothelia as compared to normal brain tissue. Co-culture of metastatic brain tumor cells and brain microvessel endothelial cells showed an upregulation of KCa channels, which may contribute to the overexpression of KCa channels in tumor microvessels and selectivity of BTB opening. Conclusion These findings suggest that KCa channels in metastatic brain tumors may serve as an effective target for biochemical modulation of BTB permeability to enhance selective delivery of chemotherapeutic drugs to metastatic brain tumors.

  13. 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

    2014-11-17

    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.

  14. Ischemia-reperfusion impairs blood-brain barrier function and alters tight junction protein expression in the ovine fetus.

    Science.gov (United States)

    Chen, X; Threlkeld, S W; Cummings, E E; Juan, I; Makeyev, O; Besio, W G; Gaitanis, J; Banks, W A; Sadowska, G B; Stonestreet, B S

    2012-12-13

    The blood-brain barrier is a restrictive interface between the brain parenchyma and the intravascular compartment. Tight junctions contribute to the integrity of the blood-brain barrier. Hypoxic-ischemic damage to the blood-brain barrier could be an important component of fetal brain injury. We hypothesized that increases in blood-brain barrier permeability after ischemia depend upon the duration of reperfusion and that decreases in tight junction proteins are associated with the ischemia-related impairment in blood-brain barrier function in the fetus. Blood-brain barrier function was quantified with the blood-to-brain transfer constant (K(i)) and tight junction proteins by Western immunoblot in fetal sheep at 127 days of gestation without ischemia, and 4, 24, or 48 h after ischemia. The largest increase in K(i) (Pbrain barrier function after ischemia. We conclude that impaired blood-brain barrier function is an important component of hypoxic-ischemic brain injury in the fetus, and that increases in quantitatively measured barrier permeability (K(i)) change as a function of the duration of reperfusion after ischemia. The largest increase in permeability occurs 4 h after ischemia and blood-brain barrier function improves early after injury because the blood-brain barrier is less permeable 24 and 48 than 4 h after ischemia. Changes in the tight junction molecular composition are associated with increases in blood-brain barrier permeability after ischemia. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

  15. Barrier mechanisms in the Drosophila blood-brain barrier.

    Science.gov (United States)

    Hindle, Samantha J; Bainton, Roland J

    2014-01-01

    The invertebrate blood-brain barrier (BBB) field is growing at a rapid pace and, in recent years, studies have shown a physiologic and molecular complexity that has begun to rival its vertebrate counterpart. Novel mechanisms of paracellular barrier maintenance through G-protein coupled receptor signaling were the first demonstrations of the complex adaptive mechanisms of barrier physiology. Building upon this work, the integrity of the invertebrate BBB has recently been shown to require coordinated function of all layers of the compound barrier structure, analogous to signaling between the layers of the vertebrate neurovascular unit. These findings strengthen the notion that many BBB mechanisms are conserved between vertebrates and invertebrates, and suggest that novel findings in invertebrate model organisms will have a significant impact on the understanding of vertebrate BBB functions. In this vein, important roles in coordinating localized and systemic signaling to dictate organism development and growth are beginning to show how the BBB can govern whole animal physiologies. This includes novel functions of BBB gap junctions in orchestrating synchronized neuroblast proliferation, and of BBB secreted antagonists of insulin receptor signaling. These advancements and others are pushing the field forward in exciting new directions. In this review, we provide a synopsis of invertebrate BBB anatomy and physiology, with a focus on insights from the past 5 years, and highlight important areas for future study.

  16. 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...

  17. 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......-extensor training and 2 weeks of deconditioning of the other leg (leg cast). Hemodynamics and muscle interstitial nucleotides were determined during exercise with the (1) deconditioned leg, (2) trained leg, and (3) trained leg with atrial pacing to the heart rate obtained with the deconditioned leg. Heart rate...

  18. 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......, respectively (P exercise in humans. These findings demonstrate an important synergistic role of NO and PG for skeletal muscle vasodilatation and hyperaemia during muscular contraction....... 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...

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

    International Nuclear Information System (INIS)

    Klin, Yael; Zlotnik, Alexander; Boyko, Matthew; Ohayon, Sharon; Shapira, Yoram; Teichberg, Vivian I.

    2010-01-01

    Research highlights: → Blood glutamate has a half-life time of 2-3 min. → Blood glutamate is submitted to rapid decarboxylation. → Blood glutamate and its metabolites are mainly absorbed in skeletal muscle and liver. → 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- 14 C] Glutamic acid (L-[1- 14 C] Glu), L-[G- 3 H] Glutamic acid (L-[G- 3 H] Glu) or D-[2,3- 3 H] Aspartic acid (D-[2,3- 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- 14 C] Glu and L-[G- 3 H] Glu was faster than that associated with glutamate non-metabolized analog, D-[2,3- 3 H] Asp. L-[1- 14 C] Glu was subjected in blood to a rapid decarboxylation with the loss of 14 CO 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- 14 C] Glu or D-[2,3- 3 H] Asp radioactivity capture. L-[U- 14 C] Glu and D-[2,3- 3 H] Asp showed a different organ sequestration pattern. We conclude that glutamate is rapidly eliminated from the blood into peripheral tissues, mainly in non-metabolized form. The liver plays a central role in glutamate metabolism

  20. Towards drug discovery for brain tumours: interaction of kinins and tumours at the blood brain barrier interface.

    Science.gov (United States)

    Harford-Wright, Elizabeth; Lewis, Kate M; Vink, Robert

    2011-01-01

    Cancers of the brain are intrinsically more complicated to treat than systemic malignancies due to the unique anatomical features of the brain. The blood-brain barrier prevents chemotherapeutic agents from reaching brain neoplasms, and angiogenesis occurs as the metabolic needs of the tumour increase, thus further complicating treatment. The newly formed blood vessels form the blood-tumour barrier and are distinct from the blood-brain barrier in that they are more permeable. Being more permeable, these abnormal blood vessels lead to the formation of peri-tumoural edema, which is the cause of much morbidity and mortality associated with central nervous system neoplasms. While the cause of the increased permeability is unclear, kinins have been implicated in regulating the permeability of normal vasculature. Kinins are also known to exert many inflammatory actions affecting both normal and angiogenic blood vessels, as well as tumour cells. The vasodilatory and vascular permeabilizing effects of kinins, and particularly bradykinin and substance P, have been investigated with regard to delivery of chemotherapeutic agents to neoplastic brain tissue through both vascular barriers. In contrast, kinin receptor antagonists have been found to exert effects on tumour cells that result in decreased angiogenesis, tumour cell motility and growth. Thus, many recent patents describe kinin activity on brain vasculature, which may play an integral role in the development of treatments for malignancies in the central nervous system through amelioration of angiogenesis. In conjunction, patents that discuss the ability of kinins to decrease tumour cell migration and proliferation demonstrate that kinins may offer novel approaches to brain tumour therapy in the future.

  1. Blood haematology, muscle pH and serum cortisol changes in pigs with different levels of drip loss.

    Science.gov (United States)

    Koomkrong, Nunyarat; Boonkaewwan, Chaiwat; Laenoi, Watchara; Kayan, Autchara

    2017-12-01

    An experiment was conducted to study the blood haematology, muscle pH, and serum cortisol changes in pigs with different levels of drip loss. Two groups (low and high) of 20 animals were selected from 100 pigs based on drip loss. All [Duroc× (Large White×Landrace)] pigs were slaughtered according to standard slaughtering procedures. At exsanguinations, blood samples were taken for the haematological parameters and serum cortisol analysis. The muscle samples were taken from longissimus dorsi muscle to evaluate the muscle pH and drip loss. Haematological parameters of low drip loss group showed higher content of white blood cells and monocytes than high drip loss group (ppH at 45 min (plevels (p>0.05). Drip loss is mainly affected by the muscle pH decline after slaughter and also might be affected by white blood cells and monocytes.

  2. 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.

  3. Low blood flow at onset of moderate-intensity exercise does not limit muscle oxygen uptake

    DEFF Research Database (Denmark)

    Nyberg, Michael Permin; Mortensen, Stefan P; Saltin, Bengt

    2010-01-01

    The effect of low blood flow at onset of moderate-intensity exercise on the rate of rise in muscle oxygen uptake was examined. Seven male subjects performed a 3.5-min one-legged knee-extensor exercise bout (24 +/- 1 W, mean +/- SD) without (Con) and with (double blockade; DB) arterial infusion of...... of exercise. Additionally, prostanoids and/or nitric oxide appear to play important roles in elevating skeletal muscle blood flow in the initial phase of exercise.......The effect of low blood flow at onset of moderate-intensity exercise on the rate of rise in muscle oxygen uptake was examined. Seven male subjects performed a 3.5-min one-legged knee-extensor exercise bout (24 +/- 1 W, mean +/- SD) without (Con) and with (double blockade; DB) arterial infusion...... of inhibitors of nitric oxide synthase (N(G)-monomethyl-l-arginine) and cyclooxygenase (indomethacin) to inhibit the synthesis of nitric oxide and prostanoids, respectively. Leg blood flow and leg oxygen delivery throughout exercise was 25-50% lower (P

  4. Low blood flow at onset of moderate intensity exercise does not limit muscle oxygen uptake

    DEFF Research Database (Denmark)

    Nyberg, Michael Permin; Mortensen, Stefan Peter; Saltin, Bengt

    2010-01-01

    The effect of low blood flow at onset of moderate intensity exercise on the rate of rise in muscle oxygen uptake was examined. Seven male subjects performed a 3.5 minute one-legged knee-extensor exercise bout (24+/-1 (+/-S.D.) W) without (CON) and with (double blockade; DB) arterial infusion of i....... Additionally, prostanoids and/or NO appear to play important roles in elevating skeletal muscle blood flow in the initial phase of exercise. Key words: Oxygen delivery, oxygen extraction, nitric oxide, prostanoids.......The effect of low blood flow at onset of moderate intensity exercise on the rate of rise in muscle oxygen uptake was examined. Seven male subjects performed a 3.5 minute one-legged knee-extensor exercise bout (24+/-1 (+/-S.D.) W) without (CON) and with (double blockade; DB) arterial infusion...... of inhibitors of nitric oxide synthase (NOS; L-NMMA) and cyclooxygenase (COX; indomethacin) in order to inhibit the synthesis of nitric oxide (NO) and prostanoids, respectively.. Leg blood flow and leg oxygen delivery throughout exercise was 25-50 % lower (P

  5. Blood-brain barrier and cerebral blood flow: Age differences in hemorrhagic stroke

    Directory of Open Access Journals (Sweden)

    Semyachkina-Glushkovskaya Oxana

    2015-11-01

    Full Text Available Neonatal stroke is similar to the stroke that occurs in adults and produces a significant morbidity and long-term neurologic and cognitive deficits. There are important differences in the factors, clinical events and outcomes associated with the stroke in infants and adults. However, mechanisms underlying age differences in the stroke development remain largely unknown. Therefore, treatment guidelines for neonatal stroke must extrapolate from the adult data that is often not suitable for children. The new information about differences between neonatal and adult stroke is essential for identification of significant areas for future treatment and effective prevention of neonatal stroke. Here, we studied the development of stress-induced hemorrhagic stroke and possible mechanisms underlying these processes in newborn and adult rats. Using histological methods and magnetic resonance imaging, we found age differences in the type of intracranial hemorrhages. Newborn rats demonstrated small superficial bleedings in the cortex while adult rats had more severe deep bleedings in the cerebellum. Using Doppler optical coherent tomography, we found higher stress-reactivity of the sagittal sinus to deleterious effects of stress in newborn vs. adult rats suggesting that the cerebral veins are more vulnerable to negative stress factors in neonatal vs. adult brain in rats. However, adult but not newborn rats demonstrated the stroke-induced breakdown of blood brain barrier (BBB permeability. The one of possible mechanisms underlying the higher resistance to stress-related stroke injures of cerebral vessels in newborn rats compared with adult animals is the greater expression of two main tight junction proteins of BBB (occludin and claudin-5 in neonatal vs. mature brain in rats.

  6. 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.

  7. "Brain-muscle loop" in the fragility of older persons: from pathophysiology to new organizing models.

    Science.gov (United States)

    Lauretani, Fulvio; Meschi, Tiziana; Ticinesi, Andrea; Maggio, Marcello

    2017-12-01

    The imperative action of the geriatric medicine is to prevent disability in older persons. Many epidemiological studies have been conducted in the last decades for improving knowledge of the aging process and their interactions with age-related diseases, especially for the identification of the relationship between sarcopenia and loss of mobility. Factors influencing muscle integrity can be classified into six main physiologic subsystems, but the central nervous system certainly plays a crucial role for maintaining muscle integrity in older persons. Recent data show that the reduced muscle strength and not muscle mass could be considered the core of the fragility in predicting changes of gait velocity and mobility and conferring a higher risk of mortality in older persons. Sarcopenia and cognitive decline could, therefore, produce slow gait velocity in older persons, with devastating effect and consequences. Perhaps the most notorious corollary is falling, which is often caused by an underlying gait problem. Injuries caused by accidental falls range from relatively innocent bruises to major fractures or head trauma. Another important consequence is reduced mobility, which leads to loss of independence. This immobility is often compounded by a fear of falling, which further immobilises patients and affects their quality of life and physical performance. When we search the association between brain pathology and muscle function in older persons, we amazingly find that established composite measure of physical frailty is associated with brain pathology. Sarcopenia, which produces muscle dysfunction, slow gait velocity and cognitive decline, could share a strong bidirectional relationship, and this suggests the coexistence of both cognitive and motor dysfunctions in older persons to characterize a new syndrome characterized by slow gait and cognitive complaints, the motoric-cognitive risk syndrome (MRC). In this review, we want to emphasize the relationship between

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

    Science.gov (United States)

    Larsson, Henrik B W; Courivaud, Frédéric; Rostrup, Egill; Hansen, Adam E

    2009-11-01

    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 imaging of a bolus of a paramagnetic contrast agent passing through the brain. The methods are applied in patients with brain tumors and in healthy subjects. Perfusion was estimated by model-free deconvolution using Tikhonov's method (gray matter/white matter/tumor: 72 +/- 16/30 +/- 8/56 +/- 45 mL/100 g/min); blood volume (6 +/- 2/4 +/- 1/7 +/- 6 mL/100 g) and permeability (0.9 +/- 0.4/0.8 +/- 0.3/3 +/- 5 mL/100 g/min) were estimated by using Patlak's method and a two-compartment model. A corroboration of these results was achieved by using model simulation. In addition, it was possible to generate maps on a pixel-by-pixel basis of cerebral perfusion, cerebral blood volume, and blood-brain barrier permeability. (c) 2009 Wiley-Liss, Inc.

  9. Rapid transport of CCL11 across the blood-brain barrier: regional variation and importance of blood cells.

    Science.gov (United States)

    Erickson, Michelle A; Morofuji, Yoichi; Owen, Joshua B; Banks, William A

    2014-06-01

    Increased blood levels of the eotaxin chemokine C-C motif ligand 11 (CCL11) in aging were recently shown to negatively regulate adult hippocampal neurogenesis. How circulating CCL11 could affect the central nervous system (CNS) is not clear, but one possibility is that it can cross the blood-brain barrier (BBB). Here, we show that CCL11 undergoes bidirectional transport across the BBB. Transport of CCL11 from blood into whole brain (influx) showed biphasic kinetics, with a slow phase preceding a rapid phase of uptake. We found that the slow phase was explained by binding of CCL11 to cellular components in blood, whereas the rapid uptake phase was mediated by direct interactions with the BBB. CCL11, even at high doses, did not cause BBB disruption. All brain regions except striatum showed a delayed rapid-uptake phase. Striatum had only an early rapid-uptake phase, which was the fastest of any brain region. We also observed a slow but saturable transport system for CCL11 from brain to blood. C-C motif ligand 3 (CCR3), an important receptor for CCL11, did not facilitate CCL11 transport across the BBB, although high concentrations of a CCR3 inhibitor increased brain uptake without causing BBB disruption. Our results indicate that CCL11 in the circulation can access many regions of the brain outside of the neurogenic niche via transport across the BBB. This suggests that blood-borne CCL11 may have important physiologic functions in the CNS and implicates the BBB as an important regulator of physiologic versus pathologic effects of this chemokine.

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

    International Nuclear Information System (INIS)

    Perides, George; Zhuge, Yuzheng; Lin, Tina; Stins, Monique F; Bronson, Roderick T; Wu, Julian K

    2006-01-01

    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

  11. 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

    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...

  12. 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

    2006-01-01

    -legged dynamic knee-extension exercise. Local blockade was produced by infusing nitro-L-arginine methyl ester and indomethacin directly in the muscle via a microdialysis catheter. Blood flow and glucose uptake were measured in the region of blockade and in two additional regions of vastus lateralis muscle 1...

  13. Effect of blood flow on muscle lactate release studied in perfused rat hindlimb

    DEFF Research Database (Denmark)

    Pilegaard, H; Bangsbo, Jens; Henningsen, P

    1995-01-01

    The influence of blood flow on muscle lactate and H+ release as well as muscle glyconeogenesis was studied in the perfused rat hindlimb. After 2 min of supramaximal stimulation the perfusate flow rate was 7 (F7), 12 (F12), or 18 (F18) ml/min for 30 min. Perfusate samples were drawn frequently...... and muscle samples were obtained before stimulation, immediately after stimulation, and at 3, 10, and 30 min of recovery from soleus, white gastrocnemius (WG) and red gastrocnemius. During the first 5 min of recovery lactate release was 35-39% lower (P F7 than in F12 and F18...... but with no differences in total release during recovery. In F7 the concentration of lactate was higher (P F7 than in F12 and F18. The difference...

  14. Brain Inositol Is a Novel Stimulator for Promoting Cryptococcus Penetration of the Blood-Brain Barrier

    Science.gov (United States)

    Wang, Yina; Toffaletti, Dena L.; Eugenin, Eliseo; Perfect, John R.; Kim, Kee Jun; Xue, Chaoyang

    2013-01-01

    Cryptococcus neoformans is the most common cause of fungal meningitis, with high mortality and morbidity. The reason for the frequent occurrence of Cryptococcus infection in the central nervous system (CNS) is poorly understood. The facts that human and animal brains contain abundant inositol and that Cryptococcus has a sophisticated system for the acquisition of inositol from the environment suggests that host inositol utilization may contribute to the development of cryptococcal meningitis. In this study, we found that inositol plays an important role in Cryptococcus traversal across the blood-brain barrier (BBB) both in an in vitro human BBB model and in in vivo animal models. The capacity of inositol to stimulate BBB crossing was dependent upon fungal inositol transporters, indicated by a 70% reduction in transmigration efficiency in mutant strains lacking two major inositol transporters, Itr1a and Itr3c. Upregulation of genes involved in the inositol catabolic pathway was evident in a microarray analysis following inositol treatment. In addition, inositol increased the production of hyaluronic acid in Cryptococcus cells, which is a ligand known to binding host CD44 receptor for their invasion. These studies suggest an inositol-dependent Cryptococcus traversal of the BBB, and support our hypothesis that utilization of host-derived inositol by Cryptococcus contributes to CNS infection. PMID:23592982

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

    International Nuclear Information System (INIS)

    Hara, Toshihiko; Iio, Masaaki; Tsukiyama, Takashi

    1988-01-01

    Positron emission tomography (PET) using 11 C-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 11 CO 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 14 C-inulin. (orig.)

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

    DEFF Research Database (Denmark)

    Nyberg, Michael Permin

    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...... that 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 hyperemia....

  17. Daily inspiratory muscle training lowers blood pressure and vascular resistance in healthy men and women.

    Science.gov (United States)

    DeLucia, Claire M; De Asis, Roxanne M; Bailey, E Fiona

    2018-02-01

    What is the central question of this study? What impact does inspiratory muscle training have on systemic vascular resistance, cardiac output and baroreflex sensitivity in adult men and women? What is the main finding and its importance? Inspiratory muscle training exerts favorable effects on blood pressure, vascular resistance and perception of stress. This exercise format is well-tolerated and equally effective whether implemented in men or women. Previous work has shown that inspiratory muscle training (IMT) lowers blood pressure after a mere 6 weeks, identifying IMT as a potential therapeutic intervention to prevent or treat hypertension. Here, we explore the effects of IMT on respiratory muscle strength and select cardiovascular parameters in recreationally active men and women. Subjects were randomly assigned to IMT (n = 12, 75% maximal inspiratory pressure) or sham training (n = 13, 15% maximal inspiratory pressure) groups and underwent a 6-week intervention comprising 30 breaths day -1 , 5 days week -1 . Pre- and post-training measures included maximal inspiratory pressure and resting measures of blood pressure, cardiac output, heart rate, spontaneous cardiac baroreflex sensitivity and systemic vascular resistance. We evaluated psychological and sleep status via administration of the Cohen-Hoberman inventory of physical symptoms and the Epworth sleepiness scale. Male and female subjects in the IMT group showed declines in systolic/diastolic blood pressures (-4.3/-3.9 mmHg, P training, 12.5 ± 8.5 versus 7.2 ± 9.7, P = 0.025). Based on these results, we suggest that a short course of IMT confers significant respiratory and cardiovascular improvements and parallel (modest) psychological benefits in healthy men and women. © 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.

  18. Dynamics of Muscle Microcirculatory and Blood-myocyte O2 Flux During Contractions

    Science.gov (United States)

    Poole, David C.; Copp, Steven W.; Hirai, Daniel M.; Musch, Timothy I.

    2011-01-01

    The O2 requirements of contracting skeletal muscle may increase 100-fold above rest. In 1919 August Krogh’s brilliant insights recognized the capillary as the principal site for this increased blood-myocyte O2 flux. Based on the premise that most capillaries did not sustain RBC flux at rest Krogh proposed that capillary recruitment (i.e., initiation of red blood cell (RBC) flux in previously non-flowing capillaries) increased the capillary surface area available for O2 flux and reduced mean capillary-to-mitochondrial diffusion distances. More modern experimental approaches reveal that most muscle capillaries may support RBC flux at rest. Thus, rather than contraction-induced capillary recruitment per se, increased RBC flux and hematocrit within already-flowing capillaries likely elevate perfusive and diffusive O2 conductances and hence blood-myocyte O2 flux. Additional surface area for O2 exchange is recruited but, crucially, this may occur along the length of already-flowing capillaries (i.e. longitudinal recruitment). Today, the capillary is still considered the principal site for O2 and substrate delivery to contracting skeletal muscle. Indeed, the presence of very low intramyocyte O2 partial pressures (PO2’s) and the absence of PO2 gradients, whilst refuting the relevance of diffusion distances, place an even greater importance on capillary hemodynamics. This emergent picture calls for a paradigm-shift in our understanding of the function of capillaries by de-emphasizing de novo ‘capillary recruitment.’ Diseases such as heart failure impair blood-myocyte O2 flux, in part, by decreasing the proportion of RBC-flowing capillaries. Knowledge of capillary function in healthy muscle is requisite for identification of pathology and efficient design of therapeutic treatments. PMID:21199399

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

    DEFF Research Database (Denmark)

    Nielsen, Bodil; Savard, G; Richter, Erik

    1990-01-01

    environment a steady state was reached at 30 min. When the subjects were shifted to the hot room, the core temperature and heart rate started to rise and reached values greater than 39 degrees C and near-maximal values, respectively, at the termination of the exercise. The leg blood flow (thermodilution......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...

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

    International Nuclear Information System (INIS)

    Hayashi, Minoru; Kobayashi, Hidenori; Kawano, Hirokazu; Handa, Yuji; Noguchi, Yoshiyuki; Shirasaki, Naoki; Hirose, Satoshi

    1986-01-01

    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)

  1. Transfection of brain capillary endothelial cells in primary culture with defined blood-brain barrier properties.

    Science.gov (United States)

    Burkhart, Annette; Thomsen, Louiza Bohn; Thomsen, Maj Schneider; Lichota, Jacek; Fazakas, Csilla; Krizbai, István; Moos, Torben

    2015-08-07

    Primary brain capillary endothelial cells (BCECs) are a promising tool to study the blood-brain barrier (BBB) in vitro, as they maintain many important characteristics of the BBB in vivo, especially when co-cultured with pericytes and/or astrocytes. A novel strategy for drug delivery to the brain is to transform BCECs into protein factories by genetic modifications leading to secretion of otherwise BBB impermeable proteins into the central nervous system. However, a huge challenge underlying this strategy is to enable transfection of non-mitotic BCECs, taking a non-viral approach. We therefore aimed to study transfection in primary, non-mitotic BCECs cultured with defined BBB properties without disrupting the cells' integrity. Primary cultures of BCECs, pericytes and astrocytes were generated from rat brains and used in three different in vitro BBB experimental arrangements, which were characterised based on a their expression of tight junction proteins and other BBB specific proteins, high trans-endothelial electrical resistance (TEER), and low passive permeability to radiolabeled mannitol. Recombinant gene expression and protein synthesis were examined in primary BCECs. The BCECs were transfected using a commercially available transfection agent Turbofect™ to express the red fluorescent protein HcRed1-C1. The BCECs were transfected at different time points to monitor transfection in relation to mitotic or non-mitotic cells, as indicated by fluorescence-activated cell sorting analysis after 5-and 6-carboxylfluorescein diacetate succinidyl ester incorporation. The cell cultures exhibited important BBB characteristics judged from their expression of BBB specific proteins, high TEER values, and low passive permeability. Among the three in vitro BBB models, co-culturing with BCECs and astrocytes was well suited for the transfection studies. Transfection was independent of cell division and with equal efficacy between the mitotic and non-mitotic BCECs. Importantly

  2. Superficial and deep blood vessel distribution in the frog telencephalon. Reference to morphological brain asymmetries.

    Science.gov (United States)

    Kemali, M; Sada, E; Fiorino, L

    1990-01-01

    Nine frogs of the species "Rana esculenta" were heart perfused with Microfile Silicone Rubber. The frogs were examined both after dissection (cut with a razor blade) to study the superficial blood vessel pattern, and histologically (the Nissl staining method) to study the distribution of the deep blood capillaries. While the superficial blood vary in pattern, the deep capillaries are distributed symmetrically. This finding does not support a correlation between blood vessel pattern and morphological brain asymmetry, at least in the frog, and thus other explanations must be sought to explain brain asymmetry.

  3. Brain-to-Blood Transporters for Endogenous Substrates and Xenobiotics at the Blood-Brain Barrier: An Overview of Biology and Methodology

    Science.gov (United States)

    Terasaki, Tetsuya; Ohtsuki, Sumio

    2005-01-01

    Summary: In the past decade, research into P-glycoprotein involving the blood-brain barrier (BBB) has seen a shift in the concept of the BBB as a structural barrier to that of a functional barrier for xenobiotics and changed simultaneously the strategy for the discovery and development of drugs acting in the CNS. As far as making advances in neurotherapeutics are concerned, the brain-to-blood transport function at the BBB will be one of the most important issues. Knowing the limitations of the in vivo and in vitro methods for BBB efflux research, it is essential to adopt a multidisciplinary approach in investigating the true physiological role of the BBB. Among several methods, the Brain Efflux Index method and the use of conditionally immortalized brain capillary endothelial cell lines, established from transgenic rats harboring temperature-sensitive simian virus 40 large T-antigen gene, are likely to be very useful tools for the BBB efflux transport research. According to our recent findings using these methods, several transporters in the brain capillary endothelial cells appear to play an important role in reducing the brain level of hydrophilic endogenous substrates produced either in the brain or peripheral organs, e.g., neurotransmitters, neuromodulators, metabolites of neurotransmitters, and uremic toxins. It has been reported also that large hydrophilic molecules, such as IgG, apo-transferrin, and amyloid-β peptide, are susceptible to brain-to-blood efflux transport. In the light of the latest findings, we have formed the hypothesis that the BBB acts as a CNS detoxifying system for both endogenous substrates and xenobiotics in the brain. A fuller understanding of the physiological role of BBB efflux transporters will provide rational insights to assist in the development of safer neurotherapeutics. PMID:15717058

  4. Atomistic modeling of the structural components of the blood-brain barrier

    Science.gov (United States)

    Glukhova, O. E.; Grishina, O. A.; Slepchenkov, M. M.

    2015-03-01

    Blood-brain barrier, which is a barrage system between the brain and blood vessels, plays a key role in the "isolation" of the brain of unnecessary information, and reduce the "noise" in the interneuron communication. It is known that the barrier function of the BBB strictly depends on the initial state of the organism and changes significantly with age and, especially in developing the "vascular accidents". Disclosure mechanisms of regulation of the barrier function will develop new ways to deliver neurotrophic drugs to the brain in the newborn. The aim of this work is the construction of atomistic models of structural components of the blood-brain barrier to reveal the mechanisms of regulation of the barrier function.

  5. Effects of Cobalt-60 on Electrical Self-Stimulation of the Brain and Blood Pressure

    National Research Council Canada - National Science Library

    Bruner, Alfred

    1974-01-01

    The effects of 1000 and 2000 rad Cobalt-60 on electrical self- stimulation of subcortical brain areas and blood pressure were investigated to determine whether radiation-induced performance decrement...

  6. 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

  7. Kenyan purple tea anthocyanins ability to cross the blood brain ...

    African Journals Online (AJOL)

    ... demonstration that Kenyan purple tea ACNs can cross the BBB, reinforcing the brain's antioxidant capacity. Hence, there is need to study ACNs as suitable candidates for dietary supplements that could support antioxidant capacity in the brain and have potential to provide neuroprotection in neurodegenerative conditions.

  8. Effects of Resistance Training on Matrix Metalloproteinase Activity in Skeletal Muscles and Blood Circulation During Aging

    Directory of Open Access Journals (Sweden)

    Ivo V. de Sousa Neto

    2018-03-01

    Full Text Available Aging is a complex, multifactorial process characterized by the accumulation of deleterious effects, including biochemical adaptations of the extracellular matrix (ECM. The purpose of this study was to investigate the effects of 12 weeks of resistance training (RT on metalloproteinase 2 (MMP-2 activity in skeletal muscles and, MMP-2 and MMP-9 activity in the blood circulation of young and old rats. Twenty-eight Wistar rats were randomly divided into four groups (n = 7 per group: young sedentary (YS; young trained (YT, old sedentary (OS, and old trained (OT. The stair climbing RT consisted of one training session every 2 other day, with 8–12 dynamic movements per climb. The animals were euthanized 48 h after the end of the experimental period. MMP-2 and MMP-9 activity was measured by zymography. There was higher active MMP-2 activity in the lateral gastrocnemius and flexor digitorum profundus muscles in the OT group when compared to the OS, YS, and YT groups (p ≤ 0.001. Moreover, there was higher active MMP-2 activity in the medial gastrocnemius muscle in the OT group when compared to the YS and YT groups (p ≤ 0.001. The YS group presented lower active MMP-2 activity in the soleus muscle than the YT, OS, OT groups (p ≤ 0.001. With respect to active MMP-2/9 activity in the bloodstream, the OT group displayed significantly reduced activity (p ≤ 0.001 when compared to YS and YT groups. In conclusion, RT up-regulates MMP-2 activity in aging muscles, while down-regulating MMP-2 and MMP-9 in the blood circulation, suggesting that it may be a useful tool for the maintenance of ECM remodeling.

  9. Delayed Onset Muscle Soreness and Perceived Exertion After Blood Flow Restriction Exercise.

    Science.gov (United States)

    Brandner, Christopher R; Warmington, Stuart A

    2017-11-01

    Brandner, CR, and Warmington, SA. Delayed onset muscle soreness and perceived exertion after blood flow restriction exercise. J Strength Cond Res 31(11): 3101-3108, 2017-The purpose of this study was to determine the perceptual responses to resistance exercise with heavy loads (80% 1 repetition maximum [1RM]), light loads (20% 1RM), or light loads in combination with blood flow restriction (BFR). Despite the use of light loads, it has been suggested that the adoption of BFR resistance exercise may be limited because of increases in delayed onset muscle soreness (DOMS) and perceived exertion. Seventeen healthy untrained males participated in this balanced, randomized cross-over study. After 4 sets of elbow-flexion exercise, participants reported ratings of perceived exertion (RPE), with DOMS also recorded for 7 days after each trial. Delayed onset muscle soreness was significantly greater for low-pressure continuous BFR (until 48 hours postexercise) and high-pressure intermittent BFR (until 72 hours postexercise) than for traditional heavy-load resistance exercise and light-load resistance exercise. In addition, RPE was higher for heavy-load resistance exercise and high-pressure intermittent BFR than for low-pressure continuous BFR, with all trials greater than light-load resistance exercise. For practitioners working with untrained participants, this study provides evidence to suggest that to minimize the perception of effort and postexercise muscle soreness associated with BFR resistance exercise, continuous low-pressure application may be more preferential than intermittent high-pressure application. Importantly, these perceptual responses are relatively short-lived (∼2 days) and have previously been shown to subside after a few exercise sessions. Combined with smaller initial training volumes (set × repetitions), this may limit RPE and DOMS to strengthen uptake and adherence and assist in program progression for muscle hypertrophy and gains in strength.

  10. Effect of extraluminal ATP application on vascular tone and blood flow in skeletal muscle: implications for exercise hyperemia

    Science.gov (United States)

    Al-Khazraji, Baraa K.; Mortensen, Stefan P.; Jackson, Dwayne N.; Ellis, Christopher G.; Hellsten, Ylva

    2013-01-01

    During skeletal muscle contractions, the concentration of ATP increases in muscle interstitial fluid as measured by microdialysis probes. This increase is associated with the magnitude of blood flow, suggesting that interstitial ATP may be important for contraction-induced vasodilation. However, interstitial ATP has solely been described to induce vasoconstriction in skeletal muscle. To examine whether interstitial ATP induces vasodilation in skeletal muscle and to what extent this vasoactive effect is mediated by formation of nitric oxide (NO) and prostanoids, three different experimental models were studied. The rat gluteus maximus skeletal muscle model was used to study changes in local skeletal muscle hemodynamics. Superfused ATP at concentrations found during muscle contractions (1–10 μM) increased blood flow by up to 400%. In this model, the underlying mechanism was also examined by inhibition of 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 confirm these findings in humans, ATP was infused into skeletal muscle interstitium of healthy subjects via microdialysis probes and found to increase muscle interstitial concentrations of NO and prostacyclin by ∼60% and ∼40%, respectively. Collectively, these data suggest that a physiologically relevant elevation in interstitial ATP concentrations increases muscle blood flow, indicating that the contraction-induced increase in skeletal muscle interstitial [ATP] is important for exercise hyperemia. The vasodilator effect of ATP application is mediated by NO and prostanoid formation. PMID:23761642

  11. Systems pharmacology and blood-brain barrier functionality in Parkinson's disease

    NARCIS (Netherlands)

    Ravenstijn, Paulien Gerarda Maria

    2009-01-01

    Parkinson’s disease is a progressive neurodegenerative disease, which is composed of many components, each caused by interplay of a number of genetic and nongenetic causes. As the blood-brain barrier (BBB) is a key player in the relationship between plasma and brain pharmacokinetics, the influences

  12. 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

  13. The effect of blood brain barrier modulation on oxime efficacy in nerve agent poisoning (Abstract)

    NARCIS (Netherlands)

    Joosen, M.; Schans, M.J. van der; Dijk, C.G.M. van; Kuijpers, WC.; Wortelboer, H.M.; Helden, H.P.M. van

    2012-01-01

    One of the shortcomings of current treatment of nerve agent poisoning is that oximes hardly penetrate the blood brain barrier (BBB), whereas nerve agents easily do. Enhancing the efficacy of current oximes in the brain, would therefore provide an attractive approach to improve medical

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

    NARCIS (Netherlands)

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

    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

  15. Vascular endothelial growth factor and blood-brain barrier disruption in tuberculous meningitis

    NARCIS (Netherlands)

    van der Flier, Michiel; Hoppenreijs, Sharon; van Rensburg, Anita Janse; Ruyken, Maartje; Kolk, Arend H. J.; Springer, Priscilla; Hoepelman, Andy I. M.; Geelen, Sibyl P. M.; Kimpen, Jan L. L.; Schoeman, Johan F.

    2004-01-01

    Tuberculous meningitis (TBM) is characterized by disruption of the blood-brain barrier (BBB), cerebral edema and increased intracranial pressure (ICP). Vascular endothelial growth factor (VEGF) is a potent vascular permeability factor and a mediator of brain edema. To investigate whether in children

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

    DEFF Research Database (Denmark)

    Gejl, Michael; Lerche, Susanne; Egefjord, Lærke

    2013-01-01

    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...... effect of GLP-1 on glucose transfer in the brain was measured by positron emission tomography (PET) during a hypoglycemic clamp (3 mM plasma glucose) with (18)F-fluoro-2-deoxy-glucose (FDG) as tracer of glucose. In addition, we jointly analyzed cerebrometabolic effects of GLP-1 from the present...

  17. Oatp58Dc contributes to blood-brain barrier function by excluding organic anions from the Drosophila brain.

    Science.gov (United States)

    Seabrooke, Sara; O'Donnell, Michael J

    2013-09-01

    The blood-brain barrier (BBB) physiologically isolates the brain from the blood and, thus, plays a vital role in brain homeostasis. Ion transporters play a critical role in this process by effectively regulating access of chemicals to the brain. Organic anion-transporting polypeptides (Oatps) transport a wide range of amphipathic substrates and are involved in efflux of chemicals across the vertebrate BBB. The anatomic complexity of the vascularized vertebrate BBB, however, creates challenges for experimental analysis of these processes. The less complex structure of the Drosophila BBB facilitates measurement of solute transport. Here we investigate a physiological function for Oatp58Dc in transporting small organic anions across the BBB. We used genetic manipulation, immunocytochemistry, and molecular techniques to supplement a whole animal approach to study the BBB. For this whole animal approach, the traceable small organic anion fluorescein was injected into the hemolymph. This research shows that Oatp58Dc is involved in maintaining a chemical barrier against fluorescein permeation into the brain. Oatp58Dc expression was found in the perineurial and subperineurial glia, as well as in postmitotic neurons. We specifically targeted knockdown of Oatp58Dc expression in the perineurial and subperineurial glia to reveal that Oatp58Dc expression in the perineurial glia is necessary to maintain the barrier against fluorescein influx into the brain. Our results show that Oatp58Dc contributes to maintenance of a functional barrier against fluorescein influx past the BBB into the brain.

  18. Evolutionarily Conserved Roles for Blood-Brain Barrier Xenobiotic Transporters in Endogenous Steroid Partitioning and Behavior

    Directory of Open Access Journals (Sweden)

    Samantha J. Hindle

    2017-10-01

    Full Text Available Summary: Central nervous system (CNS chemical protection depends upon discrete control of small-molecule access by the blood-brain barrier (BBB. Curiously, some drugs cause CNS side-effects despite negligible transit past the BBB. To investigate this phenomenon, we asked whether the highly BBB-enriched drug efflux transporter MDR1 has dual functions in controlling drug and endogenous molecule CNS homeostasis. If this is true, then brain-impermeable drugs could induce behavioral changes by affecting brain levels of endogenous molecules. Using computational, genetic, and pharmacologic approaches across diverse organisms, we demonstrate that BBB-localized efflux transporters are critical for regulating brain levels of endogenous steroids and steroid-regulated behaviors (sleep in Drosophila and anxiety in mice. Furthermore, we show that MDR1-interacting drugs are associated with anxiety-related behaviors in humans. We propose a general mechanism for common behavioral side effects of prescription drugs: pharmacologically challenging BBB efflux transporters disrupts brain levels of endogenous substrates and implicates the BBB in behavioral regulation. : Hindle et al. shed light on the curious finding that some drugs cause behavioral side-effects despite negligible access into the brain. These authors propose a unifying hypothesis that links blood-brain barrier drug transporter function and brain access of circulating steroids to common CNS adverse drug responses. Keywords: drug side effect mechanisms, central nervous system, blood brain barrier, behavior, toxicology, drug transporters, endobiotics, steroid hormones

  19. Anti-transferrin receptor antibody and antibody-drug conjugates cross the blood-brain barrier

    International Nuclear Information System (INIS)

    Friden, P.M.; Walus, L.R.; Musso, G.F.; Taylor, M.A.; Malfroy, B.; Starzyk, R.M.

    1991-01-01

    Delivery of nonlipophilic drugs to the brain is hindered by the tightly apposed capillary endothelial cells that make up the blood-brain barrier. The authors have examined the ability of a monoclonal antibody (OX-26), which recognizes the rat transferrin receptor, to function as a carrier for the delivery of drugs across the blood-brain barrier. This antibody, which was previously shown to bind preferentially to capillary endothelial cells in the brain after intravenous administration, labels the entire cerebrovascular bed in a dose-dependent manner. The initially uniform labeling of brain capillaries becomes extremely punctate ∼ 4 hr after injection, suggesting a time-dependent sequestering of the antibody. Capillary-depletion experiments, in which the brain is separated into capillary and parenchymal fractions, show a time-dependent migration of radiolabeled antibody from the capillaries into the brain parenchyma, which is consistent with the transcytosis of compounds across the blood-brain barrier. Antibody-methotrexate conjugates were tested in vivo to assess the carrier ability of this antibody. Immunohistochemical staining for either component of an OX-26-methotrexate conjugate revealed patterns of cerebrovascular labeling identical to those observed with the unaltered antibody. Accumulation of radiolabeled methotrexate in the brain parenchyma is greatly enhanced when the drug is conjugated to OX-26

  20. Coherence and Sequential Information in Brain and Muscle Signals during Muscle Fatigue

    Science.gov (United States)

    Yao, Bing; Yue, Guang; Brown, Robert; Liu, Jingzhi

    2003-10-01

    In this study we investigated coherence and sequential orders among EEG signals of different cortical locations and between EEG and EMG signals. Subjects performed 200 intermittent handgrip contractions at 100contraction level. Each contraction lasted 2 s, followed by a 5-s rest. EEG data were recorded from the scalp along with handgrip force and EMG signals. Coherence among EEG signals of different channels and between EEG and EMG signals were computed. Phase spectrum was obtained by calculating the phase difference between any two signals. Time lag between two signals was estimated by measuring the slope of the phase in the frequency range of interest. The results showed that: (1) Coherence among EEG signals from different motor-related cortical areas showed slight decrease during muscle fatigue. (2) Coherence between EEG and EMG signals became lower when fatigue was more severe. (3) Fatigue-related changes in phase and time lag were observed, indicating fatigue effects on the speed of responses in the corticomuscular system.

  1. Smooth Muscle Endothelin B Receptors Regulate Blood Pressure but Not Vascular Function or Neointimal Remodeling.

    Science.gov (United States)

    Miller, Eileen; Czopek, Alicja; Duthie, Karolina M; Kirkby, Nicholas S; van de Putte, Elisabeth E Fransen; Christen, Sibylle; Kimmitt, Robert A; Moorhouse, Rebecca; Castellan, Raphael F P; Kotelevtsev, Yuri V; Kuc, Rhoda E; Davenport, Anthony P; Dhaun, Neeraj; Webb, David J; Hadoke, Patrick W F

    2017-02-01

    The role of smooth muscle endothelin B (ET B ) receptors in regulating vascular function, blood pressure (BP), and neointimal remodeling has not been established. Selective knockout mice were generated to address the hypothesis that loss of smooth muscle ET B receptors would reduce BP, alter vascular contractility, and inhibit neointimal remodeling. ET B receptors were selectively deleted from smooth muscle by crossing floxed ET B mice with those expressing cre-recombinase controlled by the transgelin promoter. Functional consequences of ET B deletion were assessed using myography. BP was measured by telemetry, and neointimal lesion formation induced by femoral artery injury. Lesion size and composition (day 28) were analyzed using optical projection tomography, histology, and immunohistochemistry. Selective deletion of ET B was confirmed by genotyping, autoradiography, polymerase chain reaction, and immunohistochemistry. ET B -mediated contraction was reduced in trachea, but abolished from mesenteric veins, of knockout mice. Induction of ET B -mediated contraction in mesenteric arteries was also abolished in these mice. Femoral artery function was unaltered, and baseline BP modestly elevated in smooth muscle ET B knockout compared with controls (+4.2±0.2 mm Hg; P<0.0001), but salt-induced and ET B blockade-mediated hypertension were unaltered. Circulating endothelin-1 was not altered in knockout mice. ET B -mediated contraction was not induced in femoral arteries by incubation in culture medium or lesion formation, and lesion size was not altered in smooth muscle ET B knockout mice. In the absence of other pathology, ET B receptors in vascular smooth muscle make a small but significant contribution to ET B -dependent regulation of BP. These ET B receptors have no effect on vascular contraction or neointimal remodeling. © 2016 The Authors.

  2. Hypertonic/hyperoncotic solution attenuate blood-brain barrier breakdown and brain pathology in whole body hyperthermia rats.

    Science.gov (United States)

    Liu, Youtan; Tang, Jing; Ye, Jionxian; Zhan, Lifang; Huang, Shaonong; Wang, Tingting; Gu, Miaoning

    2011-01-01

    This study was designed to investigate the effects of hypertonic/hyperoncotic solution on blood-brain barrier damage, brain edema and morphological changes of rats during whole body hyperthermia. 90 adult male Sprague-Dawley rats were randomized into 5 groups: Control group (a room temperature for 4 hours); Whole body hyperthermia group without solution treatment; Whole body hyperthermia group with Ringer's solution treatment; Whole body hyperthermia group with hydroxyethyl starch and Ringer's solution treatment; Whole body hyperthermia group with Hypertonic/hyperoncotic solution treatment. All rats except those of control group were housed in a heated container and maintained at 36°C for 3 hours until the rectal temperature reached 41-42°C. Corresponding solutions were administered intravenously at the beginning of whole body hyperthermia within 30 minutes as designed. Following whole body hyperthermia, rats were subsequently cooled down for 1h. Evans blue was administered intravenously when the rectal temperature was cooled down to 37°C. The leakage of Evans blue-albumin and water content of brain were calculated and morphological changes were investigated. In group with hypertonic/hyperoncotic solution treatment, brain water content and the leakage of Evans blue-albumin were the lowest among the four whole body hyperthermia groups. Compared with the other three whole body hyperthermia groups, in which profound to moderate damages to blood-brain barrier and brain tissue and cells were found, there were only slight morphological changes in the group with hypertonic/hyperoncotic solutionon treatment. Treatment with hypertonic/hyperoncotic solution appeared to attenuate the injury to blood-brain barrier and reduce brain edema and cell morphological changes in whole body hyperthermia rats.

  3. Targeting transferrin receptors at the blood-brain barrier improves the uptake of immunoliposomes and subsequent cargo transport into the brain parenchyma

    DEFF Research Database (Denmark)

    Johnsen, Kasper B.; Burkhart, Annette; Melander, Fredrik

    2017-01-01

    Drug delivery to the brain is hampered by the presence of the blood-brain barrier, which excludes most molecules from freely diffusing into the brain, and tightly regulates the active transport mechanisms that ensure sufficient delivery of nutrients to the brain parenchyma. Harnessing the possibi......Drug delivery to the brain is hampered by the presence of the blood-brain barrier, which excludes most molecules from freely diffusing into the brain, and tightly regulates the active transport mechanisms that ensure sufficient delivery of nutrients to the brain parenchyma. Harnessing...... cargo uptake in the brain endothelium and subsequent cargo transport into the brain. These findings suggest that transferrin receptor-targeting is a relevant strategy of increasing drug exposure to the brain....

  4. 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...... the wall of brain capillaries. The restrictive nature of the BBB is due to the presence of tight junctions, which seal the paracellular space, a low number of endocytotic vesicles and the presence of efflux transporters, resulting in a very tight layer. Ischemic insult and the subsequent reperfusion...

  5. Contrast-enhanced ultrasonography to assess blood perfusion of skeletal muscles in normal dogs

    Science.gov (United States)

    OH, Juyeon; JEON, Sunghoon; CHOI, Jihye

    2015-01-01

    This study evaluated perfusion of skeletal muscle using contrast enhanced ultrasonography in humerus, radius, femur and tibia in normal dogs. Contrast enhanced ultrasonography for each region was performed after injecting 0.5 mL and 1 mL of contrast medium (SonoVue) in every dog. Blood perfusion was assessed quantitatively by measuring the peak intensity, time to the peak intensity and area under the curve from the time–intensity curve. Vascularization in skeletal muscle was qualitatively graded with a score of 0–3 according to the number of vascular signals. A parabolic shape of time–intensity curve was observed from muscles in normal dogs, and time to the peak intensity, the peak intensity and area under the curve of each muscle were not significantly different according to the appendicular regions examined and the dosage of contrast agent administered. This study reports that feasibility of contrast enhanced ultrasonography for assessment of the muscular perfusion in canine appendicular regions. PMID:25754794

  6. The Role of Neck Muscle Activities on the Risk of Mild Traumatic Brain Injury in American Football.

    Science.gov (United States)

    Jin, Xin; Feng, Zhaoying; Mika, Valerie; Li, Haiyan; Viano, David C; Yang, King H

    2017-10-01

    Concussion, or mild traumatic brain injury (mTBI), is frequently associated with sports activities. It has generally been accepted that neck strengthening exercises are effective as a preventive strategy for reducing sports-related concussion risks. However, the interpretation of the link between neck strength and concussion risks remains unclear. In this study, a typical helmeted head-to-head impact in American football was simulated using the head and neck complex finite element (FE) model. The impact scenario selected was previously reported in lab-controlled incident reconstructions from high-speed video footages of the National Football League using two head-neck complexes taken from Hybrid III dummies. Four different muscle activation strategies were designed to represent no muscle response, a reactive muscle response, a pre-activation response, and response due to stronger muscle strength. Head kinematics and various head/brain injury risk predictors were selected as response variables to compare the effects of neck muscles on the risk of sustaining the concussion. Simulation results indicated that active responses of neck muscles could effectively reduce the risk of brain injury. Also, anticipatory muscle activation played a dominant role on impact outcomes. Increased neck strength can decrease the time to compress the neck and its effects on reducing brain injury risks need to be further studied.

  7. Functional Imaging of Dolphin Brain Metabolism and Blood Flow

    National Research Council Canada - National Science Library

    Ridgway, Sam; Finneran, James; Carder, Don; Keogh, Mandy; Van Bonn, William; Smith, Cynthia; Scadeng, Miriam; Dubowitz, David; Mattrey, Robert; Hoh, Carl

    2006-01-01

    This report documents the first use of magnetic resonance images (MRls) of living dolphins to register functional brain scans, allowing for the exploration of potential mechanisms of unihemispheric sleep...

  8. Traumatic Brain Injury Induces Genome-Wide Transcriptomic, Methylomic, and Network Perturbations in Brain and Blood Predicting Neurological Disorders

    Directory of Open Access Journals (Sweden)

    Qingying Meng

    2017-02-01

    Full Text Available The complexity of the traumatic brain injury (TBI pathology, particularly concussive injury, is a serious obstacle for diagnosis, treatment, and long-term prognosis. Here we utilize modern systems biology in a rodent model of concussive injury to gain a thorough view of the impact of TBI on fundamental aspects of gene regulation, which have the potential to drive or alter the course of the TBI pathology. TBI perturbed epigenomic programming, transcriptional activities (expression level and alternative splicing, and the organization of genes in networks centered around genes such as Anax2, Ogn, and Fmod. Transcriptomic signatures in the hippocampus are involved in neuronal signaling, metabolism, inflammation, and blood function, and they overlap with those in leukocytes from peripheral blood. The homology between genomic signatures from blood and brain elicited by TBI provides proof of concept information for development of biomarkers of TBI based on composite genomic patterns. By intersecting with human genome-wide association studies, many TBI signature genes and network regulators identified in our rodent model were causally associated with brain disorders with relevant link to TBI. The overall results show that concussive brain injury reprograms genes which could lead to predisposition to neurological and psychiatric disorders, and that genomic information from peripheral leukocytes has the potential to predict TBI pathogenesis in the brain.

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

    Science.gov (United States)

    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 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.

  10. Aluminum complexing enhances amyloid beta protein penetration of blood-brain barrier.

    Science.gov (United States)

    Banks, William A; Niehoff, Michael L; Drago, Denise; Zatta, Paolo

    2006-10-20

    A significant co-morbidity of Alzheimer's disease and cerebrovascular impairment suggests that cerebrovascular dysregulation is an important feature of dementia. Amyloid beta protein (Abeta), a relevant risk factor in Alzheimer's disease, has neurotoxic properties and is thought to play a critical role in the cognitive impairments. Previously, we demonstrated that the 42mer of Abeta (Abeta42) complexed with aluminum (Al-Abeta42) is much more cytotoxic than non-complexed Abeta42. The level of Abeta in the brain is a balance between synthesis, degradation, and fluxes across the blood-brain barrier (BBB). In the present paper, we determined whether complexing with aluminum affected the ability of radioactively iodinated Abeta to cross the in vivo BBB. We found that the rates of uptake of Al-Abeta42 and Abeta42 were similar, but that Al-Abeta42 was sequestered by brain endothelial cells much less than Abeta42 and so more readily entered the parenchymal space of the brain. Al-Abeta42 also had a longer half-life in blood and had increased permeation at the striatum and thalamus. Brain-to-blood transport was similar for Al-Abeta42 and Abeta42. In conclusion, complexing with aluminum affects some aspects of blood-to-brain permeability so that Al-Abeta42 would have more ready access to brain cells than Abeta42.

  11. Increased brainstem perfusion, but no blood-brain barrier disruption, during attacks of migraine with aura

    DEFF Research Database (Denmark)

    Hougaard, Anders; Amin, Faisal M; Christensen, Casper E

    2017-01-01

    symptoms are related to the headache phase of migraine. Animal studies suggest that cortical spreading depression, the likely mechanism of migraine aura, causes disruption of the blood-brain barrier and noxious stimulation of trigeminal afferents leading to activation of brainstem nuclei and triggering...... of migraine headache. We used the sensitive and validated technique of dynamic contrast-enhanced high-field magnetic resonance imaging to simultaneously investigate blood-brain barrier permeability and tissue perfusion in the brainstem (at the level of the lower pons), visual cortex, and brain areas......-free day. The mean time from attack onset to scanning was 7.6 h. We found increased brainstem perfusion bilaterally during migraine with aura attacks. Perfusion also increased in the visual cortex and posterior white matter following migraine aura. We found no increase in blood-brain barrier permeability...

  12. Brain uptake of deltamethrin in rats as a function of plasma protein binding and blood-brain barrier maturation.

    Science.gov (United States)

    Amaraneni, Manoj; Pang, Jing; Mortuza, Tanzir B; Muralidhara, Srinivasa; Cummings, Brian S; White, Catherine A; Vorhees, Charles V; Zastre, Jason; Bruckner, James V

    2017-09-01

    Pyrethroids, including permethrin and deltamethrin (DLM), are very widely used of insecticides. It was hypothesized that lower plasma binding and increased blood-brain barrier (BBB) penetration of DLM in immature rats contribute to the higher brain concentrations of DLM and more pronounced neurotoxicity reported in this age group. The left brain of anesthetized adult rats was perfused for 2min via a carotid artery with 1μM 14 C-DLM in: 2-5% human serum albumin (HSA); plasma from adult and 15- and 21-d-old rats; and plasma from human donors of: birth-1 week, 1-4 weeks, 4 weeks-1 year, 1-3 years and adults. The fraction of DLM bound and brain uptake of DLM did not vary significantly with the HSA concentration nor with the age of rat or human plasma donors. One, 10 and 50μM 14 C-DLM were perfused into the left-brain of anesthetized adult, 15- and 21-d-old rats. DLM deposition in the brain was linear over this range of concentrations and inversely related to age. The results of this investigation indicate that increased BBB permeability in the youngest rats enhances brain deposition of the insecticide. Plasma protein binding of DLM in immature rats and humans is not sufficiently diminished to impact its brain uptake. Published by Elsevier B.V.

  13. Impaired Muscle Oxygenation and Elevated Exercise Blood Pressure in Hypertensive Patients: Links With Vascular Stiffness.

    Science.gov (United States)

    Dipla, Konstantina; Triantafyllou, Areti; Koletsos, Nikolaos; Papadopoulos, Stavros; Sachpekidis, Vasileios; Vrabas, Ioannis S; Gkaliagkousi, Eugenia; Zafeiridis, Andreas; Douma, Stella

    2017-08-01

    This study examined in vivo (1) skeletal muscle oxygenation and microvascular function, at rest and during handgrip exercise, and (2) their association with macrovascular function and exercise blood pressure (BP), in newly diagnosed, never-treated patients with hypertension and normotensive individuals. Ninety-one individuals (51 hypertensives and 40 normotensives) underwent office and 24-hour ambulatory BP, arterial stiffness, and central aortic BP assessment, followed by a 5-minute arterial occlusion and a 3-minute submaximal handgrip exercise. Changes in muscle oxygenated and deoxygenated hemoglobin and tissue oxygen saturation were continuously monitored by near-infrared spectroscopy and beat-by-beat BP by Finapres. Hypertensives had higher ( P exercising at the same submaximal intensity, hypertensives required a significantly greater ( P exercise. © 2017 American Heart Association, Inc.

  14. Cerebral blood flow of the non-affected brain in patients with malignant brain tumors as studied by SPECT

    International Nuclear Information System (INIS)

    Araki, Yuzo; Imao, Yukinori; Hirata, Toshifumi; Ando, Takashi; Sakai, Noboru; Yamada, Hiroshi

    1990-01-01

    In 40 patients (age range, 20-69 years) receiving radiation and chemotherapy for brain tumors, the mean cerebral blood flow (mCBF) in the non-affected area has been examined by single photon emission CT (SPECT) with Xe-133. Forty volunteers (age range, 25-82 years) served as controls. Although mCBF during external irradiation was transiently increased, it was significantly decreased at 3 months after beginning of external irradiation compared with that in the control group. Factors responsible for the decrease in mCBF were radiation doses, lesion volume, the degree of cerebral atrophy, and age; this was more pronounced when chemotherapy such as ACNU was combined with radiation. A decreased mCBF was independent of intraoperative radiation combined with external radiation and either local or whole brain irradiation. SPECT with Xe-133 was useful in determining minute changes in cerebral blood flow that precedes parenchymal brain damage. (N.K.)

  15. The protective influence of the locus ceruleus on the blood-brain barrier

    International Nuclear Information System (INIS)

    Harik, S.I.; McGunigal, T. Jr.

    1984-01-01

    The functions of the putative noradrenergic innervation of cerebral microvessels from the nucleus locus ceruleus remain ambiguous. Although most evidence indicates that such innervation does not have a major role in the control of cerebral blood flow, there are increasing indications that it modulates transport and permeability functions of the blood-brain barrier. In this study we investigated the effect of unilateral chemical lesioning of the locus ceruleus on the leakage of radioiodinated human serum albumin across the blood-brain barrier. Experiments were performed in awake and restrained rats under steady-state conditions and during drug-induced systemic arterial hypertension, and in anesthetized and paralyzed rats during bicuculline-induced seizures. Both hypertension and seizures are known to be associated with increased leakage of macromolecules across the blood-brain barrier. Albumin leakage into norepinephrine-depleted forebrain structures ipsilateral to the locus ceruleus lesion was compared with that of the contralateral side. There were no side-to-side differences in blood-brain barrier permeability to albumin under steady-state conditions, the stress of restraint, or angiotensin-induced hypertension, or after isoproterenol administration. Norepinephrine-induced hypertension and seizures, however, caused significant increases in albumin leakage into forebrain structures ipsilateral to the lesion. These results suggest that noradrenergic innervation of cerebral microvessels from the locus ceruleus helps preserve the integrity of the blood-brain barrier during pathophysiological states associated with hypertension and increased circulating catecholamines

  16. Effects of Chronic Blood-Flow Restriction Exercise on Skeletal Muscle Size and Myogenic Satellite Cell Expression

    DEFF Research Database (Denmark)

    Aagaard, Per; Jacobsen, Mikkel; Jensen, Kasper Y.

    2016-01-01

    of continued sports activity, resulting in visible hypertrophy of his left leg. AIM: To study the effect of chronic blood-flow restricted (BFR) exercise conditions on skeletal muscle size and myogenic satellite cell (SC) expression in an arterio-venous shunt patient. METHODS: Muscle biopsies were obtained from......-regulation in myogenic satellite cell activity within all stages of the cell cycle, which was accompanied by substantial muscle hypertrophy. Specifically, muscle fiber cross-sectional area (40%) and myonuclei number (15%) were elevated in the affected leg, together with an elevated myonuclear domain (20%). This single......-case study confirms previous result from our Lab demonstrating that blood-flow restricted muscle exercise leads to a marked activation of myogenic SCs, upregulated myonuclei number and marked myofiber hypertrophy....

  17. Multiple blood-brain barrier transport mechanisms limit bumetanide accumulation, and therapeutic potential, in the mammalian brain.

    Science.gov (United States)

    Römermann, Kerstin; Fedrowitz, Maren; Hampel, Philip; Kaczmarek, Edith; Töllner, Kathrin; Erker, Thomas; Sweet, Douglas H; Löscher, Wolfgang

    2017-05-01

    There is accumulating evidence that bumetanide, which has been used over decades as a potent loop diuretic, also exerts effects on brain disorders, including autism, neonatal seizures, and epilepsy, which are not related to its effects on the kidney but rather mediated by inhibition of the neuronal Na-K-Cl cotransporter isoform NKCC1. However, following systemic administration, brain levels of bumetanide are typically below those needed to inhibit NKCC1, which critically limits its clinical use for treating brain disorders. Recently, active efflux transport at the blood-brain barrier (BBB) has been suggested as a process involved in the low brain:plasma ratio of bumetanide, but it is presently not clear which transporters are involved. Understanding the processes explaining the poor brain penetration of bumetanide is needed for developing strategies to improve the brain delivery of this drug. In the present study, we administered probenecid and more selective inhibitors of active transport carriers at the BBB directly into the brain of mice to minimize the contribution of peripheral effects on the brain penetration of bumetanide. Furthermore, in vitro experiments with mouse organic anion transporter 3 (Oat3)-overexpressing Chinese hamster ovary cells were performed to study the interaction of bumetanide, bumetanide derivatives, and several known inhibitors of Oats on Oat3-mediated transport. The in vivo experiments demonstrated that the uptake and efflux of bumetanide at the BBB is much more complex than previously thought. It seems that both restricted passive diffusion and active efflux transport, mediated by Oat3 but also organic anion-transporting polypeptide (Oatp) Oatp1a4 and multidrug resistance protein 4 explain the extremely low brain concentrations that are achieved after systemic administration of bumetanide, limiting the use of this drug for targeting abnormal expression of neuronal NKCC1 in brain diseases. Copyright © 2017 Elsevier Ltd. All rights

  18. Brain Abnormalities in Congenital Fibrosis of the Extraocular Muscles Type 1: A Multimodal MRI Imaging Study.

    Science.gov (United States)

    Miao, Wen; Man, Fengyuan; Wu, Shaoqin; Lv, Bin; Wang, Zhenchang; Xian, Junfang; Sabel, Bernhard A; He, Huiguang; Jiao, Yonghong

    2015-01-01

    To explore the possible brain structural and functional alterations in congenital fibrosis of extraocular muscles type 1 (CFEOM1) patients using multimodal MRI imaging. T1-weighted, diffusion tensor images and functional MRI data were obtained from 9 KIF21A positive patients and 19 age- and gender-matched healthy controls. Voxel based morphometry and tract based spatial statistics were applied to the T1-weighted and diffusion tensor images, respectively. Amplitude of low frequency fluctuations and regional homogeneity were used to process the functional MRI data. We then compared these multimodal characteristics between CFEOM1 patients and healthy controls. Compared with healthy controls, CFEOM1 patients demonstrated increased grey matter volume in bilateral frontal orbital cortex and in the right temporal pole. No diffusion indices changes were detected, indicating unaffected white matter microstructure. In addition, from resting state functional MRI data, trend of amplitude of low-frequency fluctuations increases were noted in the right inferior parietal lobe and in the right frontal cortex, and a trend of ReHo increase (pabnormality of extraocular muscles and their innervating nerves. Future studies should consider the possible correlations between brain morphological/functional findings and clinical data, especially pertaining to eye movements, to obtain more precise answers about the role of brain area changes and their functional consequence in CFEOM1.

  19. SDF-1 controls the muscle and blood vessel formation of the somite.

    Science.gov (United States)

    Abduelmula, Aisha; Huang, Ruijin; Pu, Qin; Tamamura, Hirokazu; Morosan-Puopolo, Gabriela; Brand-Saberi, Beate

    2016-01-01

    Stromal-cell-derived factor-1 (SDF-1), the only ligand of the chemokine receptor CXCR4, is involved in skeletal muscle development. However, its role in the proliferation, differentiation and migration of somite cells is not well understood. Here, we investigated its function during somite development in chicken embryos by using gain-of-function and loss-of-function experiments. Overexpression of SDF-1 was performed by electroporating SDF-1 constructs into the ventrolateral part of the somite, or by injecting SDF-1-expressing cells into the somites of stages HH14-16 chicken embryos. We found that enhanced SDF-1 signaling induced cell proliferation in the somite. This resulted in an increase in number of both myotomal and endothelial cells. In contrast, inhibition of SDF-1/CXCR4 signaling led to a reduction of myotomal cells. Injection of SDF-1 producing cells into the somite induced ectopic localization of myotomal cells in the sclerotome. Although many SDF-1-expressing somite cells colonized the limb, only a few of them developed into muscle cells. This resulted in a reduction of the limb muscle mass. This means that most myogenic progenitors were stopped on their migration towards the limb due to the high concentration of the SDF-1 signal in the somite. Most of the SDF-1-expressing somite cells found in the limb were of endothelial cell fate and they contributed to the increase in limb blood vessels. These results reveal that SDF-1 promotes the proliferation of both myogenic and angiogenic progenitor cells of the somite and controls myotome formation. Furthermore, SDF-1 controls muscle and blood vessel formation in the limb in different ways.

  20. Impact of Blood Flow Restriction Exercise on Muscle Fatigue Development and Recovery.

    Science.gov (United States)

    Husmann, Florian; Mittlmeier, Thomas; Bruhn, Sven; Zschorlich, Volker; Behrens, Martin

    2018-03-01

    The present study was designed to provide mechanistic insight into the time course and etiology of muscle fatigue development and recovery during and after low-intensity exercise when it is combined with blood flow restriction (BFR). Seventeen resistance-trained males completed four sets of low-intensity isotonic resistance exercise under two experimental conditions: knee extension exercise (i) with BFR and (ii) without BFR (CON). Neuromuscular tests were performed before, during (immediately after each set of knee extension exercise), and 1, 2, 4, and 8 min after each experimental condition. Maximal voluntary torque, quadriceps twitch torque in response to paired electrical stimuli at 10 Hz (PS10) and 100 Hz (PS100), PS10·PS100 ratio as an index of low-frequency fatigue, and voluntary activation were measured under isometric conditions. Perceptual and EMG data were recorded during each exercise condition. After the first set of exercise, BFR induced significantly greater reductions in maximal voluntary torque, PS100, and PS10·PS100 ratio compared with CON. These parameters progressively declined throughout the BFR protocol but recovered substantially within 2 min postexercise when blood flow was restored. Neither a progressive decline in the course of the exercise protocol nor a substantial recovery of these parameters occurred during and after CON. Only at exercise termination, voluntary activation differed significantly between BFR and CON with greater reductions during BFR. At the early stage of exercise, BFR exacerbated the development of muscle fatigue mainly due to a pronounced impairment in contractile function. Despite the high level of muscle fatigue during BFR exercise, the effect of BFR on muscle fatigue was diminished after 2 min of reperfusion, suggesting that BFR has a strong but short-lasting effect on neuromuscular function.

  1. 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...... evidence of such a limitation was obtained using the single injection technique of Crone (1963). 14-C-labelled sucrose was used as intravascular reference substance and tritium-labelled water as test substance. The non-exchanging (transmitted) fraction, I-E equals T, of labelled water during a single...... 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....

  2. Exercise training improves blood flow to contracting skeletal muscle of older men via enhanced cGMP signaling

    DEFF Research Database (Denmark)

    Piil, Peter Bergmann; Smith Jørgensen, Tue; Egelund, Jon

    2018-01-01

    -induced adaptations in the regulation of skeletal muscle blood flow and oxidative metabolism during exercise in aging humans. We measured leg hemodynamics and oxidative metabolism during exercise engaging the knee-extensor muscles in young (n=15, 25 ± 1 years) and older (n=15, 72 ± 1 years) subjects before and after...... group; however, these effects of PDE5 inhibition were not detected after training. These findings suggest a role for enhanced cGMP signaling in the training-induced improvement of regulation of blood flow in contracting skeletal muscle of older men.......Physical activity has the potential to offset age-related impairments in the regulation of blood flow and O2 delivery to the exercising muscles; however, the mechanisms underlying this effect of physical activity remain poorly understood. The present study examined the role of cGMP in training...

  3. Blood flow after contraction and cuff occlusion is reduced in subjects with muscle soreness after eccentric exercise.

    Science.gov (United States)

    Souza-Silva, E; Christensen, S W; Hirata, R P; Larsen, R G; Graven-Nielsen, T

    2018-01-01

    Delayed onset muscle soreness (DOMS) occurs within 1-2 days after eccentric exercise, but the mechanism mediating hypersensitivity is unclear. This study hypothesized that eccentric exercise reduces the blood flow response following muscle contractions and cuff occlusion, which may result in accumulated algesic substances being a part of the sensitization in DOMS. Twelve healthy subjects (five women) performed dorsiflexion exercise (five sets of 10 repeated eccentric contractions) in one leg, while the contralateral leg was the control. The maximal voluntary contraction (MVC) of the tibialis anterior muscle was recorded. Blood flow was assessed by ultrasound Doppler on the anterior tibialis artery (ATA) and within the anterior tibialis muscle tissue before and immediately after 1-second MVC, 5-seconds MVC, and 5-minutes thigh cuff occlusion. Pressure pain thresholds (PPTs) were recorded on the tibialis anterior muscle. All measures were done bilaterally at day 0 (pre-exercise), day 2, and day 6 (post-exercise). Subjects scored the muscle soreness on a Likert scale for 6 days. Eccentric exercise increased Likert scores at day 1 and day 2 compared with day 0 (Pcontraction/occlusion blood flow (~16%, Peccentric contractions decreased vessel diameter, impaired the blood flow response, and promoted hyperalgesia. Thus, the results suggest that the blood flow reduction may be involved in the increased pain response after eccentric exercise. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

    International Nuclear Information System (INIS)

    Gur, R.E.

    1984-01-01

    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

  5. 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.

  6. Synchronized reconstitution of muscle fibers, peripheral nerves and blood vessels by murine skeletal muscle-derived CD34(-)/45 (-) cells.

    Science.gov (United States)

    Tamaki, Tetsuro; Okada, Yoshinori; Uchiyama, Yoshiyasu; Tono, Kayoko; Masuda, Maki; Wada, Mika; Hoshi, Akio; Akatsuka, Akira

    2007-10-01

    In order to establish the practical isolation and usage of skeletal muscle-derived stem cells (MDSCs), we determined reconstitution capacity of CD34(-)/CD45(-) (Sk-DN) cells as a candidate somatic stem cell source for transplantation. Sk-DN cells were enzymatically isolated from GFP transgenic mice (C57/BL6N) skeletal muscle and sorted using fluorescence activated cell sorting (FACS), and expanded by collagen gel-based cell culture with bFGF and EGF. The number of Sk-DN cells was small after sorting (2-8 x 10(4)); however, the number increased 10-20 fold (2-16 x 10(5)) after 6 days of expansion culture, and the cells maintained immature state and multipotency, expressing mRNAs for mesodermal and ectodermal cell lineages. Transplantation of expanded Sk-DN cells into the severe muscle damage model (C57/BL6N wild-type) resulted in the synchronized reconstitution of blood vessels, peripheral nerves and muscle fibers following significant recovery of total muscle mass (57%) and contractile function (55%), whereas the non-cell-transplanted control group showed around 20% recovery in both factors. These reconstitution capacities were supported by the intrinsic plasticity of Sk-DN cells that can differentiate into muscular (skeletal muscle), vascular (pericyte, endothelial cell and smooth muscle) and peripheral nerve (Schwann cells and perineurium) cell lineages that was revealed by transplantation to non-muscle tissue (beneath renal capsule) and fluorescence in situ hybridization (FISH) analysis.

  7. Lipophilic manganese porphyrin crosses blood-brain barrier

    International Nuclear Information System (INIS)

    Nelson, J.A.; Cegnar, J.; Spence, A.M.; Richards, T.L.; Golden, R.N.; Muzi, M.

    1987-01-01

    Most reports on manganese porphyrins as MR imaging contrast agents have focused on a water-soluble compound, Mn-TPPS4. Phototherapy researchers have noted that lipophilic components of hematoporphyrin derivative sensitize normal brain tissue to light-stimulated photodestruction. This observation suggests that a lipophilic paramagnetic agent might be useful for brain contrast enhancement. The current experiments were designed to test the MR imaging effects of a lipid-soluble compound, Mn-mesoporphyrin. An intravenous injection of 0.05 μmoles/kg was administered to rats with a well-characterized astrocytic glioma implanted into the right cerebral hemisphere. MR imaging experiments performed at 2 T on a General Electric CSI-II system revealed T1 relaxation shortening in both normal brain and tumor. Delayed images at 24 hours revealed persistent selective contrast agent enhancement at the gross tumor site

  8. Neuroimmune Axes of the Blood-Brain Barriers and Blood-Brain Interfaces: Bases for Physiological Regulation, Disease States, and Pharmacological Interventions.

    Science.gov (United States)

    Erickson, Michelle A; Banks, William A

    2018-04-01

    Central nervous system (CNS) barriers predominantly mediate the immune-privileged status of the brain, and are also important regulators of neuroimmune communication. It is increasingly appreciated that communication between the brain and immune system contributes to physiologic processes, adaptive responses, and disease states. In this review, we discuss the highly specialized features of brain barriers that regulate neuroimmune communication in health and disease. In section I , we discuss the concept of immune privilege, provide working definitions of brain barriers, and outline the historical work that contributed to the understanding of CNS barrier functions. In section II , we discuss the unique anatomic, cellular, and molecular characteristics of the vascular blood-brain barrier (BBB), blood-cerebrospinal fluid barrier, and tanycytic barriers that confer their functions as neuroimmune interfaces. In section III , we consider BBB-mediated neuroimmune functions and interactions categorized as five neuroimmune axes: disruption, responses to immune stimuli, uptake and transport of immunoactive substances, immune cell trafficking, and secretions of immunoactive substances. In section IV , we discuss neuroimmune functions of CNS barriers in physiologic and disease states, as well as pharmacological interventions for CNS diseases. Throughout this review, we highlight many recent advances that have contributed to the modern understanding of CNS barriers and their interface functions. Copyright © 2018 by The Author(s).

  9. Effects of exercise training on calf muscle oxygen extraction and blood flow in patients with peripheral artery disease.

    Science.gov (United States)

    Baker, Wesley B; Li, Zhe; Schenkel, Steven S; Chandra, Malavika; Busch, David R; Englund, Erin K; Schmitz, Kathryn H; Yodh, Arjun G; Floyd, Thomas F; Mohler, Emile R

    2017-12-01

    We employed near-infrared optical techniques, diffuse correlation spectroscopy (DCS), and frequency-domain near-infrared spectroscopy (FD-NIRS) to test the hypothesis that supervised exercise training increases skeletal muscle microvascular blood flow and oxygen extraction in patients with peripheral artery disease (PAD) who experience claudication. PAD patients ( n = 64) were randomly assigned to exercise and control groups. Patients in the exercise group received 3 mo of supervised exercise training. Calf muscle blood flow and oxygen extraction were optically monitored before, during, and after performance of a graded treadmill protocol at baseline and at 3 mo in both groups. Additionally, measurements of the ankle-brachial index (ABI) and peak walking time (PWT) to maximal claudication were made during each patient visit. Supervised exercise training was found to increase the maximal calf muscle blood flow and oxygen extraction levels during treadmill exercise by 29% (13%, 50%) and 8% (1%, 12%), respectively [ P group population were significantly higher than corresponding changes in the control group ( P training also increased PWT by 49% (18%, 101%) ( P = 0.01). However, within statistical error, the ABI, resting calf muscle blood flow and oxygen extraction, and the recovery half-time for hemoglobin\\myoglobin desaturation following cessation of maximal exercise were not altered by exercise training. The concurrent monitoring of both blood flow and oxygen extraction with the hybrid DCS/FD-NIRS instrument revealed enhanced muscle oxidative metabolism during physical activity from exercise training, which could be an underlying mechanism for the observed improvement in PWT. NEW & NOTEWORTHY We report on noninvasive optical measurements of skeletal muscle blood flow and oxygen extraction dynamics before/during/after treadmill exercise in peripheral artery disease patients who experience claudication. The measurements tracked the effects of a 3-mo supervised

  10. 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.

  11. Development of the blood-brain barrier: a historical point of view.

    Science.gov (United States)

    Ribatti, Domenico; Nico, Beatrice; Crivellato, Enrico; Artico, Marco

    2006-01-01

    Although there has been considerable controversy since the observation by Ehrlich more than 100 years ago that the brain did not take up dyes from the vascular system, the concept of an endothelial blood-brain barrier (BBB) was confirmed by the unequivocal demonstration that the passage of molecules from blood to brain and vice versa was prevented by endothelial tight junctions (TJs). There are three major functions implicated in the term "BBB": protection of the brain from the blood milieu, selective transport, and metabolism or modification of blood- or brain-borne substances. The BBB phenotype develops under the influence of associated brain cells, especially astrocytic glia, and consists of complex TJs and a number of specific transport and enzyme systems that regulate molecular traffic across the endothelial cells. The development of the BBB is a complex process that leads to endothelial cells with unique permeability characteristics due to high electrical resistance and the expression of specific transporters and metabolic pathways. This review article summarizes the historical background underlying our current knowledge of the cellular and molecular mechanisms involved in the development and maintenance of the BBB. (c) 2006 Wiley-Liss, Inc.

  12. Imaging blood-brain barrier dysfunction as a biomarker for epileptogenesis.

    Science.gov (United States)

    Bar-Klein, Guy; Lublinsky, Svetlana; Kamintsky, Lyn; Noyman, Iris; Veksler, Ronel; Dalipaj, Hotjensa; Senatorov, Vladimir V; Swissa, Evyatar; Rosenbach, Dror; Elazary, Netta; Milikovsky, Dan Z; Milk, Nadav; Kassirer, Michael; Rosman, Yossi; Serlin, Yonatan; Eisenkraft, Arik; Chassidim, Yoash; Parmet, Yisrael; Kaufer, Daniela; Friedman, Alon

    2017-06-01

    A biomarker that will enable the identification of patients at high-risk for developing post-injury epilepsy is critically required. Microvascular pathology and related blood-brain barrier dysfunction and neuroinflammation were shown to be associated with epileptogenesis after injury. Here we used prospective, longitudinal magnetic resonance imaging to quantitatively follow blood-brain barrier pathology in rats following status epilepticus, late electrocorticography to identify epileptic animals and post-mortem immunohistochemistry to confirm blood-brain barrier dysfunction and neuroinflammation. Finally, to test the pharmacodynamic relevance of the proposed biomarker, two anti-epileptogenic interventions were used; isoflurane anaesthesia and losartan. Our results show that early blood-brain barrier pathology in the piriform network is a sensitive and specific predictor (area under the curve of 0.96, P brain barrier pathology as a clinically relevant predictive, diagnostic and pharmaco!dynamics biomarker for acquired epilepsy. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  13. 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.

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

    International Nuclear Information System (INIS)

    Okada, Kazunori; Kobayashi, Shoutai; Yamaguchi, Shuhei; Kitani, Mituhiro; Tsunematsu, Tokugoro

    1987-01-01

    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 133 Xe 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)

  15. Brain delivery property and accelerated blood clearance of cationic albumin conjugated pegylated nanoparticle.

    Science.gov (United States)

    Lu, Wei; Wan, Jin; She, Zhenjue; Jiang, Xinguo

    2007-03-12

    Cationic bovine serum albumin (CBSA) conjugated poly(ethyleneglycol)-poly(lactide) (PEG-PLA) nanoparticle (CBSA-NP), was designed as a novel drug carrier for brain delivery. In this paper, three formulations of CBSA-NP with different surface CBSA density as well as native bovine serum albumin conjugated nanoparticle (BSA-NP) and CBSA unconjugated pegylated nanoparticle (NP), were formulated. Their brain transcytosis across the blood-brain barrier (BBB) coculture and brain delivery in mice were investigated using 6-coumarin as fluorescent probe. By using free CBSA as specific inhibitor, it was evidenced that CBSA-NP crossed the brain capillary endothelium through absorptive mediated transcytosis. The result of transcytosis across the BBB coculture and brain delivery in mice proved that the increase of surface CBSA density of the nanoparticle enhanced the BBB permeability-surface area but decreased blood AUC. The optimized CBSA number conjugated per averaged nanoparticle was 110, with the maleimide-PEG-PLA/methoxy-PEG-PLA weight ratio 1:10, which can acquire the greatest percentage of injected dose per gram brain (%ID/g brain) by 2.3-fold compared with NP. Besides, "accelerated blood clearance phenomenon" was found through evaluating blood clearance profile of CBSA-NP post-injection of single dose or over a period of successive high doses of CBSA-NP. Understanding these issues is important for the future development of CBSA-NP as a brain delivery carrier and for the attenuation of toxicity or immunological responses to the nanodevice following a consequence of nanomedication.

  16. Brain Abnormalities in Congenital Fibrosis of the Extraocular Muscles Type 1: A Multimodal MRI Imaging Study.

    Directory of Open Access Journals (Sweden)

    Wen Miao

    Full Text Available To explore the possible brain structural and functional alterations in congenital fibrosis of extraocular muscles type 1 (CFEOM1 patients using multimodal MRI imaging.T1-weighted, diffusion tensor images and functional MRI data were obtained from 9 KIF21A positive patients and 19 age- and gender-matched healthy controls. Voxel based morphometry and tract based spatial statistics were applied to the T1-weighted and diffusion tensor images, respectively. Amplitude of low frequency fluctuations and regional homogeneity were used to process the functional MRI data. We then compared these multimodal characteristics between CFEOM1 patients and healthy controls.Compared with healthy controls, CFEOM1 patients demonstrated increased grey matter volume in bilateral frontal orbital cortex and in the right temporal pole. No diffusion indices changes were detected, indicating unaffected white matter microstructure. In addition, from resting state functional MRI data, trend of amplitude of low-frequency fluctuations increases were noted in the right inferior parietal lobe and in the right frontal cortex, and a trend of ReHo increase (p<0.001 uncorrected in the left precentral gyrus, left orbital frontal cortex, temporal pole and cingulate gyrus.CFEOM1 patients had structural and functional changes in grey matter, but the white matter was unaffected. These alterations in the brain may be due to the abnormality of extraocular muscles and their innervating nerves. Future studies should consider the possible correlations between brain morphological/functional findings and clinical data, especially pertaining to eye movements, to obtain more precise answers about the role of brain area changes and their functional consequence in CFEOM1.

  17. Clinical, radiological, and genetic survey of patients with muscle-eye-brain disease caused by mutations in POMGNT1.

    Science.gov (United States)

    Yiş, Uluç; Uyanik, Gökhan; Rosendahl, Deborah Morris; Carman, Kürşat Bora; Bayram, Erhan; Heise, Marisol; Cömertpay, Gamze; Kurul, Semra Hız

    2014-05-01

    To evaluate clinical, genetic, and radiologic features of our patients with muscle-eye-brain disease. The data of patients who were diagnosed with muscle-eye-brain disease from a cohort of patients with congenital muscular dystrophy in the Division of Pediatric Neurology of Dokuz Eylül University School of Medicine and Gaziantep Children's Hospital between 2005 and 2013 were analyzed retrospectively. From a cohort of 34 patients with congenital muscular dystrophy, 12 patients from 10 families were diagnosed with muscle-eye-brain disease. The mean age of the patients was 9 ± 5.5 years (2-19 years). Mean serum creatine kinase value was 2485.80 ± 1308.54 IU/L (700-4267 IU/L). All patients presented with muscular hypotonia at birth followed by varying degrees of spasticity and exaggerated deep tendon reflexes in later stages of life. Three patients were able to walk. The most common ophthalmologic and radiologic abnormalities were cataracts, retinal detachment, periventricular white matter abnormalities, ventriculomegaly, pontocerebellar hypoplasia, and multiple cerebellar cysts. All of the patients had mutations in the POMGNT1 gene. The most common mutation detected in 66% of patients was c.1814 G > A (p.R605H). Two novel mutations were identified. We suggest that muscle-eye-brain disease is a relatively common muscular dystrophy in Turkey. It should be suspected in patients with muscular hypotonia, increased creatine kinase, and structural eye and brain abnormalities. The c.1814 G > A mutation in exon 21 of the POMGNT1 gene is apparently a common mutation in the Turkish population. Individuals with this mutation show classical features of muscle-eye-brain disease, but others may exhibit a milder phenotype and retain the ability to walk independently. Congenital muscular dystrophy patients from Turkey carrying the clinical and radiologic features of muscle-eye-brain disease should be evaluated for mutations in POMGNT1 gene. Copyright © 2014 Elsevier Inc. All

  18. Intra-Arterial Delivery of AAV Vectors to the Mouse Brain After Mannitol Mediated Blood Brain Barrier Disruption

    Science.gov (United States)

    Santillan, Alejandro; Sondhi, Dolan; Dyke, Jonathan P.; Crystal, Ronald G.; Gobin, Y. Pierre; Ballon, Douglas J.

    2014-01-01

    The delivery of therapeutics to neural tissue is greatly hindered by the blood brain barrier (BBB). Direct local delivery via diffusive release from degradable implants or direct intra-cerebral injection can bypass the BBB and obtain high concentrations of the therapeutic in the targeted tissue, however the total volume of tissue that can be treated using these techniques is limited. One treatment modality that can potentially access large volumes of neural tissue in a single treatment is intra-arterial (IA) injection after osmotic blood brain barrier disruption. In this technique, the therapeutic of interest is injected directly into the arteries that feed the target tissue after the blood brain barrier has been disrupted by exposure to a hyperosmolar mannitol solution, permitting the transluminal transport of the therapy. In this work we used contrast enhanced magnetic resonance imaging (MRI) studies of IA injections in mice to establish parameters that allow for extensive and reproducible BBB disruption. We found that the volume but not the flow rate of the mannitol injection has a significant effect on the degree of disruption. To determine whether the degree of disruption we observed with this method was sufficient for delivery of nanoscale therapeutics, we performed IA injections of an adeno-associated viral vector containing the CLN2 gene (AAVrh.10CLN2), which is mutated in the lysosomal storage disorder Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL). We demonstrated that IA injection of AAVrh.10CLN2 after BBB disruption can achieve widespread transgene production in the mouse brain after a single administration. Further, we showed that there exists a minimum threshold of BBB disruption necessary to permit the AAV.rh10 vector to pass into the brain parenchyma from the vascular system. These results suggest that IA administration may be used to obtain widespread delivery of nanoscale therapeutics throughout the murine brain after a single

  19. 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

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

    Science.gov (United States)

    Roatta, S; Mohammed, M; Turturici, M; Milano, L; Passatore, M

    2010-09-01

    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.

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

    Science.gov (United States)

    Peterson, Sarah; Ackerman, Joshua T.; 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.

  2. The blood-brain barrier in vitro using primary culture

    DEFF Research Database (Denmark)

    Larsen, Annette Burkhart

    of the thesis involves the establishment and characterization of an in vitro BBB models based on primary cells isolated from the rat brain. Co-culture and triple culture models with astrocytes and pericytes were found to be the superior to mono cultured BCECs with respect to many important BBB characteristics...... obstacle for the treatment of central nervous system (CNS) diseases, as many potentially CNS active drugs are unable to reach their site of action within the brain. In vitro BBB models are, therefore, being developed to investigate the BBB permeability of a drug early in its development. The first part....... In the second part of the thesis, the ability of turning BCECs into protein factories is investigated using a non-viral gene carrier. Transfection and protein synthesis of BCECs cultured with confined BBB properties were found to be feasible without disrupting the BBB properties, although it was not possible...

  3. Increased cerebral blood volume and oxygen consumption in neonatal brain injury

    Science.gov (United States)

    Grant, P Ellen; Roche-Labarbe, Nadege; Surova, Andrea; Themelis, George; Selb, Juliette; Warren, Elizabeth K; Krishnamoorthy, Kalpathy S; Boas, David A; Franceschini, Maria Angela

    2009-01-01

    With the increasing interest in treatments for neonatal brain injury, bedside methods for detecting and assessing injury status and evolution are needed. We aimed to determine whether cerebral tissue oxygenation (StO2), cerebral blood volume (CBV), and estimates of relative cerebral oxygen consumption (rCMRO2) determined by bedside frequency-domain near-infrared spectroscopy (FD-NIRS) have the potential to distinguish neonates with brain injury from those with non-brain issues and healthy controls. We recruited 43 neonates ≤ 15 days old and > 33 weeks gestational age (GA): 14 with imaging evidence of brain injury, 29 without suspicion of brain injury (4 unstable, 6 stable, and 19 healthy). A multivariate analysis of variance with Newman–Keuls post hoc comparisons confirmed group similarity for GA and age at measurement. StO2 was significantly higher in brain injured compared with unstable neonates, but not statistically different from stable or healthy neonates. Brain-injured neonates were distinguished from all others by significant increases in CBV and rCMRO2. In conclusion, although NIRS measures of StO2 alone may be insensitive to evolving brain injury, increased CBV and rCMRO2 seem to be useful for detecting neonatal brain injury and suggest increased neuronal activity and metabolism occurs acutely in evolving brain injury. PMID:19675563

  4. GLP-1 analog raises glucose transport capacity of blood-brain barrier in Alzheimer's disease

    DEFF Research Database (Denmark)

    Gejl, M.; Brock, B.; Egefjord, L.

    2017-01-01

    Objectives: Glucose enters the brain tissue from plasma by facilitated diffusion across the two membranes of the endothelium of the blood-brain barrier (BBB), mediated by the glucose transporter 1 (GLUT1). There is evidence in Alzheimer's disease (AD) of reduction of glucose transport across...... the blood-brain barrier, due to diminished GLUT1 translocation and expression at the BBB. Reduced BBB GLUT1 expression is known to aggravate AD pathology and further impair cognitive function, implying that GLUT1 may be a potential target of therapy directed towards AD neurovascular dysfunction...... and degeneration. Hypothesis: The incretin hormone GLP-1 prevents the decline of the cerebral metabolic rate of glucose that signifies cognitive impairment, synaptic dysfunction, and disease evolution in AD, and GLP-1 may directly activate GLUT1 transport in brain capillary endothelium. For this reason, we here...

  5. GLUT-1 GLUCOSE TRANSPORTERS IN THE BLOOD-BRAIN BARRIER: DIFFERENTIAL PHOSPHORYLATION

    Science.gov (United States)

    Devraj, Kavi; Klinger, Marianne E.; Myers, Roland L.; Mokashi, Ashwini; Hawkins, Richard A.; Simpson, Ian A.

    2013-01-01

    Glucose is the primary metabolic fuel for the mammalian brain and a continuous supply is required to maintain normal CNS function. The transport of glucose across the blood-brain barrier (BBB) into the brain is mediated by the facilitative glucose transporter GLUT-1. Prior studies (Simpson et al. 2001) had revealed that the conformations of the GLUT-1 transporter were different in luminal (blood facing) and abluminal (brain facing) membranes of bovine cerebral endothelial cells, based on differential antibody recognition. In this study we have extended these observations and using a combination of 2D-PAGE/Western blotting and immunogold electron microscopy we determined that these different conformations are exhibited in vivo and arise from differential phosphorylation of GLUT-1 and not from alternative splicing or altered O- or N-linked glycosylation. PMID:21910135

  6. Zebrafish: a model animal for analyzing the impact of environmental pollutants on muscle and brain mitochondrial bioenergetics.

    Science.gov (United States)

    Bourdineaud, Jean-Paul; Rossignol, R; Brèthes, D

    2013-01-01

    Mercury, anthropogenic release of uranium (U), and nanoparticles constitute hazardous environmental pollutants able to accumulate along the aquatic food chain with severe risk for animal and human health. The impact of such pollutants on living organisms has been up to now approached by classical toxicology in which huge doses of toxic compounds, environmentally irrelevant, are displayed through routes that never occur in the lifespan of organisms (for instance injecting a bolus of mercury to an animal although the main route is through prey and fish eating). We wanted to address the effect of such pollutants on the muscle and brain mitochondrial bioenergetics under realistic conditions, at unprecedented low doses, using an aquatic model animal, the zebrafish Danio rerio. We developed an original method to measure brain mitochondrial respiration: a single brain was put in 1.5 mL conical tube containing a respiratory buffer. Brains were gently homogenized by 13 strokes with a conical plastic pestle, and the homogenates were immediately used for respiration measurements. Skinned muscle fibers were prepared by saponin permeabilization. Zebrafish were contaminated with food containing 13 μg of methylmercury (MeHg)/g, an environmentally relevant dose. In permeabilized muscle fibers, we observed a strong inhibition of both state 3 mitochondrial respiration and cytochrome c oxidase activity after 49 days of MeHg exposure. We measured a dramatic decrease in the rate of ATP release by skinned muscle fibers. Contrarily to muscles, brain mitochondrial respiration was not modified by MeHg exposure although brain accumulated twice as much MeHg than muscles. When zebrafish were exposed to 30 μg/L of waterborne U, the basal mitochondrial respiratory control ratio was decreased in muscles after 28 days of exposure. This was due to an increase of the inner mitochondrial membrane permeability. The impact of a daily ration of food containing gold nanoparticles of two sizes (12 and

  7. Routes for drug translocation across the blood-brain barrier

    DEFF Research Database (Denmark)

    Kristensen, Mie; Brodin, Birger

    2017-01-01

    -mediated transcytosis, adsorptive-mediated transcytosis, and the paracellular route. The latter, however, being controversial due to the risk of co-delivery of blood-borne potential harmful substances. On the other hand a number of studies report on drug delivery across the BBB exploiting receptor-mediated transcytosis...

  8. 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...

  9. Interferon-λ restricts West Nile virus neuroinvasion by tightening the blood-brain barrier.

    Science.gov (United States)

    Lazear, Helen M; Daniels, Brian P; Pinto, Amelia K; Huang, Albert C; Vick, Sarah C; Doyle, Sean E; Gale, Michael; Klein, Robyn S; Diamond, Michael S

    2015-04-22

    Although interferon-λ [also known as type III interferon or interleukin-28 (IL-28)/IL-29] restricts infection by several viruses, its inhibitory mechanism has remained uncertain. We used recombinant interferon-λ and mice lacking the interferon-λ receptor (IFNLR1) to evaluate the effect of interferon-λ on infection with West Nile virus, an encephalitic flavivirus. Cell culture studies in mouse keratinocytes and dendritic cells showed no direct antiviral effect of exogenous interferon-λ, even though expression of interferon-stimulated genes was induced. We observed no differences in West Nile virus burden between wild-type and Ifnlr1(-/-) mice in the draining lymph nodes, spleen, or blood. We detected increased West Nile virus infection in the brain and spinal cord of Ifnlr1(-/-) mice, yet this was not associated with a direct antiviral effect in mouse neurons. Instead, we observed an increase in blood-brain barrier permeability in Ifnlr1(-/-) mice. Treatment of mice with pegylated interferon-λ2 resulted in decreased blood-brain barrier permeability, reduced West Nile virus infection in the brain without affecting viremia, and improved survival against lethal virus challenge. An in vitro model of the blood-brain barrier showed that interferon-λ signaling in mouse brain microvascular endothelial cells increased transendothelial electrical resistance, decreased virus movement across the barrier, and modulated tight junction protein localization in a protein synthesis- and signal transducer and activator of transcription 1 (STAT1)-independent manner. Our data establish an indirect antiviral function of interferon-λ in which noncanonical signaling through IFNLR1 tightens the blood-brain barrier and restricts viral neuroinvasion and pathogenesis. Copyright © 2015, American Association for the Advancement of Science.

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

    Science.gov (United States)

    Ma, Shang; Kwon, Hyo Jun; Huang, Zhen

    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 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.

  11. 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 ...... positive correlation between frontal cortex and hippocampal BDNF levels in mice (r2=0.81, p=0.0139). Our data support the view that measures of blood and plasma BDNF levels reflect brain-tissue BDNF levels....

  12. Acute Inflammatory Response in Rodent Brain and Blood Following a Blast Induced Traumatic Brain Injury

    Science.gov (United States)

    2014-11-01

    dehydrated with 30% sucrose before storing at -80 °C. Thirty micron coronal sections were stained with a primary antibody against microglia ...strongly Iba-1 stained cells as compared to controls. These results indicate blast exposure induces activation of microglia in the hippocampus... Neuroinflammation after traumatic brain injury: Opportunities for therapeutic intervention. Brain, behaviour and Immunity 26: 1191-1201. Loane, D. J

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

    Science.gov (United States)

    Alam, Monzurul; Chen, Xi; Zhang, Zicong; Li, Yan; He, Jufang

    2014-01-01

    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.

  14. Brain Functional Connectivity Is Different during Voluntary Concentric and Eccentric Muscle Contraction.

    Science.gov (United States)

    Yao, Wan X; Jiang, Zhiguo; Li, Jinqi; Jiang, Changhao; Franlin, Crystal G; Lancaster, Jack L; Huang, Yufei; Yue, Guang H

    2016-01-01

    Previous studies report greater activation in the cortical motor network in controlling eccentric contraction (EC) than concentric contraction (CC) of human skeletal muscles despite lower activation level of the muscle associated with EC. It is unknown, however, whether the strength of functional coupling between the primary motor cortex (M1) and other involved areas in the brain differs as voluntary movements are controlled by a network of regions in the primary, secondary and association cortices. Examining fMRI-based functional connectivity (FC) offers an opportunity to measure strength of such coupling. To address the question, we examined functional MRI (fMRI) data acquired during EC and CC (20 contractions each with similar movement distance and speed) of the right first dorsal interosseous (FDI) muscle in 11 young (20-32 years) and healthy individuals and estimated FC between the M1 and a number of cortical regions in the motor control network. The major findings from the mechanical and fMRI-based FC analysis were that (1) no significant differences were seen in movement distance, speed and stability between the EC and CC; (2) significantly stronger mean FC was found for CC than EC. Our finding provides novel insights for a better understanding of the control mechanisms underlying voluntary movements produced by EC and CC. The finding is potentially helpful for guiding the development of targeted sport training and/or therapeutic programs for performance enhancement and injury prevention.

  15. 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.

  16. Brain-muscle-computer interface: mobile-phone prototype development and testing.

    Science.gov (United States)

    Vernon, Scott; Joshi, Sanjay S

    2011-07-01

    We report prototype development and testing of a new mobile-phone-based brain-muscle-computer interface for severely paralyzed persons, based on previous results from our group showing that humans may actively create specified power levels in two separate frequency bands of a single surface electromyography (sEMG) signal. EMG activity on the surface of a single face muscle site (auricularis superior) is recorded with a standard electrode. This analog electrical signal is imported into an Android-based mobile phone and digitized via an internal A/D converter. The digital signal is split, and then simultaneously filtered with two band-pass filters to extract total power within two separate frequency bands. The user-modulated power in each frequency band serves as two separate control channels for machine control. After signal processing, the Android phone sends commands to external devices via a Bluetooth interface. Users are trained to use the device via visually based operant conditioning, with simple cursor-to-target activities on the phone screen. The mobile-phone prototype interface is formally evaluated on a single advanced Spinal Muscle Atrophy subject, who has successfully used the interface in his home in evaluation trials and for remote control of a television. Development of this new device will not only guide future interface design for community use, but will also serve as an information technology bridge for in situ data collection to quantify human sEMG manipulation abilities for a relevant population.

  17. Brain Functional Connectivity is Different during VoluntaryConcentric and Eccentric Muscle Contraction

    Directory of Open Access Journals (Sweden)

    Wan X Yao

    2016-11-01

    Full Text Available Previous studies report greater activation in the cortical motor network in controlling eccentric contraction (EC than concentric contraction (CC of human skeletal muscles despite lower activation level of the muscle associated with EC. It is unknown, however, whether the strength of functional coupling between the primary motor cortex (M1 and other involved areas in the brain differs as voluntary movements are controlled by a network of regions in the primary, secondary and association cortices. Examining fMRI-based functional connectivity (FC offers an opportunity to measure strength of such coupling. To address the question, we examined functional MRI (fMRI data acquired during EC and CC (20 contractions each with similar movement distance and speed of the right first dorsal interosseous (FDI muscle in 11 young (20-32 years and healthy individuals and estimated FC between the M1 and a number of cortical regions in the motor control network. The major findings from the behavioral and fMRI-based FC analysis were that (1 no significant differences were seen in movement distance, speed and stability between the EC and CC; (2 significantly stronger mean FC was found for CC than EC. Our finding provides novel insights for a better understanding of the control mechanisms underlying voluntary movements produced by EC and CC. The finding is potentially helpful for guiding the development of targeted sport training and/or therapeutic programs for performance enhancement and injury prevention.

  18. Increased brainstem perfusion, but no blood-brain barrier disruption, during attacks of migraine with aura.

    Science.gov (United States)

    Hougaard, Anders; Amin, Faisal M; Christensen, Casper E; Younis, Samaira; Wolfram, Frauke; Cramer, Stig P; Larsson, Henrik B W; Ashina, Messoud

    2017-06-01

    See Moskowitz (doi:10.1093/brain/awx099) for a scientific commentary on this article.The migraine aura is characterized by transient focal cortical disturbances causing dramatic neurological symptoms that are usually followed by migraine headache. It is currently not understood how the aura symptoms are related to the headache phase of migraine. Animal studies suggest that cortical spreading depression, the likely mechanism of migraine aura, causes disruption of the blood-brain barrier and noxious stimulation of trigeminal afferents leading to activation of brainstem nuclei and triggering of migraine headache. We used the sensitive and validated technique of dynamic contrast-enhanced high-field magnetic resonance imaging to simultaneously investigate blood-brain barrier permeability and tissue perfusion in the brainstem (at the level of the lower pons), visual cortex, and brain areas of the anterior, middle and posterior circulation during spontaneous attacks of migraine with aura. Patients reported to our institution to undergo magnetic resonance imaging during the headache phase after presenting with typical visual aura. Nineteen patients were scanned during attacks and on an attack-free day. The mean time from attack onset to scanning was 7.6 h. We found increased brainstem perfusion bilaterally during migraine with aura attacks. Perfusion also increased in the visual cortex and posterior white matter following migraine aura. We found no increase in blood-brain barrier permeability in any of the investigated regions. There was no correlation between blood-brain barrier permeability, brain perfusion, and time from symptom onset to examination or pain intensity. Our findings demonstrate hyperperfusion in brainstem during the headache phase of migraine with aura, while the blood-brain barrier remains intact during attacks of migraine with aura. These data thus contradict the preclinical hypothesis of cortical spreading depression-induced blood-brain barrier

  19. Application of Blood-Brain Barrier Permeability Imaging in Global Cerebral Edema.

    Science.gov (United States)

    Ivanidze, J; Kallas, O N; Gupta, A; Weidman, E; Baradaran, H; Mir, D; Giambrone, A; Segal, A Z; Claassen, J; Sanelli, P C

    2016-09-01

    Blood-brain barrier permeability is not routinely evaluated in the clinical setting. Global cerebral edema occurs after SAH and is associated with BBB disruption. Detection of global cerebral edema using current imaging techniques is challenging. Our purpose was to apply blood-brain barrier permeability imaging in patients with global cerebral edema by using extended CT perfusion. Patients with SAH underwent CTP in the early phase after aneurysmal rupture (days 0-3) and were classified as having global cerebral edema or nonglobal cerebral edema using established noncontrast CT criteria. CTP data were postprocessed into blood-brain barrier permeability quantitative maps of PS (permeability surface-area product), K(trans) (volume transfer constant from blood plasma to extravascular extracellular space), Kep (washout rate constant of the contrast agent from extravascular extracellular space to intravascular space), VE (extravascular extracellular space volume per unit of tissue volume), VP (plasmatic volume per unit of tissue volume), and F (plasma flow) by using Olea Sphere software. Mean values were compared using t tests. Twenty-two patients were included in the analysis. Kep (1.32 versus 1.52, P cerebral edema compared with nonglobal cerebral edema while VE (0.81 versus 0.39, P cerebral edema. Kep is an important indicator of altered blood-brain barrier permeability in patients with decreased blood flow, as Kep is flow-independent. Further study of blood-brain barrier permeability is needed to improve diagnosis and monitoring of global cerebral edema. © 2016 by American Journal of Neuroradiology.

  20. 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.

  1. Brain antibodies in the cortex and blood of people with schizophrenia and controls.

    Science.gov (United States)

    Glass, L J; Sinclair, D; Boerrigter, D; Naude, K; Fung, S J; Brown, D; Catts, V S; Tooney, P; O'Donnell, M; Lenroot, R; Galletly, C; Liu, D; Weickert, T W; Shannon Weickert, C

    2017-08-08

    The immune system is implicated in the pathogenesis of schizophrenia, with elevated proinflammatory cytokine mRNAs found in the brains of ~40% of individuals with the disorder. However, it is not clear if antibodies (specifically immunoglobulin-γ (IgG)) can be found in the brain of people with schizophrenia and if their abundance relates to brain inflammatory cytokine mRNA levels. Therefore, we investigated the localization and abundance of IgG in the frontal cortex of people with schizophrenia and controls, and the impact of proinflammatory cytokine status on IgG abundance in these groups. Brain IgGs were detected surrounding blood vessels in the human and non-human primate frontal cortex by immunohistochemistry. IgG levels did not differ significantly between schizophrenia cases and controls, or between schizophrenia cases in 'high' and 'low' proinflammatory cytokine subgroups. Consistent with the existence of IgG in the parenchyma of human brain, mRNA and protein of the IgG transporter (FcGRT) were present in the brain, and did not differ according to diagnosis or inflammatory status. Finally, brain-reactive antibody presence and abundance was investigated in the blood of living people. The plasma of living schizophrenia patients and healthy controls contained antibodies that displayed positive binding to Rhesus macaque cerebellar tissue, and the abundance of these antibodies was significantly lower in patients than controls. These findings suggest that antibodies in the brain and brain-reactive antibodies in the blood are present under normal circumstances.

  2. Tick-borne encephalitis virus infects human brain microvascular endothelial cells without compromising blood-brain barrier integrity

    Czech Academy of Sciences Publication Activity Database

    Palus, Martin; Vancová, Marie; Širmarová, J.; Elsterová, Jana; Perner, Jan; Růžek, Daniel

    2017-01-01

    Roč. 507, JUL (2017), s. 110-122 ISSN 0042-6822 R&D Projects: GA MZd(CZ) NV16-34238A; GA MŠk(CZ) LM2015062; GA TA ČR(CZ) TE01020118 Institutional support: RVO:60077344 Keywords : tick-borne encephalitis * tick-borne encephalitis virus * blood-brain barrier * neuroinfection Subject RIV: EE - Microbiology, Virology OBOR OECD: Virology Impact factor: 3.353, year: 2016

  3. Scintigraphic assessment of vascularity and blood-tissue barrier of human brain tumours

    International Nuclear Information System (INIS)

    Front, D.

    1978-01-01

    Assessment of vascularity and blood-tissue barrier was performed by sequential scintigraphy in 43 patients with brain tumours. The blood-tumour barrier was evaluated by use of sup(99m)Tc-pertechnetate, and vascularity using sup(99m)Tc-labelled red blood cells. Three groups of tumours were found: tumours with low vascularity and permeable barrier, tumours with high vascularity and permeable barrier, and tumours with low vascularity and relatively impermeable barrier. The first group indicates that when vessels are permeable, there may be a rapid penetration of large amounts of pertechnetate into the tumour even when vascularity is not increased. In the other two groups penetration of pertechnetate into the tumour is affected by vascularity, as it determines the total area where passage of the radiopharmaceutical takes place. It is suggested that the permeability of the blood-tumour barrier and the amount of vascularity may have an effect on the success of chemotherapy in brain tumours. (author)

  4. Arginine-Vasopressin Receptor Blocker Conivaptan Reduces Brain Edema and Blood-Brain Barrier Disruption after Experimental Stroke in Mice.

    Directory of Open Access Journals (Sweden)

    Emil Zeynalov

    Full Text Available Stroke is a major cause of morbidity and mortality. Stroke is complicated by brain edema and blood-brain barrier (BBB disruption, and is often accompanied by increased release of arginine-vasopressin (AVP. AVP acts through V1a and V2 receptors to trigger hyponatremia, vasospasm, and platelet aggregation which can exacerbate brain edema. The AVP receptor blockers conivaptan (V1a and V2 and tolvaptan (V2 are used to correct hyponatremia, but their effect on post-ischemic brain edema and BBB disruption remains to be elucidated. Therefore, we conducted this study to investigate if these drugs can prevent brain edema and BBB disruption in mice after stroke.Experimental mice underwent the filament model of middle cerebral artery occlusion (MCAO with reperfusion. Mice were treated with conivaptan, tolvaptan, or vehicle. Treatments were initiated immediately at reperfusion and administered IV (conivaptan or orally (tolvaptan for 48 hours. Physiological variables, neurological deficit scores (NDS, plasma and urine sodium and osmolality were recorded. Brain water content (BWC and Evans Blue (EB extravasation index were evaluated at the end point.Both conivaptan and tolvaptan produced aquaresis as indicated by changes in plasma and urine sodium levels. However plasma and urine osmolality was changed only by conivaptan. Unlike tolvaptan, conivaptan improved NDS and reduced BWC in the ipsilateral hemisphere: from 81.66 ± 0.43% (vehicle to 78.28 ± 0.48% (conivaptan, 0.2 mg, p < 0.05 vs vehicle. Conivaptan also attenuated the EB extravasation from 1.22 ± 0.08 (vehicle to 1.01 ± 0.02 (conivaptan, 0.2 mg, p < 0.05.Continuous IV infusion with conivaptan for 48 hours after experimental stroke reduces brain edema, and BBB disruption. Conivaptan but not tolvaptan may potentially be used in patients to prevent brain edema after stroke.

  5. Intact blood-brain barrier during spontaneous attacks of migraine without aura

    DEFF Research Database (Denmark)

    Amin, F M; Hougaard, A; Cramer, S P

    2017-01-01

    , brain stem, posterior pons and whole brain. The paired samples t test was used to compare Ki (permeability) values between the attack and headache-free days. RESULTS: Nineteen patients completed the study. Median time from onset of migraine attack to scan was 6.5 h (range 4.0-15.5 h). No change......BACKGROUND AND PURPOSE: The integrity of the blood-brain barrier (BBB) has been questioned in migraine, but BBB permeability has never been investigated during spontaneous migraine attacks. In the present study, BBB permeability during spontaneous attacks of migraine without aura was investigated...

  6. The observation of blood-brain barrier of organic mercury poisoned rat

    International Nuclear Information System (INIS)

    Kuwabara, Takeo; Yuasa, Tatsuhiko; Hidaka, Kazuyuki; Igarashi, Hironaka; Kaneko, Kiyotoshi; Miyatake, Tadashi

    1989-01-01

    Permeability of the blood-brain barrier (BBB) of methymercury chrolide (MMC) intoxicated rat brain was studied in vivo by gadlinium diethylenetriamine pentaacetic acid (Gd-DTPA) enhanced magnetic resonance imaging (MRI), measuring the longitudinal relaxation time (T 1 ) and the transverse relaxation time (T 2 ). MMC intoxicated rat brain showed the prolonged T 1 in the cerebral white matter and prolonged T 2 in the cerebellar cortex. After Gd-DTPA administration, T 1 of cerebral and cerebellar white matter shortened from 1.647 to 1.344 sec., and 1.290 to 1.223 sec. respectively. On the contrary, T 2 showed no change after Gd-DTPA injection. It was concluded that, although the shortening of T 1 after Gd-DTPA enhancement was rather little when compared with experimental brain ischemia, the shortening of the relaxation time of the MMC intoxicated rat brain was caused by the increased permeability of BBB. (author)

  7. Brain-derived neurotrophic factor correlated with muscle strength in subjects undergoing stationary bicycle exercise training.

    Science.gov (United States)

    Tsai, Sen-Wei; Chan, Yin-Ching; Liang, Francois; Hsu, Chiann-Yi; Lee, I-Te

    2015-04-01

    Several central nervous disorders are associated with metabolic syndrome (MetS) and type 2 diabetes. Reduction in brain-derived neurotrophic factor (BDNF) is involved in the mechanism of central nervous dysfunction. BDNF is up-regulated after exercise, but it is not known whether increased BDNF is related to increases in muscle strength. In the present study, subjects with MetS or type 2 diabetes were enrolled in an exercise program. All participants underwent an indoor bicycle exercise program for twelve weeks. Serum BDNF was determined after overnight fasting. Muscle strength was assessed by extension of the dominant lower extremity. A total of 33 subjects were enrolled in this study. The body mass index did not change significantly (from 30.4±6.0 to 30.2±5.8kg/m(2), P=0.436), but serum BDNF increased significantly (from 17.1±9.1 to 24.2±10.7ng/mL, Pexercise-associated BDNF was significantly correlated with the increased strength in lower-extremity extension test (r=0.54, P=0.001). Using multivariate regression analysis, muscle-strength increment, but not body-weight change, was an independent factor for serum BDNF (95% CI=0.009-0.044, P=0.005). After a twelve-week program of stationary bicycle exercise, serum BDNF concentration increased, and this change was positively correlated with muscle strength of lower-extremity extension, but not body weight. ( NCT02268292, ClinicalTrials.gov). Copyright © 2015 Elsevier Inc. All rights reserved.

  8. The bidirectional association between reduced cerebral blood flow and brain atrophy in the general population.

    Science.gov (United States)

    Zonneveld, Hazel I; Loehrer, Elizabeth A; Hofman, Albert; Niessen, Wiro J; van der Lugt, Aad; Krestin, Gabriel P; Ikram, M Arfan; Vernooij, Meike W

    2015-11-01

    The question remains whether reduced cerebral blood flow (CBF) leads to brain atrophy or vice versa. We studied the longitudinal relation between CBF and brain volume in a community-dwelling population. In the Rotterdam Study, 3011 participants (mean age 59.6 years (s.d. 8.0)) underwent repeat brain magnetic resonance imaging to quantify brain volume and CBF at two time points. Adjusted linear regression models were used to investigate the bidirectional relation between CBF and brain volume. We found that smaller brain volume at baseline was associated with a steeper decrease in CBF in the whole population (standardized change per s.d. increase of total brain volume (TBV)=0.296 (95% confidence interval (CI) 0.200; 0.393)). Only in persons aged ⩾65 years, a lower CBF at baseline was associated with steeper decline of TBV (standardized change per s.d. increase of CBF=0.003 (95% CI -0.004; 0.010) in the whole population and 0.020 (95% CI 0.004; 0.036) in those aged ⩾65 years of age). Our results indicate that brain atrophy causes CBF to decrease over time, rather than vice versa. Only in persons aged >65 years of age did we find lower CBF to also relate to brain atrophy.

  9. Agrin, aquaporin-4, and astrocyte polarity as an important feature of the blood-brain barrier.

    Science.gov (United States)

    Wolburg, Hartwig; Noell, Susan; Wolburg-Buchholz, Karen; Mack, Andreas; Fallier-Becker, Petra

    2009-04-01

    The blood-brain barrier (BBB) does not exclusively refer to brain endothelial cells, which are the site of the barrier proper. In the past few years, it has become increasingly clear that BBB endothelial cells depend considerably on the brain microenvironment to a degree exceeding the environmental influence in other organs. The concept of the BBB has been continuously developed over the decades, culminating now in the recognition that endothelial cell function in the brain is not limited to simply mediating energy and oxygen transfer between blood and neural tissue. Endothelial cells are rather "Janus-headed beings" that are active partners of both luminal molecules and cells, as well as subendothelial cells such as pericytes, astrocytes, and neurons. In this overview, the authors present and discuss both the role of astroglial cells in managing the BBB and aspects of pathological alterations in the brain as far as the BBB is involved. After a brief introduction of the BBB that describes the structure and function of the brain capillary endothelial cells, the authors report on both the water channel protein aquaporin-4 (AQP4) in astrocytes and the extracellular matrix between astrocytes/pericytes and endothelial cells. The AQP4 has an important impact on the homeostasis in the brain parenchyma; however, the mechanistic cascade from the composition of the astrocyte membrane to the maintenance of BBB properties in the endothelial cells, including their tight junction formation, is still completely unknown.

  10. 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.

  11. Short-term resistance training with blood flow restriction enhances microvascular filtration capacity of human calf muscles.

    Science.gov (United States)

    Evans, Colin; Vance, Steven; Brown, Maggie

    2010-07-01

    Resistance training increases muscle strength and endurance but may require high intensity and long duration to enhance capillarity. Vascular occlusion during low-load resistance training augments the strength and endurance gains compared with low-load resistance training alone, but in this study we investigated whether it also promotes microvascular filtration capacity, an index of capillarity. Nine healthy males performed short-term low-intensity resistance training of the calf muscles (four sets of 50 heel raises, three times a week for 4 weeks) under restricted (thigh cuff inflated to 150 mmHg on the non-dominant leg) or unrestricted (dominant leg without thigh cuff) blood flow conditions. Before and after resistance training, calf filtration capacity and resting blood flow were assessed by strain gauge plethysmography, and calf muscle strength and fatigue were assessed respectively by maximal voluntary contraction and force decline during electrically evoked ischaemic contractions in both legs. Calf filtration capacity increased by 26% in the restricted leg but did not increase significantly in the unrestricted leg. Calf muscle strength was 18% greater in the restricted leg but unchanged in the unrestricted leg. Calf muscle fatigue and resting blood flow did not change in either leg. Resistance training promoted microvascular filtration capacity, an effect that was somewhat enhanced by blood flow restriction, and could be due to increased capillarization.

  12. Longer repetition duration increases muscle activation and blood lactate response in matched resistance training protocols

    Directory of Open Access Journals (Sweden)

    Hugo Cesar Martins-Costa

    2016-03-01

    Full Text Available Abstract This study analyzed the effect of different repetition durations on electromyographic and blood lactate responses of the bench press exercise. Fifteen recreationally trained male volunteers completed two training protocols, matched for intensity (% one-repetition maximum; 1RM, number of sets, number of repetitions, and rest intervals. One of the protocols was performed with a repetition duration of 4 s (2 s concentric: 2 s eccentric; 2:2 protocol, whereas the second protocol had a repetition duration of 6 s (2 s concentric: 4 s eccentric; 2:4 protocol. The results showed higher normalized integrated electromyography (pectoralis major and triceps brachii for the 2:4 protocol. Blood lactate concentration was also higher in the 2:4 protocol across all sets. These results show that adding 2 s to the eccentric action in matched training protocols increases muscle activation and blood lactate response, which reinforces the notion that increasing repetition duration is an alternative load progression in resistance training.

  13. Astrocyte-Derived Pentraxin 3 Supports Blood-Brain Barrier Integrity Under Acute Phase of Stroke.

    Science.gov (United States)

    Shindo, Akihiro; Maki, Takakuni; Mandeville, Emiri T; Liang, Anna C; Egawa, Naohiro; Itoh, Kanako; Itoh, Naoki; Borlongan, Mia; Holder, Julie C; Chuang, Tsu Tshen; McNeish, John D; Tomimoto, Hidekazu; Lok, Josephine; Lo, Eng H; Arai, Ken

    2016-04-01

    Pentraxin 3 (PTX3) is released on inflammatory responses in many organs. However, roles of PTX3 in brain are still mostly unknown. Here we asked whether and how PTX3 contributes to blood-brain barrier dysfunction during the acute phase of ischemic stroke. In vivo, spontaneously hypertensive rats were subjected to focal cerebral ischemia by transient middle cerebral artery occlusion. At day 3, brains were analyzed to evaluate the cellular origin of PTX3 expression. Correlations with blood-brain barrier breakdown were assessed by IgG staining. In vitro, rat primary astrocytes and rat brain endothelial RBE.4 cells were cultured to study the role of astrocyte-derived PTX3 on vascular endothelial growth factor-mediated endothelial permeability. During the acute phase of stroke, reactive astrocytes in the peri-infarct area expressed PTX3. There was negative correlation between gradients of IgG leakage and PTX3-positive astrocytes. Cell culture experiments showed that astrocyte-conditioned media increased levels of tight junction proteins and reduced endothelial permeability under normal conditions. Removing PTX3 from astrocyte-conditioned media by immunoprecipitation increased endothelial permeability. PTX3 strongly bound vascular endothelial growth factor in vitro and was able to decrease vascular endothelial growth factor-induced endothelial permeability. Astrocytes in peri-infarct areas upregulate PTX3, which may support blood-brain barrier integrity by regulating vascular endothelial growth factor-related mechanisms. This response in astrocytes may comprise a compensatory mechanism for maintaining blood-brain barrier function after ischemic stroke. © 2016 American Heart Association, Inc.

  14. In vitro evidence for the brain glutamate efflux hypothesis: brain endothelial cells cocultured with astrocytes display a polarized brain-to-blood transport of glutamate.

    Science.gov (United States)

    Helms, Hans Christian; Madelung, Rasmus; Waagepetersen, Helle Sønderby; Nielsen, Carsten Uhd; Brodin, Birger

    2012-05-01

    The concentration of the excitotoxic amino acid, L-glutamate, in brain interstitial fluid is tightly regulated by uptake transporters and metabolism in astrocytes and neurons. The aim of this study was to investigate the possible role of the blood-brain barrier endothelium in brain L-glutamate homeostasis. Transendothelial transport- and accumulation studies of (3) H-L-glutamate, (3) H-L-aspartate, and (3) H-D-aspartate in an electrically tight bovine endothelial/rat astrocyte blood-brain barrier coculture model were performed. After 6 days in culture, the endothelium displayed transendothelial resistance values of 1014 ± 70 Ω cm(2) , and (14) C-D-mannitol permeability values of 0.88 ± 0.13 × 10(-6) cm s(-1) . Unidirectional flux studies showed that L-aspartate and L-glutamate, but not D-aspartate, displayed polarized transport in the brain-to-blood direction, however, all three amino acids accumulated in the cocultures when applied from the abluminal side. The transcellular transport kinetics were characterized with a K(m) of 69 ± 15 μM and a J(max) of 44 ± 3.1 pmol min(-1) cm(-2) for L-aspartate and a K(m) of 138 ± 49 μM and J(max) of 28 ± 3.1 pmol min(-1) cm(-2) for L-glutamate. The EAAT inhibitor, DL-threo-ß-Benzyloxyaspartate, inhibited transendothelial brain-to-blood fluxes of L-glutamate and L-aspartate. Expression of EAAT-1 (Slc1a3), -2 (Slc1a2), and -3 (Slc1a1) mRNA in the endothelial cells was confirmed by conventional PCR and localization of EAAT-1 and -3 in endothelial cells was shown with immunofluorescence. Overall, the findings suggest that the blood-brain barrier itself may participate in regulating brain L-glutamate concentrations. Copyright © 2012 Wiley Periodicals, Inc.

  15. Role of opioid peptides in brain mechanisms regulating blood pressure.

    Science.gov (United States)

    de Jong, W; Petty, M A; Sitsen, J M

    1983-02-01

    Beta-endorphin and related opioid peptides are neuropeptides which appear to play a role in cardiovascular regulation which is supported by altered nociceptive responsiveness in hypertensive animals. In spontaneously hypertensive rats the pain threshold for electric stimulation is elevated; these rats show increased response latency time in a hot plate test. The opiate antagonist naloxone reverses these values to that of the normotensive controls. In other forms of experimental hypertension, eg, renal hypertension (one-clip, two-kidney model), no change in pain sensitivity is apparent. Sinoaortic baroreceptor denervation causes a labile hypertension without changes in hot plate response. Administration of beta-endorphin into the nucleus of the solitary tract (NTS) gradually decreases blood pressure and heart rate without affecting respiratory frequency. These cardiovascular effects are blocked by naloxone as well as by an antibody to beta-endorphin. In contrast to the effects of beta-endorphin, microinjection of enkephalins into the NTS increases blood pressure and heart rate. The data suggest the existence of two separate endorphin systems at the level of the NTS, one a depressor and another a pressor system. The depressor influence of beta-endorphin may play a role in the mechanism of action of antihypertensive agents such as methyldopa and clonidine. Our data support a role of endorphins as neuropeptides involved in cardiovascular regulation, exerting a dual influence at the level of the NTS.

  16. 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

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

    Science.gov (United States)

    Sartorius, Tina; Peter, Andreas; Heni, Martin; Maetzler, Walter; Fritsche, Andreas; Häring, Hans-Ulrich; Hennige, Anita M

    2015-01-01

    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.

  18. Interrelationships between body fat and skin blood flow and the current required for electrical stimulation of human muscle.

    Science.gov (United States)

    Petrofsky, Jerrold S; Suh, Hye Jin; Gunda, Shashi; Prowse, Michelle; Batt, Jennifer

    2008-09-01

    There is variability between individuals in the current needed to elicit a contraction in human muscle with surface electrodes. To understand what might be causing some of this variability, 25 subjects whose average age was 24.4+/-2.3 years, whose height was 165.5+/-9.5 cm, and whose average weight was 70.3+/-21 kg were examined. Electrical stimulation was applied above the motor point of the quadriceps, biceps, and lateral gastrocnemius muscles. To assess body fat, 2D ultrasound was used with a 1cm stand off. Electrical stimulation was applied with sine wave stimulation at 100 micros pulse width and at a frequency of 30 Hz. To alter skin blood flow, aside from the natural difference in skin blood flow at rest, hot packs and cold packs were used for 5 min. The average fat thickness below the quadriceps and gastrocnemius muscles was 0.75+/-0.13 cm and under the biceps was 0.48+/-0.16 cm. Without the use of hot or cold packs, the currents for the quadriceps and gastrocnemius muscles were significantly higher than that of the biceps (phot or cold packs, when hot packs were applied, skin blood flow increased as did the current required to stimulate muscle to threshold. When cold packs were applied, there was a decrease in the current required to stimulate these muscles. In conclusion, there is a causal relationship between skin blood flow, the thickness of the fat layer below the skin, and the current required to stimulate the muscle.

  19. Radiofrequency and extremely low-frequency electromagnetic field effects on the blood-brain barrier.

    Science.gov (United States)

    Nittby, Henrietta; Grafström, Gustav; Eberhardt, Jacob L; Malmgren, Lars; Brun, Arne; Persson, Bertil R R; Salford, Leif G

    2008-01-01

    During the last century, mankind has introduced electricity and during the very last decades, the microwaves of the modern communication society have spread a totally new entity--the radiofrequency fields--around the world. How does this affect biology on Earth? The mammalian brain is protected by the blood-brain barrier, which prevents harmful substances from reaching the brain tissue. There is evidence that exposure to electromagnetic fields at non thermal levels disrupts this barrier. In this review, the scientific findings in this field are presented. The result is a complex picture, where some studies show effects on the blood-brain barrier, whereas others do not. Possible mechanisms for the interactions between electromagnetic fields and the living organisms are discussed. Demonstrated effects on the blood-brain barrier, as well as a series of other effects upon biology, have caused societal anxiety. Continued research is needed to come to an understanding of how these possible effects can be neutralized, or at least reduced. Furthermore, it should be kept in mind that proven effects on biology also should have positive potentials, e.g., for medical use.

  20. 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.

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

    International Nuclear Information System (INIS)

    Ciobanu, Luisa; Reynaud, Olivier; Le Bihan, Denis; Uhrig, Lynn; Jarraya, Bechir

    2012-01-01

    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 T2'*-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 7 T and 17.2 T under general anesthesia using different anesthetics (isoflurane, ketamine-xylazine, medetomidine). We showed that the brain/vessels contrast in T2'*- weighted images at 17.2 T varied directly according to the applied pharmacological anesthetic agent, a phenomenon that was visible, but to a much smaller extent at 7 T. 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. (authors)

  2. Blood-Based Bioenergetic Profiling Reflects Differences in Brain Bioenergetics and Metabolism

    Directory of Open Access Journals (Sweden)

    Daniel J. Tyrrell

    2017-01-01

    Full Text Available Blood-based bioenergetic profiling provides a minimally invasive assessment of mitochondrial health shown to be related to key features of aging. Previous studies show that blood cells recapitulate mitochondrial alterations in the central nervous system under pathological conditions, including the development of Alzheimer’s disease. In this study of nonhuman primates, we focus on mitochondrial function and bioenergetic capacity assessed by the respirometric profiling of monocytes, platelets, and frontal cortex mitochondria. Our data indicate that differences in the maximal respiratory capacity of brain mitochondria are reflected by CD14+ monocyte maximal respiratory capacity and platelet and monocyte bioenergetic health index. A subset of nonhuman primates also underwent [18F] fluorodeoxyglucose positron emission tomography (FDG-PET imaging to assess brain glucose metabolism. Our results indicate that platelet respiratory capacity positively correlates to measures of glucose metabolism in multiple brain regions. Altogether, the results of this study provide early evidence that blood-based bioenergetic profiling is related to brain mitochondrial metabolism. While these measures cannot substitute for direct measures of brain metabolism, provided by measures such as FDG-PET, they may have utility as a metabolic biomarker and screening tool to identify individuals exhibiting systemic bioenergetic decline who may therefore be at risk for the development of neurodegenerative diseases.

  3. Changes in the permeability of the blood-brain barrier in acute hyperammonemia. Effect of dexamethasone.

    Science.gov (United States)

    Ziylan, Y Z; Uzüm, G; Bernard, G; Diler, A S; Bourre, J M

    1993-12-01

    This study was designed to determine the contribution of elevated plasma ammonia levels to blood-brain barrier (BBB) abnormalities in the presence of intact liver. The permeability changes of the BBB were investigated grossly with Evans blue (EB) and quantitatively by measuring the blood-to-brain transfer content for alpha-aminoisobutyric acid (AIB) in normal rats and rats subjected to sublethal doses of ammonium acetate (NH4OAc) (750 and 600 mg/kg ip; at 30-min intervals). Some rats were pretreated with dexamethasone (DXN). Injection of NH4OAc increased both plasma and brain ammonia concentrations about 16-and 5-fold, respectively, above the control level. In rats receiving NH4OAc injection, the blood-to-brain transfer constant (Ki) for AIB was increased 3- to 11-fold. The elevated Ki values were limited to certain gray matter areas and less pronounced permeability changes were detected in white matter. Extravasation sites of EB were more restricted and were especially observed in thalamus and cerebellum, whereas cortex and white matter were unaffected. Dexamethasone pretreatment for 3 d reduced both leakage of EB and the Ki for AIB in NH4OAc injected animals, whereas acute treatment appeared ineffective. Dexamethasone did not prevent the development of coma but slightly decreased the ammonia concentration in plasma and brain. The results obtained indicate that hyperammonemia may disrupt BBB integrity not only to AIB and EB but also enhance the transport of other solutes.

  4. Studies on blood-brain barrier permeability after microwave-radiation

    International Nuclear Information System (INIS)

    Merritt, J.H.; Chamness, A.F.; Allen, S.J.

    1978-01-01

    Since the reported alternations of permeability of the blood-brain barrier by microwave radiation have implications for safety considerations in man, studies were conducted to replicate some of the initial investigations. No transfer of parenterally-administered fluorescin across the blood-brain barrier of rats after 30 min 1.2-GHz radiation at power densities from 2-75 mW/cm 2 was noted. Increased fluorescin uptake was seen only when the rats were made hyperthermic in a warm air-environment. Similarly, no increase of brain uptake of 14 C-mannitol using the Oldendorf dual isotope technique was seen as a result of exposure to pulsed 1.3-GHz radiation at peak power densities up to 20 mW/cm 2 , or in the continuous wave mode from 0.1-50 mW/cm 2 . An attempt to alter the permeability of the blood-brain barrier for serotonin with microwave radiation was unsuccessful. From these studies it would appear that the brain must be made hyperthermic for changes in permeability of the barrier induced by microwave radiation to occur. (orig.) [de

  5. Theranastic USPIO-loaded microbubbles for mediating and monitoring blood-brain barrier permeation

    NARCIS (Netherlands)

    Lammers, Twan Gerardus Gertudis Maria; Koczera, Patrick; Fokong, Stanley; Gremse, Felix; Ehling, Josef; Vogt, Michael; Pich, Andrij; Storm, Gerrit; van Zandvoort, Marc; Kiessling, Fabian

    2015-01-01

    Efficient and safe drug delivery across the blood-brain barrier (BBB) remains one of the major challenges of biomedical and (nano-) pharmaceutical research. Here, it is demonstrated that poly(butyl cyanoacrylate)-based microbubbles (MB), carrying ultrasmall superparamagnetic iron oxide (USPIO)

  6. Theranostic USPIO-loaded microbubbles for mediating and monitoring blood-brain barrier permeation

    NARCIS (Netherlands)

    Lammers, Twan; Koczera, Patrick; Fokong, Stanley; Gremse, Felix; Ehling, Josef; Vogt, Michael; Pich, Andrij; Storm, G; Van Zandvoort, Marc; Kiessling, Fabian

    2015-01-01

    Efficient and safe drug delivery across the blood-brain barrier (BBB) remains one of the major challenges of biomedical and (nano-) pharmaceutical research. Here, it is demonstrated that poly(butyl cyanoacrylate)-based microbubbles (MB), carrying ultrasmall superparamagnetic iron oxide (USPIO)

  7. Protective effects of monomethyl fumarate at the inflamed blood-brain barrier

    NARCIS (Netherlands)

    Lim, J.L.; van der Pol, S.M.A.; Di Dio, F.; van het Hof, B.; Kooij, G.; de Vries, H.E.; van Horssen, J.

    2015-01-01

    Background: Reactive oxygen species play a key role in the pathogenesis of multiple sclerosis as they induce blood-brain barrier disruption and enhance transendothelial leukocyte migration. Thus, therapeutic compounds with antioxidant and anti-inflammatory potential could have clinical value in

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

    DEFF Research Database (Denmark)

    Madsen, P L; Holm, S; Herning, M

    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...

  9. Blood-Brain Barrier Permeability and Monocyte Infiltration in Experimental Allergic Encephalomyelitis

    Science.gov (United States)

    Floris, S.; Blezer, E. L. A.; Schreibelt, G.; Dopp, E.; van der Pol, S. M. A.; Schadee-Eestermans, I. L.; Nicolay, K.; Dijkstra, C. D.; de Vries, H. E.

    2004-01-01

    Enhanced cerebrovascular permeability and cellular infiltration mark the onset of early multiple sclerosis lesions. So far, the precise sequence of these events and their role in lesion formation and disease progression remain unknown. Here we provide quantitative evidence that blood-brain barrier leakage is an early event and precedes massive…

  10. 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...

  11. Lack of blood-brain barrier properties in microvessels of the prelaminar optic nerve head

    NARCIS (Netherlands)

    Hofman, P.; Hoyng, P.; VanderWerf, F.; Vrensen, G. F.; Schlingemann, R. O.

    2001-01-01

    PURPOSE: To define the blood-brain barrier (BBB) characteristics of microvessels in the optic nerve head (ONH). METHODS: Immunohistochemical staining of different regions of the ONH, retro-laminar optic nerve, and retina of human and monkey eyes was carried out, using antibodies against BBB markers

  12. Blood-brain barrier permeability of bioactive withanamides present in Withania somnifera fruit extract.

    Science.gov (United States)

    Vareed, Shaiju K; Bauer, Alison K; Nair, Kavitha M; Liu, Yunbao; Jayaprakasam, Bolleddula; Nair, Muraleedharan G

    2014-08-01

    The neuroprotective effect of Withania somnifera L. Dunal fruit extract, in rodent models, is known. Withanamides, the primary active constituents in W.somnifera fruit extract exhibited neuroprotective effects against β-amyloid-induced cytotoxicity in neuronal cell culture studies. Therefore, we investigated the blood-brain barrier permeability of withanamides in W.somnifera fruit extract in mice using HPLC coupled with high resolution quadrupole time of flight mass spectrometer (Q-TOF/MS) detection. Mice were administered with 250 mg/kg of W.somnifera extract by intraperitoneal injection, and the blood and brain samples analyzed by Q-TOF/MS detection. Four major withanamides were detected in brain and blood of mice administered with W.somnifera extract. The results suggested that the withanamides crossed the blood-brain barrier. These results may help to develop W.somnifera fruit extract as a preventive or therapeutic botanical drug for stress-induced neurological disorders. Copyright © 2014 John Wiley & Sons, Ltd.

  13. Blood lactate response, oxygen consumption, and muscle activity during treadmill running with constraint.

    Science.gov (United States)

    Haudum, A; Birklbauer, J; Sieghartsleitner, R; Gonaus, C; Müller, E

    2014-08-01

    The induction of self-organization during running with a special harness may lead to reduced energy requirements. This experiment was designed to investigate the effect of practicing with a rubber tubing constraint attached between the heel and the hip for 7 wk. (18 treadmill running sessions) on oxygen consumption, caloric unit cost, blood lactate concentration, and muscle activity. 18 male recreational runners (M age = 26.3 yr.) were assigned to either an intervention or a control group. The intervention group trained with the constraint and the control group trained without it. Test 1 was conducted before the intervention, Test 2 after the intervention, and Test 3 7 wk. after Test 2 (no training between Tests 2 and 3). At Test 1, lactate and muscle activity were significantly increased during constrained running. For lactate, a significant decrease was found in the intervention group for running with the constraint; at Test 3, lactate returned to Test 1 level. No notable changes occurred in the physiological parameters. Furthermore, there was no observed transfer effect on normal running.

  14. Clinical features and molecular characterization of a patient with muscle-eye-brain disease: a novel mutation in the POMGNT1 gene.

    Science.gov (United States)

    Raducu, Madalina; Cotarelo, Rocío P; Simón, Rogelio; Camacho, Ana; Rubio-Fernández, Marcos; Hernández-Laín, Aurelio; Cruces, Jesús

    2014-02-01

    Muscle-eye-brain disease is a congenital muscular dystrophy characterized by structural brain and eye defects. Here, we describe a 12-year-old boy with partial agenesis of corpus callosum, ventriculomegaly, flattened brain stem, diffuse pachygyria, blindness, profound cognitive deficiencies, and generalized muscle weakness, yet without a clear dystrophic pattern on muscle biopsy. There was no glycosylation of α-dystroglycan and the genetic screening revealed a novel truncating mutation, c.1545delC (p.Tyr516Thrfs*21), and a previously identified missense mutation, c.1469G>A (p.Cys490Tyr), in the protein O-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1) gene. These findings broaden the clinical spectrum of muscle-eye-brain disease to include pronounced hypotonia with severe brain and eye malformations, yet with mild histopathologic changes in the muscle specimen, despite the absence of glycosylated α-dystroglycan.

  15. Impact of exercising muscles to exhaustion on blood markers in weight-training

    Directory of Open Access Journals (Sweden)

    Roberto Burini

    2008-06-01

    Full Text Available Metabolic markers of physical exhaustion were evaluated in venous blood drawn from 8 men (20-30 years old with at least 3 years’ experience in weight-lifting training. They were submitted, in the morning, to an overload (exhaustion test starting at 80% of 1 RM (one repetition maximum on 8 muscle groups. Heart rate (HR was measured and samples of venous blood were collected before and immediately after the exhaustion test (ET and sent to a laboratory for blood gas analysis (pH, lactate, pO2, pCO2 and HCO-3 and measurement of electrolytes (Na+, Cl-, K+ and Ca++ and glycemia. The HR/kg ratios observed were in the following sequence of descending order: arm and hamstrings > shoulder and back > chest > quadriceps > calf. Results for NH4, pH, lactate and HCO-3 levels were changed in all 8 muscle groups, whereas Ca++, K+, Na+, Cl-, and uric acid did not change significantly after the ET. The muscle groups: back, biceps, triceps, chest, and hamstrings exhibited changes in seven to nine indicators while only 4 to 6 biochemical indicators changed in response to shoulder, calf, and quadriceps exercises. Thus, blood markers indicating acidosis, hemoconcentration and hyperglycemia were sensitive markers although with low specificity for the eight muscle groups. Calf and quadriceps had the highest tolerance for weight loading along with the smallest HR increase and lowest number of biochemical indicators changed. Therefore, it appears possible to reach muscle exhaustion with systemic responses in the blood by working out the arm muscles and hamstrings with lighter weights than for quadriceps and calf muscles.ResumoO impacto da exaustão (com pesos de grupos musculares, sobre indicadores sanguíneos de acidose e de hemoconcentração foi estudado em 8 jovens (20-30 anos treinados em musculação. Todos foram submetidos a sobrecarga inicial de 80% de 1RM, até a exaustão (TE, em 8 exercícios distintos, com coleta de sangue e registro da freqüência card

  16. 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

  17. Role of blood and vascular smooth muscle in the vasoactivity of nitrite.

    Science.gov (United States)

    Liu, Taiming; Schroeder, Hobe J; Barcelo, Lisa; Bragg, Shannon L; Terry, Michael H; Wilson, Sean M; Power, Gordon G; Blood, Arlin B

    2014-10-01

    Recent evidence from humans and rats indicates that nitrite is a vasodilator under hypoxic conditions by reacting with metal-containing proteins to produce nitric oxide (NO). We tested the hypothesis that near-physiological concentrations of nitrite would produce vasodilation in a hypoxia- and concentration-dependent manner in the hind limb of sheep. Anesthetized sheep were instrumented to measure arterial blood pressure and femoral blood flows continuously in both hind limbs. Nitrite was infused into one femoral artery to raise the nitrite concentration in the femoral vein by 10 to 15-fold while the sheep breathed 50%, 14% or 12% oxygen in inspired air. In contrast to reports in humans and rats, the nitrite infusion had no measurable effect on mean femoral blood flows or vascular conductances, regardless of inspired O2 levels. In vitro experiments showed no significant difference in the release of NO from nitrite in sheep and human red blood cells. Further experiments demonstrated nitrite is converted to NO in rat artery homogenates faster than sheep arteries, and that this source of NO production is attenuated in the presence of a heme oxidizer. Finally, western blots indicate that concentrations of the heme-containing protein cytoglobin, but not myoglobin, are markedly lower in sheep arteries compared with rats. Overall, the results demonstrate that nitrite is not a physiological vasodilator in sheep. This is likely due to a lack of conversion of nitrite to NO within the vascular smooth muscle, perhaps due to deficient amounts of the heme-containing protein cytoglobin. Copyright © 2014 the American Physiological Society.

  18. Role of blood and vascular smooth muscle in the vasoactivity of nitrite

    Science.gov (United States)

    Liu, Taiming; Schroeder, Hobe J.; Barcelo, Lisa; Bragg, Shannon L.; Terry, Michael H.; Wilson, Sean M.; Power, Gordon G.

    2014-01-01

    Recent evidence from humans and rats indicates that nitrite is a vasodilator under hypoxic conditions by reacting with metal-containing proteins to produce nitric oxide (NO). We tested the hypothesis that near-physiological concentrations of nitrite would produce vasodilation in a hypoxia- and concentration-dependent manner in the hind limb of sheep. Anesthetized sheep were instrumented to measure arterial blood pressure and femoral blood flows continuously in both hind limbs. Nitrite was infused into one femoral artery to raise the nitrite concentration in the femoral vein by 10 to 15-fold while the sheep breathed 50%, 14% or 12% oxygen in inspired air. In contrast to reports in humans and rats, the nitrite infusion had no measurable effect on mean femoral blood flows or vascular conductances, regardless of inspired O2 levels. In vitro experiments showed no significant difference in the release of NO from nitrite in sheep and human red blood cells. Further experiments demonstrated nitrite is converted to NO in rat artery homogenates faster than sheep arteries, and that this source of NO production is attenuated in the presence of a heme oxidizer. Finally, western blots indicate that concentrations of the heme-containing protein cytoglobin, but not myoglobin, are markedly lower in sheep arteries compared with rats. Overall, the results demonstrate that nitrite is not a physiological vasodilator in sheep. This is likely due to a lack of conversion of nitrite to NO within the vascular smooth muscle, perhaps due to deficient amounts of the heme-containing protein cytoglobin. PMID:25108012

  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...... 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...... 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. 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.

  2. Effects of radiofrequency radiation exposure on blood-brain barrier permeability in male and female rats.

    Science.gov (United States)

    Sirav, Bahriye; Seyhan, Nesrin

    2011-12-01

    During the last several decades, numerous studies have been performed aiming at the question of whether or not exposure to radiofrequency radiation (RFR) influences the permeability of the blood-brain barrier (BBB). The objective of this study was to investigate the effect of RFR on the permeability of BBB in male and female Wistar albino rats. Right brain, left brain, cerebellum, and total brain were analyzed separately in the study. Rats were exposed to 0.9 and 1.8 GHz continuous-wave (CW) RFR for 20 min (at SARs of 4.26 mW/kg and 1.46 mW/kg, respectively) while under anesthesia. Control rats were sham-exposed. Disruption of BBB integrity was detected spectrophotometrically using the Evans-blue dye, which has been used as a BBB tracer and is known to be bound to serum albumin. Right brain, left brain, cerebellum, and total brain were evaluated for BBB permeability. In female rats, no albumin extravasation was found in in the brain after RFR exposure. A significant increase in albumin was found in the brains of the RF-exposed male rats when compared to sham-exposed male brains. These results suggest that exposure to 0.9 and 1.8 GHz CW RFR at levels below the international limits can affect the vascular permeability in the brain of male rats. The possible risk of RFR exposure in humans is a major concern for the society. Thus, this topic should be investigated more thoroughly in the future.

  3. The effect of muscle relaxant on the paraspinal muscle blood flow: a randomized controlled trial in patients with chronic low back pain.

    Science.gov (United States)

    Sakai, Yoshihito; Matsuyama, Yukihiro; Nakamura, Hiroshi; Katayama, Yoshito; Imagama, Shiro; Ito, Zenya; Okamoto, Akira; Ishiguro, Naoki

    2008-03-15

    A randomized controlled trial. To investigate the effect of muscle relaxant for muscle blood flow at the trunk muscle in patients with chronic low back pain (LBP). Paraspinal muscle function is widely believed to play a role and considered to be of etiologic significance in LBP, and intramuscular pressure increases and blood flow decreases in the flexion position. Decrease in oxygenated hemoglobin at the trunk muscle is seen in patients with LBP. A total of 74 male patients with LBP lasting more than 6 months were randomized to 3 treatment groups: (1) physical therapy only (control) (n = 25), (2) administration of eperisone hydrochloride (EMPP) for 4 weeks (n = 24), and (3) McKenzie therapy (n = 25). The primary outcome variables, observed at 2 and 4 weeks, are the Japanese Orthopedic Association LBP score, visual analogue scale (VAS), Faces Pain Scale-Revised, and SF-36. Intramuscular oxygenation was evaluated using near-infrared spectroscopy during lumbar extension and flexion, and oxygenated hemoglobin and deoxygenated hemoglobin were compared. VAS was significantly lower at 4 weeks in the McKenzie group than in the control group. There were no significant changes at 2 weeks in all parameters, however, the relative change of oxygenated hemoglobin during lumbar extension at 4 weeks was significantly higher in the EMPP group when compared with the other 2 groups. The relative change of deoxygenated hemoglobin during lumbar flexion showed a significant difference at 4 weeks in the EMPP group when compared with the control group. Administration of EMPP for 4 weeks improved the LBP in VAS, though not as effective as McKenzie therapy. Our data demonstrated the effects of eperisone hydrochloride on paraspinal muscle hemodynamics improving intramuscular oxygenation during lumbar extension and flexion in patients with chronic LBP.

  4. Regional cerebral blood perfusion SPECT imaging in brain ischemic injury due to cerebral hemorrhage

    International Nuclear Information System (INIS)

    Zhang Chunyin; Chen Yue; Li Zuoxiao; Tan Hua; Li Xiaohong

    2006-01-01

    Objective: To explore the clinical value of SPECT perfusion imaging in brain ischemic injury due to cerebral hemorrhage before and after treatment. Methods: Sixty cases of cerebral hemorrhage were randomly divided into nimodipine treated group and routine treated group. The volume of primary ischemic focus, changes of regional cerebral blood perfusion around hematoma and other cerebral areas were observed by SPECT imaging. Results: Volume of the primary focus was reduced apparently in both groups, but much more in nimodipine treated group (P<0.01). Also the regional cerebral blood flow in ischemic focus and remote areas increased much more in nimodipine treated group than routine treated group (P< 0.01). Conclusions: Brain SPECT imaging can sensitively reflect the regional cerebral blood flow before and after treatment. Thereby, it is useful for therapeutic monitoring. (authors)

  5. Regional brain glucose metabolism and blood flow in streptozocin-induced diabetic rats

    International Nuclear Information System (INIS)

    Jakobsen, J.; Nedergaard, M.; Aarslew-Jensen, M.; Diemer, N.H.

    1990-01-01

    Brain regional glucose metabolism and regional blood flow were measured from autoradiographs by the uptake of [ 3 H]-2-deoxy-D-glucose and [ 14 C]iodoantipyrine in streptozocin-induced diabetic (STZ-D) rats. After 2 days of diabetes, glucose metabolism in the neocortex, basal ganglia, and white matter increased by 34, 37, and 8%, respectively, whereas blood flow was unchanged. After 4 mo, glucose metabolism in the same three regions was decreased by 32, 43, and 60%. This reduction was paralleled by a statistically nonsignificant reduction in blood flow in neocortex and basal ganglia. It is suggested that the decrease of brain glucose metabolism in STZ-D reflects increased ketone body oxidation and reduction of electrochemical work

  6. 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)

    Blomqvist, G.; Widen, L.; Hellstrand, E.; Gutniak, M.; Grill, V.

    1991-01-01

    The effect of steady-state moderate hypoglycaemia on human brain homeostasis has been studied with positron emission tomography using D-glucose 11 C(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.)

  7. Creatine uptake in brain and skeletal muscle of mice lacking guanidinoacetate methyltransferase assessed by magnetic resonance spectroscopy.

    NARCIS (Netherlands)

    Kan, H.E.; Meeuwissen, E.; Asten, J.J.A. van; Veltien, A.A.; Isbrandt, D.; Heerschap, A.

    2007-01-01

    Creatine (Cr) levels in skeletal muscle and brain of a mouse model of Cr deficiency caused by guanidinoacetate methyltransferase absence (GAMT-/-) were studied after Cr supplementation with 2 g.kg body wt-1.day-1 Cr for 35 days. Localized 1H magnetic resonance spectroscopy (MRS) was performed in

  8. 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…

  9. Running pace decrease during a marathon is positively related to blood markers of muscle damage.

    Directory of Open Access Journals (Sweden)

    Juan Del Coso

    Full Text Available BACKGROUND: Completing a marathon is one of the most challenging sports activities, yet the source of running fatigue during this event is not completely understood. The aim of this investigation was to determine the cause(s of running fatigue during a marathon in warm weather. METHODOLOGY/PRINCIPAL FINDINGS: We recruited 40 amateur runners (34 men and 6 women for the study. Before the race, body core temperature, body mass, leg muscle power output during a countermovement jump, and blood samples were obtained. During the marathon (27 °C; 27% relative humidity running fatigue was measured as the pace reduction from the first 5-km to the end of the race. Within 3 min after the marathon, the same pre-exercise variables were obtained. RESULTS: Marathoners reduced their running pace from 3.5 ± 0.4 m/s after 5-km to 2.9 ± 0.6 m/s at the end of the race (P 15% pace reduction had elevated post-race myoglobin (1318 ± 1411 v 623 ± 391 µg L(-1; P<0.05, lactate dehydrogenase (687 ± 151 v 583 ± 117 U L(-1; P<0.05, and creatine kinase (564 ± 469 v 363 ± 158 U L(-1; P = 0.07 in comparison with marathoners that preserved their running pace reasonably well throughout the race. However, they did not differ in their body mass change (-3.1 ± 1.0 v -3.0 ± 1.0%; P = 0.60 or post-race body temperature (38.7 ± 0.7 v 38.9 ± 0.9 °C; P = 0.35. CONCLUSIONS/SIGNIFICANCE: Running pace decline during a marathon was positively related with muscle breakdown blood markers. To elucidate if muscle damage during a marathon is related to mechanistic or metabolic factors requires further investigation.

  10. Blood pressure and calf muscle oxygen extraction during plantar flexion exercise in peripheral artery disease.

    Science.gov (United States)

    Luck, J Carter; Miller, Amanda J; Aziz, Faisal; Radtka, John F; Proctor, David N; Leuenberger, Urs A; Sinoway, Lawrence I; Muller, Matthew D

    2017-07-01

    Peripheral artery disease (PAD) is an atherosclerotic vascular disease that affects 200 million people worldwide. Although PAD primarily affects large arteries, it is also associated with microvascular dysfunction, an exaggerated blood pressure (BP) response to exercise, and high cardiovascular mortality. We hypothesized that fatiguing plantar flexion exercise that evokes claudication elicits a greater reduction in skeletal muscle oxygenation (SmO 2 ) and a higher rise in BP in PAD compared with age-matched healthy subjects, but low-intensity steady-state plantar flexion elicits similar responses between groups. In the first experiment, eight patients with PAD and eight healthy controls performed fatiguing plantar flexion exercise (from 0.5 to 7 kg for up to 14 min). In the second experiment, seven patients with PAD and seven healthy controls performed low-intensity plantar flexion exercise (2.0 kg for 14 min). BP, heart rate (HR), and SmO 2 were measured continuously using near-infrared spectroscopy (NIRS). SmO 2 is the ratio of oxygenated hemoglobin to total hemoglobin, expressed as a percent. At fatigue, patients with PAD had a greater increase in mean arterial BP (18 ± 2 vs. vs. 10 ± 2 mmHg, P = 0.029) and HR (14 ± 2 vs. 6 ± 2 beats/min, P = 0.033) and a greater reduction in SmO 2 (-54 ± 10 vs. -12 ± 4%, P = 0.001). However, both groups had similar physiological responses to low-intensity, nonpainful plantar flexion exercise. These data suggest that patients with PAD have altered oxygen uptake and/or utilization during fatiguing exercise coincident with an augmented BP response. NEW & NOTEWORTHY In this laboratory study, patients with peripheral artery disease performed plantar flexion exercise in the supine posture until symptoms of claudication occurred. Relative to age- and sex-matched healthy subjects we found that patients had a higher blood pressure response, a higher heart rate response, and a greater reduction in skeletal muscle oxygenation as

  11. Breaking the Blood-Brain Barrier With Mannitol to Aid Stem Cell Therapeutics in the Chronic Stroke Brain.

    Science.gov (United States)

    Tajiri, Naoki; Lee, Jea Young; Acosta, Sandra; Sanberg, Paul R; Borlongan, Cesar V

    2016-01-01

    Blood-brain barrier (BBB) permeabilizers, such as mannitol, can facilitate peripherally delivered stem cells to exert therapeutic benefits on the stroke brain. Although this BBB permeation-aided stem cell therapy has been demonstrated in the acute stage of stroke, such BBB permeation in the chronic stage of the disease remains to be examined. Adult Sprague-Dawley rats initially received sham surgery or experimental stroke via the 1-h middle cerebral artery occlusion (MCAo) model. At 1 month after the MCAo surgery, stroke animals were randomly assigned to receive human umbilical cord stem cells only (2 million viable cells), mannitol only (1.1 mol/L mannitol at 4°C), combined human umbilical cord stem cells (200,000 viable cells) and mannitol (1.1 mol/L mannitol at 4°C), and vehicle (phosphate-buffered saline) only. Stroke animals that received human umbilical cord blood cells alone or combined human umbilical cord stem cells and mannitol exhibited significantly improved motor performance and significantly better brain cell survival in the peri-infarct area compared to stroke animals that received vehicle or mannitol alone, with mannitol treatment reducing the stem cell dose necessary to afford functional outcomes. Enhanced neurogenesis in the subventricular zone accompanied the combined treatment of human umbilical cord stem cells and mannitol. We showed that BBB permeation facilitates the therapeutic effects of a low dose of peripherally transplanted stem cells to effectively cause functional improvement and increase neurogenesis in chronic stroke.

  12. 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

    /min); blood volume (6 +/- 2/4 +/- 1/7 +/- 6 mL/100 g) and permeability (0.9 +/- 0.4/0.8 +/- 0.3/3 +/- 5 mL/100 g/min) were estimated by using Patlak's method and a two-compartment model. A corroboration of these results was achieved by using model simulation. In addition, it was possible to generate maps...... imaging of a bolus of a paramagnetic contrast agent passing through the brain. The methods are applied in patients with brain tumors and in healthy subjects. Perfusion was estimated by model-free deconvolution using Tikhonov's method (gray matter/white matter/tumor: 72 +/- 16/30 +/- 8/56 +/- 45 mL/100 g...

  13. Loss of chromosome Y in blood, but not in brain, of suicide completers.

    Science.gov (United States)

    Kimura, Atsushi; Hishimoto, Akitoyo; Otsuka, Ikuo; Okazaki, Satoshi; Boku, Shuken; Horai, Tadasu; Izumi, Takeshi; Takahashi, Motonori; Ueno, Yasuhiro; Shirakawa, Osamu; Sora, Ichiro

    2018-01-01

    Men have a higher rate of completed suicide than women, which suggests that sex chromosome abnormalities may be related to the pathophysiology of suicide. Recent studies have found an aberrant loss of chromosome Y (LOY) in various diseases; however, no study has investigated whether there is an association between LOY and suicide. The purpose of this study was to determine whether LOY occurs in men who completed suicide. Our study consisted of 286 male Japanese subjects comprised of 140 suicide completers without severe physical illness (130 post-mortem samples of peripheral blood and 10 brains) and 146 age-matched control subjects (130 peripheral blood samples from healthy individuals and 16 post-mortem brains). LOY was measured as the chromosome Y/chromosome X ratio of the fluorescent signal of co-amplified short sequences from the Y-X homologous amelogenin genes (AMELY and AMELX). Regression analyses showed that LOY in the blood of suicide completers was significantly more frequent than that found in controls (odds ratio = 3.50, 95% confidence interval = 1.21-10.10), but not in the dorsolateral prefrontal cortex (DLPFC) region of brain. Normal age-dependent LOY in blood was found in healthy controls (r = -0.353, p suicide completers (r = -0.119, p = 0.177). DLPFC tissue had age-dependent LOY (B = -0.002, p = 0.015), which was independent of phenotype. To our knowledge, this is the first study demonstrating that LOY in blood is associated with suicide completion. In addition, our findings are the first to also indicate that age-dependent LOY may occur not only in blood, but also in specific brain regions.

  14. How hormones influence composition and physiological function of the brain-blood barrier.

    Science.gov (United States)

    Hampl, R; Bičíková, M; Sosvorová, L

    2015-01-01

    Hormones exert many actions in the brain. Their access and effects in the brain are regulated by the blood-brain barrier (BBB). Hormones as other substances may enter the brain and vice versa either by paracellular way requiring breaching tight junctions stitching the endothelial cells composing the BBB, or by passage through the cells (transcellular way). Hormones influence both ways through their receptors, both membrane and intracellular, present on/in the BBB. In the review the main examples are outlined how hormones influence the expression and function of proteins forming the tight junctions, as well as how they regulate expression and function of major protein transporters mediating transport of various substances including hormone themselves.

  15. Dysautonomia after severe traumatic brain injury.

    NARCIS (Netherlands)

    Hendricks, H.T.; Heeren, J.H.M.; Vos, P.E.

    2010-01-01

    BACKGROUND: Dysautonomia after traumatic brain injury (TBI) is characterized by episodes of increased heart rate, respiratory rate, temperature, blood pressure, muscle tone, decorticate or decerebrate posturing, and profuse sweating. This study addresses the incidence of dysautonomia after severe

  16. Depletion of selenium in blood, liver and muscle from beef heifers previously fed forages containing high levels of selenium.

    Science.gov (United States)

    Benes, Sharon E; Robinson, Peter H; Cun, Grace S

    2015-12-01

    Beef heifers which had grazed 'Jose' tall wheatgrass (TWG; Thinopyrum ponticum var. 'Jose'; 10 heifers) and creeping wildrye (CWR; Leymus triticoides var. 'Rio'; 10 heifers) with high levels of Se (>2 mg/kg DM) due to growth in saline soils, accumulated high Se levels in blood, liver and muscle (Juchem et al., 2012). We determined the decrease in Se levels in blood, liver and muscle from these heifers, particularly the decrease of Se in muscle, in order to determine the maximum feeding length of a low Se diet (LSeD) required sustaining Se-enriched beef. Immediately after grazing, all heifers were fed a LSeD containing forages with high Se levels can result in Se-enriched beef, but a LSeD feeding period of <82 d is required to maintain enrichment. Copyright © 2015. Published by Elsevier B.V.

  17. Lycium barbarum Extracts Protect the Brain from Blood-Brain Barrier Disruption and Cerebral Edema in Experimental Stroke

    Science.gov (United States)

    Yang, Di; Li, Suk-Yee; Yeung, Chung-Man; Chang, Raymond Chuen-Chung; So, Kwok-Fai; Wong, David; Lo, Amy C. Y.

    2012-01-01

    Background and Purpose Ischemic stroke is a destructive cerebrovascular disease and a leading cause of death. Yet, no ideal neuroprotective agents are available, leaving prevention an attractive alternative. The extracts from the fruits of Lycium barbarum (LBP), a Chinese anti-aging medicine and food supplement, showed neuroprotective function in the retina when given prophylactically. We aim to evaluate the protective effects of LBP pre-treatment in an experimental stroke model. Methods C57BL/6N male mice were first fed with either vehicle (PBS) or LBP (1 or 10 mg/kg) daily for 7 days. Mice were then subjected to 2-hour transient middle cerebral artery occlusion (MCAO) by the intraluminal method followed by 22-hour reperfusion upon filament removal. Mice were evaluated for neurological deficits just before sacrifice. Brains were harvested for infarct size estimation, water content measurement, immunohistochemical analysis, and Western blot experiments. Evans blue (EB) extravasation was determined to assess blood-brain barrier (BBB) disruption after MCAO. Results LBP pre-treatment significantly improved neurological deficits as well as decreased infarct size, hemispheric swelling, and water content. Fewer apoptotic cells were identified in LBP-treated brains by TUNEL assay. Reduced EB extravasation, fewer IgG-leaky vessels, and up-regulation of occludin expression were also observed in LBP-treated brains. Moreover, immunoreactivity for aquaporin-4 and glial fibrillary acidic protein were significantly decreased in LBP-treated brains. Conclusions Seven-day oral LBP pre-treatment effectively improved neurological deficits, decreased infarct size and cerebral edema as well as protected the brain from BBB disruption, aquaporin-4 up-regulation, and glial activation. The present study suggests that LBP may be used as a prophylactic neuroprotectant in patients at high risk for ischemic stroke. PMID:22438957

  18. Alpha-Tocopherol Reduces Brain Edema and Protects Blood-Brain Barrier Integrity following Focal Cerebral Ischemia in Rats.

    Science.gov (United States)

    Haghnejad Azar, Adel; Oryan, Shahrbanoo; Bohlooli, Shahab; Panahpour, Hamdollah

    2017-01-01

    This study was conducted to examine the neuroprotective effects of α-tocopherol against edema formation and disruption of the blood-brain barrier (BBB) following transient focal cerebral ischemia in rats. Ninety-six male Sprague-Dawley rats were divided into 3 major groups (n = 32 in each), namely the sham, and control and α-tocopherol-treated (30 mg/kg) ischemic groups. Transient focal cerebral ischemia (90 min) was induced by occlusion of the left middle cerebral artery. At the end of the 24-hour reperfusion period, the animals were randomly selected and used for 4 investigations (n = 8) in each of the 3 main groups: (a) assessment of neurological score and measurement of infarct size, (b) detection of brain edema formation by the wet/dry method, (c) evaluation of BBB permeability using the Evans blue (EB) extravasation technique, and (d) assessment of the malondialdehyde (MDA) and reduced glutathione (GSH) concentrations using high-performance liquid chromatography methods. Induction of cerebral ischemia in the control group produced extensive brain edema (brain water content 83.8 ± 0.11%) and EB leakage into brain parenchyma (14.58 ± 1.29 µg/g) in conjunction with reduced GSH and elevated MDA levels (5.86 ± 0.31 mmol/mg and 63.57 ± 5.42 nmol/mg, respectively). Treatment with α-tocopherol significantly lowered brain edema formation and reduced EB leakage compared with the control group (p edema formation and produced protective effects on BBB function following ischemic stroke occurrence. This effect could be through increasing antioxidant activity. © 2016 S. Karger AG, Basel.

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

    NARCIS (Netherlands)

    Groothuis, Jan T.; van Dijk, Nynke; ter Woerds, Walter; Wieling, Wouter; Hopman, Maria T. E.

    2007-01-01

    In patients with orthostatic intolerance, the mechanisms to maintain BP (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

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

    NARCIS (Netherlands)

    Groothuis, J.T.; Dijk, N. van; Woerds, W. ter; Wieling, W.; Hopman, M.T.E.

    2007-01-01

    In patients with orthostatic intolerance, the mechanisms to maintain BP (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

  1. THE ROLE OF MULTIDRUG RESISTANCE ASSOCIATED PROTEIN (MRP) IN THE BLOOD-BRAIN BARRIER AND OPIOID ANALGESIA

    Science.gov (United States)

    Su, Wendy; Pasternak, Gavril W.

    2013-01-01

    The blood brain barrier protects the brain from circulating compounds and drugs. The ATP-binding cassette (ABC) transporter P-glycoprotein (Pgp) is involved with the barrier, both preventing the influx of agent from the blood into the brain and facilitating the efflux of compounds from the brain into the blood, raising the possibility of a similar role for other transporters. Multidrug resistance associated protein (MRP), a 190 kDa protein similar to Pgp is also ABC transport that has been implicated in the blood brain barrier. The current study explores its role in opioid action. Immunohistochemically, it is localized in the choroid plexus in ratsand can be selectively downregulated by antisense treatment at both the level of mRNA, as shown by RT-PCR, and protein, as demonstrated immunohistochemically. Behaviorally, downregulation of MRP significantly enhances the analgesic potency of systemic morphine in MRP knockout mice and in antisense-treated rats by lowering the blood brain barrier. Following intracerebroventricular administration, a number of compounds, including some opioids, are rapidly secreted from the brain into the blood where they contribute to the overall analgesic effects by activating peripheral systems. MRP plays a role in this efflux. Downregulating MRP expression leads to a corresponding decrease in the transport and a diminished analgesic response from opioids administered intracerebroventricularly. Thus, the transporter protein MRP plays a role in maintaining the blood-brain barrier and modulates the activity of opioids. PMID:23508590

  2. Blood flow after contraction and cuff occlusion is reduced in subjects with muscle soreness after eccentric exercise

    DEFF Research Database (Denmark)

    Souza-Silva, Eduardo; Wittrup Christensen, Steffan; Hirata, Rogerio Pessoto

    2018-01-01

    Purpose: Delayed onset muscle soreness (DOMS) occur within 1-2 days after eccentric exercise but the mechanism mediating hypersensitivity is unclear. This study hypothesized that eccentric exercise reduces the blood flow response following muscle contractions and cuff occlusion, which may result...... anterior muscle. All measures were done bilaterally at day-0 (pre-exercise), day-2 and day-6 (post-exercise). Subjects scored the muscle soreness on a Likert scale for 6 days. Results: Eccentric exercise increased Likert scores at day-1 and day-2 compared with day-0 (P... in accumulated algesic substances being a part of the sensitization in DOMS. Methods: Twelve healthy subjects (5 women) performed dorsiflexion exercise (5 sets of 10 repeated eccentric contractions) in one leg, while the contralateral leg was the control. The maximal voluntary contraction (MVC) of the tibialis...

  3. Effects of exercise with and without different degrees of blood flow restriction on torque and muscle activation.

    Science.gov (United States)

    Loenneke, Jeremy P; Kim, Daeyeol; Fahs, Christopher A; Thiebaud, Robert S; Abe, Takashi; Larson, Rebecca D; Bemben, Debra A; Bemben, Michael G

    2015-05-01

    An unresolved question in resistance training combined with blood flow restriction (BFR) is what percentage of estimated arterial occlusion pressure provides the most robust acute muscular response. Forty participants were assigned to Experiments 1, 2, or 3. Each experiment completed exercise protocols differing by pressure, exercise load, and/or volume. Torque was measured pre- and postexercise, and muscle activation was measured pre- and during each set. Pressure and load did not affect torque greatly. Muscle activation increased in all conditions (P muscle activation from 40% to 50% arterial occlusion [66% vs. 87% maximal voluntary contraction (30% 1RM)] but was not further increased with higher pressure. Different levels of BFR may alter the acute muscular response to a degree, although higher pressures do not appear to augment these changes. © 2014 The Authors. Muscle & Nerve Published by Wiley Periodicals, Inc.

  4. 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

    Cerebral blood flow (CBF) was studied in non-exteriorized near-term sheep fetuses using the radioactive microsphere technique. By partially occluding the umbilical vessels for a period of 1--1 1/2 hours a progressive and severe asphyxia with a final arterial pH of 6.90 was achieved. Varying...... 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...

  5. Glucose predictability, blood capillary permeability, and glucose utilization rate in subcutaneous, skeletal muscle, and visceral fat tissues.

    Science.gov (United States)

    Koutny, Tomas

    2013-11-01

    This study suggests an approach for the comparison and evaluation of particular compartments with modest experimental setup costs. A glucose level prediction model was used to evaluate the compartment's glucose transport rate across the blood capillary membrane and the glucose utilization rate by the cells. The glucose levels of the blood, subcutaneous tissue, skeletal muscle tissue, and visceral fat were obtained in experiments conducted on hereditary hypertriglyceridemic rats. After the blood glucose level had undergone a rapid change, the experimenter attempted to reach a steady blood glucose level by manually correcting the glucose infusion rate and maintaining a constant insulin infusion rate. The interstitial fluid glucose levels of subcutaneous tissue, skeletal muscle tissue, and visceral fat were evaluated to determine the reaction delay compared with the change in the blood glucose level, the interstitial fluid glucose level predictability, the blood capillary permeability, the effect of the concentration gradient, and the glucose utilization rate. Based on these data, the glucose transport rate across the capillary membrane and the utilization rate in a particular tissue were determined. The rates obtained were successfully verified against positron emission tomography experiments. The subcutaneous tissue exhibits the lowest and the most predictable glucose utilization rate, whereas the skeletal muscle tissue has the greatest glucose utilization rate. In contrast, the visceral fat is the least predictable and has the shortest reaction delay compared with the change in the blood glucose level. The reaction delays obtained for the subcutaneous tissue and skeletal muscle tissue were found to be approximately equal using a metric based on the time required to reach half of the increase in the interstitial fluid glucose level. © 2013 Published by Elsevier Ltd.

  6. Improvement of Blood-Brain Barrier Integrity in Traumatic Brain Injury and Hemorrhagic Shock Following Treatment With Valproic Acid and Fresh Frozen Plasma.

    Science.gov (United States)

    Nikolian, Vahagn C; Dekker, Simone E; Bambakidis, Ted; Higgins, Gerald A; Dennahy, Isabel S; Georgoff, Patrick E; Williams, Aaron M; Andjelkovic, Anuska V; Alam, Hasan B

    2018-01-01

    Combined traumatic brain injury and hemorrhagic shock are highly lethal. Following injuries, the integrity of the blood-brain barrier can be impaired, contributing to secondary brain insults. The status of the blood-brain barrier represents a potential factor impacting long-term neurologic outcomes in combined injuries. Treatment strategies involving plasma-based resuscitation and valproic acid therapy have shown efficacy in this setting. We hypothesize that a component of this beneficial effect is related to blood-brain barrier preservation. Following controlled traumatic brain injury, hemorrhagic shock, various resuscitation and treatment strategies were evaluated for their association with blood-brain barrier integrity. Analysis of gene expression profiles was performed using Porcine Gene ST 1.1 microarray. Pathway analysis was completed using network analysis tools (Gene Ontology, Ingenuity Pathway Analysis, and Parametric Gene Set Enrichment Analysis). Female Yorkshire swine were subjected to controlled traumatic brain injury and 2 hours of hemorrhagic shock (40% blood volume, mean arterial pressure 30-35 mmHg). Subjects were resuscitated with 1) normal saline, 2) fresh frozen plasma, 3) hetastarch, 4) fresh frozen plasma + valproic acid, or 5) hetastarch + valproic acid (n = 5 per group). After 6 hours of observation, brains were harvested for evaluation. Immunofluoroscopic evaluation of the traumatic brain injury site revealed significantly increased expression of tight-junction associated proteins (zona occludin-1, claudin-5) following combination therapy (fresh frozen plasma + valproic acid and hetastarch + valproic acid). The extracellular matrix protein laminin was found to have significantly improved expression with combination therapies. Pathway analysis indicated that valproic acid significantly modulated pathways involved in endothelial barrier function and cell signaling. Resuscitation with fresh frozen plasma results in improved expression of

  7. 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.

  8. In Vitro and Ex Vivo Model Systems to Measure ABC Transporter Activity at the Blood-Brain Barrier.

    Science.gov (United States)

    de Wit, Nienke M; Kooij, Gijs; de Vries, Helga E

    2016-01-01

    With the aging population the occurrence of central nervous system diseases such as cancer, mental disorders and neurodegenerative diseases, is expected to increase and hence, the demand for effective drugs. However, the passage of drugs across the blood-brain barrier represents a major challenge in accomplishing efficient brain delivery of therapeutic agents. This highly efficient barrier is composed of a monolayer of capillary endothelial cells supported by pericytes and astrocytic end-feet, that together effectively shield the brain from the blood. The brain microvascular endothelial cells form a physical and metabolic barrier where paracellular and transcellular transport of molecules in and out of the brain is closely regulated, allowing nutrients to pass but preventing the entry of harmful neurotoxic substances, including drugs. For this purpose brain endothelial cells express efficient efflux pumps, such as ATP binding cassette (ABC) transporters, which limit the delivery of drugs into the brain. To treat the above-mentioned chronic central nervous system disorders, it is crucial to design compounds that can pass the blood-brain barrier and thus the ABC transporters. In order to achieve this, representative models of the blood-brain barrier with predictive validity are necessary. This review discusses the current in vitro and ex vivo model systems that are used to measure ABC transporter activity in order to study potential in vivo efficacy of blood-brain barrier-drug passage.

  9. Regulatory mechanisms for iron transport across the blood-brain barrier.

    Science.gov (United States)

    Duck, Kari A; Simpson, Ian A; Connor, James R

    2017-12-09

    Many critical metabolic functions in the brain require adequate and timely delivery of iron. However, most studies when considering brain iron uptake have ignored the iron requirements of the endothelial cells that form the blood-brain barrier (BBB). Moreover, current models of BBB iron transport do not address regional regulation of brain iron uptake or how neurons, when adapting to metabolic demands, can acquire more iron. In this study, we demonstrate that both iron-poor transferrin (apo-Tf) and the iron chelator, deferoxamine, stimulate release of iron from iron-loaded endothelial cells in an in vitro BBB model. The role of the endosomal divalent metal transporter 1 (DMT1) in BBB iron acquisition and transport has been questioned. Here, we show that inhibition of DMT1 alters the transport of iron and Tf across the endothelial cells. These data support an endosome-mediated model of Tf-bound iron uptake into the brain and identifies mechanisms for local regional regulation of brain iron uptake. Moreover, our data provide an explanation for the disparity in the ratio of Tf to iron transport into the brain that has confounded the field. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. 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.

  11. Paving the Way Toward Complex Blood-Brain Barrier Models Using Pluripotent Stem Cells.

    Science.gov (United States)

    Lauschke, Karin; Frederiksen, Lise; Hall, Vanessa Jane

    2017-06-15

    A tissue with great need to be modeled in vitro is the blood-brain barrier (BBB). The BBB is a tight barrier that covers all blood vessels in the brain and separates the brain microenvironment from the blood system. It consists of three cell types [neurovascular unit (NVU)] that contribute to the unique tightness and selective permeability of the BBB and has been shown to be disrupted in many diseases and brain disorders, such as vascular dementia, stroke, multiple sclerosis, and Alzheimer's disease. Given the progress that pluripotent stem cells (PSCs) have made in the past two decades, it is now possible to produce many cell types from the BBB and even partially recapitulate this complex tissue in vitro. In this review, we summarize the most recent developments in PSC differentiation and modeling of the BBB. We also suggest how patient-specific human-induced PSCs could be used to model BBB dysfunction in the future. Lastly, we provide perspectives on how to improve production of the BBB in vitro, for example by improving pericyte differentiation protocols and by better modeling the NVU in the dish.

  12. Regional distribution of opiate alkaloids in experimental animals' brain tissue and blood

    Directory of Open Access Journals (Sweden)

    Đurendić-Brenesel Maja

    2012-01-01

    Full Text Available The aim of this study was to examine the regional distribution of opiate alkaloids from seized heroin in experimental animals' brain regions and blood. Results could be used in the examination of opiate alkaloids' distribution in human biological samples in order to contribute to the solution of the causes of death due to heroin intake. Experimental animals (Wistar rats were treated with seized heroin, and were sacrificed at different time periods: 5, 15, 45 and 120 min after treatment. Opiate alkaloids' (codeine, morphine, acetylcodeine, 6- acetylmorphine and 3,6-diacetylmorphine content was determined in the brain regions (cortex, brainstem, amygdala and basal ganglia and blood of animals using gas chromatography-mass spectrometry (GC-MS method. The highest content of opiate alkaloids in the blood was measured 15 min, and in the brain tissue 45 min after the treatment with heroin. The maximal concentration of opiates was determined in the basal ganglia. The obtained results offer the possibility of selecting this part of the brain tissue as a representative sample for identifying and assessing the content of opiates.

  13. Study on measurement of free ligand concentration in blood and quantitative analysis of brain benzodiazepine receptor

    International Nuclear Information System (INIS)

    Hashimoto, Kenji; Goromaru, Tsuyoshi; Inoue, Osamu; Itoh, Takashi; Yamasaki, Toshiro.

    1988-01-01

    We developed the method to determine rapidly the free ligand concentration in the blood as an input function for the purpose of quantitative analysis of binding potential (B max /K d ) of brain benzodiazepine receptor in vivo. It was found that the unmetabolized radioligand in the blood after intravenous administration of 3 H-Ro 15 - 1788 could be extracted by chloroform, whereas the radioactive metabolites could not be extracted. And the plasma protein binding of 3 H-Ro 15 - 1788 was determined using an ultrafiltration method. The biodistribution of 3 H-Ro 15 - 1788 in the cerebral cortex, cerebellum and pons-medulla after intravenous administration of the radiotracer in the control and forced-swimmed mice was examined. And the time course of the free ligand concentration in the blood was determined as described above. Further, the binding potential of benzodiazepine receptor in the mouse brain was analyzed using a simple mathematical model. It was suggested that the binding potential of benzodiazepine receptor in the mouse brain was significantly decreased by forced-swimming. In conclusion, it was found that these methods would be useful for quantitative analysis of clinical data in the human brain using 11 C-Ro 15 - 1788 and positron emission tomography (PET). (author)

  14. 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

  15. Assessing Brain–Muscle Connectivity in Human Locomotion through Mobile Brain/Body Imaging: Opportunities, Pitfalls, and Future Directions

    Directory of Open Access Journals (Sweden)

    Federico Gennaro

    2018-02-01

    Full Text Available Assessment of the cortical role during bipedalism has been a methodological challenge. While surface electroencephalography (EEG is capable of non-invasively measuring cortical activity during human locomotion, it is associated with movement artifacts obscuring cerebral sources of activity. Recently, statistical methods based on blind source separation revealed potential for resolving this issue, by segregating non-cerebral/artifactual from cerebral sources of activity. This step marked a new opportunity for the investigation of the brains’ role while moving and was tagged mobile brain/body imaging (MoBI. This methodology involves simultaneous mobile recording of brain activity with several other body behavioral variables (e.g., muscle activity and kinematics, through wireless recording wearable devices/sensors. Notably, several MoBI studies using EEG–EMG approaches recently showed that the brain is functionally connected to the muscles and active throughout the whole gait cycle and, thus, rejecting the long-lasting idea of a solely spinal-driven bipedalism. However, MoBI and brain/muscle connectivity assessments during human locomotion are still in their fledgling state of investigation. Mobile brain/body imaging approaches hint toward promising opportunities; however, there are some remaining pitfalls that need to be resolved before considering their routine clinical use. This article discusses several of these pitfalls and proposes research to address them. Examples relate to the validity, reliability, and reproducibility of this method in ecologically valid scenarios and in different populations. Furthermore, whether brain/muscle connectivity within the MoBI framework represents a potential biomarker in neuromuscular syndromes where gait disturbances are evident (e.g., age-related sarcopenia remains to be determined.

  16. Aging and sex influence the permeability of the blood-brain barrier in the rat

    International Nuclear Information System (INIS)

    Saija, A.; Princi, P.; D'Amico, N.; De Pasquale, R.; Costa, G.

    1990-01-01

    The aim of the present study was to investigate the existence of aging- and sex-related alterations in the permeability of the blood-brain barrier (BBB) in the rat, by calculating a unidirectional blood-to-brain transfer constant (Ki) for the circulating tracer [ 14 C]-α-aminoisobutyric acid. The authors observed that: (a) the permeability of the BBB significantly increased within the frontal and temporo-parietal cortex, hypothalamus and cerebellum in 28-30 week old rats, in comparison with younger animals; (b) in several brain areas of female intact rats higher Ki values (even though not significantly different) were calculated at oestrus than at proestrus; (c) in 1-week ovariectomized rats there was a marked increase of Ki values at the level of the frontal, temporo-parietal and occipital cortex, cerebellum and brain-stem. One can speculate that aging and sex-related alterations in thee permeability of the BBB reflect respectively changes in brain neurochemical system activity and in plasma steroid hormone levels

  17. Ionizing radiation alters beta-endorphin-like immunoreactivity in brain but not blood

    Energy Technology Data Exchange (ETDEWEB)

    Mickley, G.A.; Stevens, K.E.; Moore, G.H.; Deere, W.; White, G.A.; Gibbs, G.L.; Mueller, G.P.

    1983-12-01

    Previous behavioral and pharmacological studies have implicated endorphins in radiation-induced locomotor hyperactivity of the C57BL/6J mouse. However, the endogenous opiate(s) responsible for this behavioral change have not been identified. The present study measured beta-endorphin-like immunoreactivity (beta-END-LI) in brain, blood, and combined brain and pituitary samples from irradiated and sham-irradiated C57BL/6J mice. After radiation exposure, levels of beta-END-LI decreased significantly in the brain. A similar, but not statistically significant, decline was measured in combined brain and pituitary samples. Concentrations of blood beta-END-LI were not changed by irradiation. These radiogenic changes in beta-END-LI are in some ways similar to those observed after other stresses. However, radiation-induced locomotor hyperactivity may be mediated more by alterations of beta-END-LI in the brain than in the periphery. Other endogenous opiate systems may also contribute to this behavioral change in the C57BL/6J mouse.

  18. Regulation of ABC transporters blood-brain barrier: the good, the bad, and the ugly.

    Science.gov (United States)

    Miller, David S

    2015-01-01

    The brain capillary endothelial cells that constitute the blood-brain barrier express multiple ABC transport proteins on the luminal, blood-facing, plasma membrane. These transporters function as ATP-driven efflux pumps for xenobiotics and endogenous metabolites. High expression of these ABC transporters at the barrier is a major obstacle to the delivery of therapeutics, including chemotherapeutics, to the CNS. Here, I review the signals that alter ABC transporter expression and transport function with an emphasis on P-glycoprotein, Mrp2, and breast cancer resistance protein (BCRP), the efflux transporters for which we have the most detailed picture of regulation. Recent work shows that transporter protein expression can be upregulated in response to inflammatory and oxidative stress, therapeutic drugs, diet, and persistent environmental pollutants; as a consequence, drug delivery to the brain is reduced (potentially bad and ugly). In contrast, basal transport activity of P-glycoprotein and BCRP can be reduced through complex signaling pathways that involve events in and on the brain capillary endothelial cells. Targeting these signaling events provides opportunities to rapidly and reversibly increase brain accumulation of drugs that are substrates for the transporters (potentially good). The clinical usefulness of targeting signaling to reduce efflux transporter activity and improve drug delivery to the CNS remains to be established. © 2015 Elsevier Inc. All rights reserved.

  19. Effect of taurine on chronic and acute liver injury: Focus on blood and brain ammonia

    Directory of Open Access Journals (Sweden)

    Reza Heidari

    2016-01-01

    Full Text Available Hyperammonemia is associated with chronic and acute liver injury. There is no promising therapeutic agent against ammonia-induced complications. Hence, finding therapeutic molecules with safe profile of administration has clinical value. The present study was conducted to evaluate the role of taurine (TA administration on plasma and brain ammonia and its consequent events in different models of chronic and acute liver injury and hyperammonemia. Bile duct ligated (BDL rats were used as a model of chronic liver injury. Thioacetamide and acetaminophen-induced acute liver failure were used as acute liver injury models. A high level of ammonia was detected in blood and brain of experimental groups. An increase in brain ammonia level coincided with a decreased total locomotor activity of animals and significant changes in the biochemistry of blood and also liver tissue. TA administration (500 and 1000 mg/kg, i.p, effectively alleviated liver injury and its consequent events including rise in plasma and brain ammonia and brain edema. The data suggested that TA is not only a useful and safe agent to preserve liver function, but also prevented hyperammonemia as a deleterious consequence of acute and chronic liver injury.

  20. Quantitative assessment of postoperative blood collection in brain tumor surgery under valproate medication.

    Science.gov (United States)

    Psaras, T; Will, B E; Schoeber, W; Rona, S; Mittelbronn, M; Honegger, J B

    2008-11-01

    The aim of the study was to evaluate whether valproate (VPA) increases the risk of bleeding complications in patients undergoing brain tumor surgery. A retrospective chart review of 85 patients operated on between January and December 2005 was performed. 19 patients received VPA, 22 patients were given other anti-epileptic drugs (AEDs), 44 patients received no AEDs. Data analyzed included intraoperative blood loss, transfusion, important comorbidity factors and concomitant diseases. Preoperative and postoperative laboratory data included hemoglobin, hematocrit, fibrinogen, platelet count, INR, prothrombin time, partial thromboplastin time and RBC count. The tumor volume was evaluated by preoperative MRI and CT scans of the brain. All 85 patients underwent a native CT scan of the brain on the first day after the operation. The volume of the resection cavity and the volume of blood were documented. We could show that the volume of the tumor had a significant effect on the amount of blood in the tumor cavity, whereas VPA medication had no effect. In our dataset, we found that tumor size had a significant effect on postoperative blood volume. In contrast, no serious bleeding complications occurred in the patients receiving VPA. Therefore, the present study does not provide any evidence for the need to discontinue VPA medication prior to and during surgery.

  1. 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

  2. The Role of Blood Lactate Levels as Outcome Predictor of Isolated Traumatic Brain Injury Patients

    Directory of Open Access Journals (Sweden)

    R Laode

    2012-01-01

    Full Text Available Objectives: Traumatic brain injury (TBI is accompanied by regional alterations of brain metabolism, reduction in metabolic rates and possible energy crisis. This metabolic disturbance reflected by increase and accumulation of the brain lactate levels. Objective of this study was to determine the correlation between abnormalities in lactate metabolism for predicting neurologic outcome after moderate or severe traumatic brain injury. Methods: An observational prospective study in 60 patients with isolated TBI. Blood sample taken from vein of the limbs after underwent initial resuscitation. Serial assessment of the blood lactate level was measured in 1st, 2nd and 7th day with Lact2 Roche Cobas® C-System. Neurologic outcome assessed on 7th days using Modified GCS. Results: On initial assessment, 38.3% of patients with normal lactate (≤ 2 mMol/L, 61.7% of patients was hyperlactatemia ( > 2 mMol/L. In this study, it was obtained that the lower of GCS level, the higher of blood lactate level, and vice versa (p = 0.033. In both treatment, there was a significant lactate clearance 24-hour as 37.96% ± 32.76 (p = 0.001 and 13.49% ± 40.32 (p = 0.011, respectively. No significant changes between blood lactate level on the 2nd and 7th day, both operative (p = 0.938; p > 0.05 neither conservative (p = 0.280; p > 0.05 patient. While, there was no correlation between neurologic outcome with 24-hour lactate clearance (p = 0.349. The higher of the initial blood lactate level, the patient’s outcome was worsen (p = 0.029. Conclusion: There is a significant correlation between blood lactate level and severity TBI according to GCS level. The lower GCS level, the higher blood lactate level and vice versa. This study also demonstrates that 24-hour lactate clearance did not affect patient’s outcome, but more influence by initial blood lactate level. Therefore, initial blood lactate level can used as an outcome predictor in TBI patients.

  3. Early alterations in cerebral hemodynamics, brain metabolism, and blood-brain barrier permeability in experimental intracerebral hemorrhage.

    Science.gov (United States)

    Lee, E J; Hung, Y C; Lee, M Y

    1999-12-01

    The authors sought to ascertain the nature of the hemodynamic and metabolic derangement underlying acute pathophysiological events that occur after intracerebral hemorrhage (ICH). Cerebral perfusion pressure (CPP), flow velocity (FV) of the middle cerebral artery, and the arteriovenous contents of oxygen and lactate were investigated in 24 dogs subjected to sham operations (Group A, four animals) or intracerebral injections of 3 ml (Group B, 11 animals) or 5 ml (Group C, nine animals) autologous arterial blood. Twelve additional dogs received intravenous injections of 2% Evans blue or trypan blue dye to evaluate blood-brain barrier (BBB) changes. Within 1 hour, animals with ICH exhibited a rise in FV associated with significant reductions (pglycolysis. Furthermore, the data suggest that a selective increase in permeability, rather than anatomical disruption, of the BBB is involved in the acute pathophysiological events that occur after ICH, which may provide a possible gateway for systemic arterial lactate entering the SSS.

  4. Elucidation of mechanism of blood-brain barrier damage for prevention and treatment of vascular dementia.

    Science.gov (United States)

    Ueno, Masaki

    2017-03-28

    It is well-known that the blood-brain barrier (BBB) plays significant roles in transporting intravascular substances into the brain. The BBB in cerebral capillaries essentially impedes the influx of intravascular compounds from the blood to the brain, while nutritive substances, such as glucose, can be selectively transported through several types of influx transporters in endothelial cells. In the choroid plexus, intravascular substances can invade the parenchyma as fenestrations exist in endothelial cells of capillaries. However, the substances cannot invade the ventricles easily as there are tight junctions between epithelial cells in the choroid plexus. This restricted movement of the substances across the cytoplasm of the epithelial cells constitutes a blood-cerebrospinal fluid barrier (BCSFB). In the brain, there are circumventricular organs, in which the barrier function is imperfect in capillaries. Accordingly, it is reasonable to consider that intravascular substances can move in and around the parenchyma of the organs. Actually, it was reported in mice that intravascular substances moved in the corpus callosum, medial portions of the hippocampus, and periventricular areas via the subfornical organs or the choroid plexus. Regarding pathways of intracerebral interstitial and cerebrospinal fluids to the outside of the brain, two representative drainage pathways, or perivascular drainage and glymphatic pathways, are being established. The first is the pathway in a retrograde direction to the blood flow through the basement membrane in walls of cerebral capillaries, the tunica media of arteries, and the vessels walls of the internal carotid artery. The second is in an anterograde direction to blood flow through the para-arterial routes, aquaporin 4-dependent transport through the astroglial cytoplasm, and para-venous routes, and then the fluids drain into the subarachnoid CSF. These fluids are finally considered to drain into the cervical lymph nodes or veins

  5. Alpha adrenergic receptor blockade increases capillarisation and fractional O2 extraction and lowers blood flow in contracting human skeletal muscle

    DEFF Research Database (Denmark)

    Mortensen, Stefan Peter; Egginton, Stuart; Madsen, Mads

    2017-01-01

    . CONCLUSIONS: These results demonstrate that daily treatment with an α-adrenergic receptor blocker induces capillary growth in human skeletal muscle, likely due to increased shear stress. The increase in capillarisation resulted in an increased fractional O2 extraction, a lower blood flow and venous lactate......AIM: To investigate the effect of elevated basal shear stress on angiogenesis in humans, and the role of enhanced skeletal muscle capillarisation on blood flow and O2 extraction. METHODS: Limb haemodynamics and O2 extraction was measured at rest and during one-leg knee-extensor exercise (12 and 24W......) in 10 healthy untrained young men before and after 4 weeks treatment with an α1 receptor-antagonist (Terazosin, 1-2 mg day(-1) ). Corresponding biopsies were taken from the m. vastus lateralis. RESULTS: Resting leg blood flow was increased by 57% 6 hours following Terazosin treatment (P

  6. Multicellular Self-Assembled Spheroidal Model of the Blood Brain Barrier

    OpenAIRE

    Urich, Eduard; Patsch, Christoph; Aigner, Stefan; Graf, Martin; Iacone, Roberto; Freskg?rd, Per-Ola

    2013-01-01

    The blood brain barrier (BBB) has evolved unique characteristics such as dense coverage of the endothelial cells by pericytes and interactions with astrocytes through perivascular endfeet. We study BBB formation in a 3-dimensional multicellular spheroid system of human primary brain endothelial cells (hpBECs), primary pericytes (hpPs) and primary astrocytes (hpAs). We show for the first time that hpBECs, hpPs and hpAs spontaneously self-organize into a defined multicellular structure which re...

  7. Reference Brain/Blood Concentrations of Citalopram, Duloxetine, Mirtazapine and Sertraline

    DEFF Research Database (Denmark)

    Nedahl, Michael; Johansen, Sys Stybe; Linnet, Kristian

    2018-01-01

    according to their role in the cause of death, as follows: (A) concentrations where the drug was the sole cause of fatal intoxication; (B) concentrations where the drug contributed to a fatal outcome; and (C) concentrations where the drug was not related to the cause of death. The analytical method...... was successfully validated in brain tissue in terms of linearity, process efficiency, precision and accuracy. Quantification of analytes was performed by ultra-performance liquid chromatography with tandem mass spectrometry. Correlations between blood and brain concentrations were achieved with R2-values between 0...

  8. Expression of manganese superoxide dismutase in rat blood, heart and brain during induced systemic hypoxia

    Directory of Open Access Journals (Sweden)

    Septelia I. Wanandi

    2011-02-01

    Full Text Available Background: Hypoxia results in an increased generation of ROS. Until now, little is known about the role of MnSOD - a major endogenous antioxidant enzyme - on the cell adaptation response against hypoxia. The aim of this study was to  determine the MnSOD mRNA expression and levels of specific activity in blood, heart and brain of rats during induced systemic hypoxia.Methods: Twenty-five male Sprague Dawley rats were subjected to systemic hypoxia in an hypoxic chamber (at 8-10% O2 for 0, 1, 7, 14 and 21 days, respectively. The mRNA relative expression of MnSOD was analyzed using Real Time RT-PCR. MnSOD specific activity was determined using xanthine oxidase inhibition assay.Results: The MnSOD mRNA relative expression in rat blood and heart was decreased during early induced systemic hypoxia (day 1 and increased as hypoxia continued, whereas the mRNA expression in brain was increased since day 1 and reached its maximum level at day 7. The result of MnSOD specific activity during early systemic hypoxia was similar to the mRNA expression. Under very late hypoxic condition (day 21, MnSOD specific activity in blood, heart and brain was significantly decreased. We demonstrate a positive correlation between MnSOD mRNA expression and specific activity in these 3 tissues during day 0-14 of induced systemic hypoxia. Furthermore, mRNA expression and specific activity levels in heart strongly correlate with those in blood.Conclusion: The MnSOD expression at early and late phases of induced systemic hypoxia is distinctly regulated. The MnSOD expression in brain differs from that in blood and heart revealing that brain tissue can  possibly survive better from induced systemic hypoxia than heart and blood. The determination of MnSOD expression in blood can be used to describe its expression in heart under systemic hypoxic condition. (Med J Indones 2011; 20:27-33Keywords: MnSOD, mRNA expression, ROS, specific activity, systemic hypoxia

  9. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Lerebours, Adelaide; Adam-Guillermin, Christelle [Laboratoire de Radioecologie et d' Ecotoxicologie, Institut de Radioprotection et de Surete Nucleaire, Bat 186, BP 3, 13115 Saint-Paul-Lez-Durance Cedex (France); Brethes, Daniel [CNRS, UMR 5095, Institut de Biochimie et Genetique Cellulaires, Universite Victor Segalen-Bordeaux 2 (France); Frelon, Sandrine; Floriani, Magali; Camilleri, Virginie; Garnier-Laplace, Jacqueline [Laboratoire de Radioecologie et d' Ecotoxicologie, Institut de Radioprotection et de Surete Nucleaire, Bat 186, BP 3, 13115 Saint-Paul-Lez-Durance Cedex (France); Bourdineaud, Jean-Paul, E-mail: jp.bourdineaud@epoc.u-bordeaux1.fr [CNRS, UMR 5095, Institut de Biochimie et Genetique Cellulaires, Universite Victor Segalen-Bordeaux 2 (France)

    2010-10-01

    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 {mu}g 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 {mu}g/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.

  11. Effects of propranolol and clonidine on brain edema, blood-brain barrier permeability, and endothelial glycocalyx disruption after fluid percussion brain injury in the rat

    DEFF Research Database (Denmark)

    Genét, Gustav Folmer; Bentzer, Peter; Hansen, Morten Bagge

    2018-01-01

    ), vehicle (n = 16), or sham (n = 5) for 24 hours. Primary outcome was brain water content at 24 hours. Secondary outcomes were blood-brain barrier permeability and plasma levels of syndecan-1 (glycocalyx disruption), cell damage (histone-complexed DNA fragments), epinephrine, norepinephrine, and animal...... motor function. RESULTS: We found no difference in brain water content (mean ± SD) between propranolol (80.8 ± 0.3%; 95% confidence interval [CI], 80.7-81.0) and vehicle (81.1 ± 0.6%; 95% CI, 80.8-81.4) (p = 0.668) or between propranolol/clonidine (80.8 ± 0.3%; 95% CI, 80.7-81.0) and vehicle (p = 0...... beta-blockade with propranolol or the combination of propranolol and the alfa2-agonist clonidine on brain water content. The novel finding of an increase in plasma concentrations of epinephrine and syndecan-1 after propranolol treatment in traumatic brain injury is of unclear significance and should...

  12. Blood-brain barrier P-glycoprotein function decreases in specific brain regions with aging : A possible role in progressive neurodegeneration

    NARCIS (Netherlands)

    Bartels, Anna L.; Kortekaas, Rudie; Bart, Joost; Willemsen, Antoon T. M.; de Klerk, Onno L.; de Vries, Jeroen J.; van Oostrom, Joost C. H.; Leenders, Klaus L.

    2009-01-01

    Cerebrovascular P-glycoprotein (P-gp) acts at the blood-brain barrier (BBB) as an active cell membrane efflux pump for several endogenous and exogenous compounds. Age-associated decline in P-gp function could facilitate the accumulation of toxic substances in the brain, thus increasing the risk of

  13. CB2 Receptor Activation Inhibits Melanoma Cell Transmigration through the Blood-Brain Barrier

    Directory of Open Access Journals (Sweden)

    János Haskó

    2014-05-01

    Full Text Available During parenchymal brain metastasis formation tumor cells need to migrate through cerebral endothelial cells, which form the morphological basis of the blood-brain barrier (BBB. The mechanisms of extravasation of tumor cells are highly uncharacterized, but in some aspects recapitulate the diapedesis of leukocytes. Extravasation of leukocytes through the BBB is decreased by the activation of type 2 cannabinoid receptors (CB2; therefore, in the present study we sought to investigate the role of CB2 receptors in the interaction of melanoma cells with the brain endothelium. First, we identified the presence of CB1, CB2(A, GPR18 (transcriptional variant 1 and GPR55 receptors in brain endothelial cells, while melanoma cells expressed CB1, CB2(A, GPR18 (transcriptional variants 1 and 2, GPR55 and GPR119. We observed that activation of CB2 receptors with JWH-133 reduced the adhesion of melanoma cells to the layer of brain endothelial cells. JWH-133 decreased the transendothelial migration rate of melanoma cells as well. Our results suggest that changes induced in endothelial cells are critical in the mediation of the effect of CB2 agonists. Our data identify CB2 as a potential target in reducing the number of brain metastastes originating from melanoma.

  14. 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

    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......Optic neuritis is an acute inflammatory condition that is highly associated with multiple sclerosis. Currently, the best predictor of future development of multiple sclerosis is the number of T2 lesions visualized by magnetic resonance imaging. Previous research has found abnormalities...... in the 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...

  15. Blood borne hormones in a cross-talk between peripheral and brain mechanisms regulating blood pressure, the role of circumventricular organs.

    Science.gov (United States)

    Ufnal, Marcin; Skrzypecki, Janusz

    2014-04-01

    Accumulating evidence suggests that blood borne hormones modulate brain mechanisms regulating blood pressure. This appears to be mediated by the circumventricular organs which are located in the walls of the brain ventricular system and lack the blood-brain barrier. Recent evidence shows that neurons of the circumventricular organs express receptors for the majority of cardiovascular hormones. Intracerebroventricular infusions of hormones and their antagonists is one approach to evaluate the influence of blood borne hormones on the neural mechanisms regulating arterial blood pressure. Interestingly, there is no clear correlation between peripheral and central effects of cardiovascular hormones. For example, angiotensin II increases blood pressure acting peripherally and centrally, whereas peripherally acting pressor catecholamines decrease blood pressure when infused intracerebroventricularly. The physiological role of such dual hemodynamic responses has not yet been clarified. In the paper we review studies on hemodynamic effects of catecholamines, neuropeptide Y, angiotensin II, aldosterone, natriuretic peptides, endothelins, histamine and bradykinin in the context of their role in a cross-talk between peripheral and brain mechanisms involved in the regulation of arterial blood pressure. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Muscle activation and blood flow do not explain the muscle length-dependent variation in quadriceps isometric endurance

    NARCIS (Netherlands)

    Kooistra, R.D.; de Ruiter, C.J.; de Haan, A.

    2005-01-01

    We investigated the role of central activation in muscle length-dependent endurance. Central activation ratio (CAR) and rectified surface electromyogram (EMG) were studied during fatigue of isometric contractions of the knee extensors at 30 and 90° knee angles (full extension = 0°). Subjects (n = 8)

  17. Blood-brain barrier-on-a-chip: Microphysiological systems that capture the complexity of the blood-central nervous system interface.

    Science.gov (United States)

    Phan, Duc Tt; Bender, R Hugh F; Andrejecsk, Jillian W; Sobrino, Agua; Hachey, Stephanie J; George, Steven C; Hughes, Christopher Cw

    2017-11-01

    The blood-brain barrier is a dynamic and highly organized structure that strictly regulates the molecules allowed to cross the brain vasculature into the central nervous system. The blood-brain barrier pathology has been associated with a number of central nervous system diseases, including vascular malformations, stroke/vascular dementia, Alzheimer's disease, multiple sclerosis, and various neurological tumors including glioblastoma multiforme. There is a compelling need for representative models of this critical interface. Current research relies heavily on animal models (mostly mice) or on two-dimensional (2D) in vitro models, neither of which fully capture the complexities of the human blood-brain barrier. Physiological differences between humans and mice make translation to the clinic problematic, while monolayer cultures cannot capture the inherently three-dimensional (3D) nature of the blood-brain barrier, which includes close association of the abluminal side of the endothelium with astrocyte foot-processes and pericytes. Here we discuss the central nervous system diseases associated with blood-brain barrier pathology, recent advances in the development of novel 3D blood-brain barrier -on-a-chip systems that better mimic the physiological complexity and structure of human blood-brain barrier, and provide an outlook on how these blood-brain barrier-on-a-chip systems can be used for central nervous system disease modeling. Impact statement The field of microphysiological systems is rapidly evolving as new technologies are introduced and our understanding of organ physiology develops. In this review, we focus on Blood-Brain Barrier (BBB) models, with a particular emphasis on how they relate to neurological disorders such as Alzheimer's disease, multiple sclerosis, stroke, cancer, and vascular malformations. We emphasize the importance of capturing the three-dimensional nature of the brain and the unique architecture of the BBB - something that until recently

  18. Intravenous immunoglobulins prevent the breakdown of the blood-brain barrier in experimentally induced sepsis.

    Science.gov (United States)

    Esen, Figen; Senturk, Evren; Ozcan, Perihan E; Ahishali, Bulent; Arican, Nadir; Orhan, Nurcan; Ekizoglu, Oguzhan; Kucuk, Mutlu; Kaya, Mehmet

    2012-04-01

    The effects of immunoglobulin G and immunoglobulins enriched with immunoglobulin A and immunoglobulin M on blood-brain barrier integrity and survival rates in septic rats were comparatively investigated. Sepsis was induced by cecal ligation and perforation in Sprague-Dawley rats. The animals were divided into the following groups: Sham, cecal ligation and perforation, cecal ligation and perforation plus immunoglobulin G (250 mg/kg, intravenous), and cecal ligation and perforation plus immunoglobulins enriched with immunoglobulin A and immunoglobulin M (250 mg/kg, intravenous). Immunoglobulins were administered 5 mins before cecal ligation and perforation and the animals were observed for behavioral changes for 24 hrs following cecal ligation and perforation. Blood-brain barrier permeability was functionally and structurally evaluated by determining the extravasation of Evans Blue and horseradish peroxidase tracers, respectively. Immunohistochemistry and Western blotting for occludin were performed. The high mortality rate (34%) noted in the septic rats was decreased to 15% and 3% by immunoglobulin G and immunoglobulins enriched with immunoglobulin A and immunoglobulin M, respectively (p immunoglobulin G and immunoglobulins enriched with immunoglobulin A and immunoglobulin M alleviated the symptoms of sickness behavior in the septic rats, with the animals becoming healthy and active. Increased extravasation of Evans Blue into the brain tissue of the septic rats was markedly decreased with the administration of both immunoglobulin G and immunoglobulins enriched with immunoglobulin A and immunoglobulin M (p immunoglobulin G or immunoglobulins enriched with immunoglobulin A and immunoglobulin M treatment, no ultrastructural evidence of leaky capillaries in the brain was observed in the septic rats, indicating the blockade of the transcellular pathway by immunoglobulins administration. Our study suggests that immunoglobulin G and immunoglobulins enriched with

  19. Iron supplement prevents lead-induced disruption of the blood-brain barrier during rat development

    International Nuclear Information System (INIS)

    Wang Qiang; Luo Wenjing; Zheng Wei; Liu Yiping; Xu Hui; Zheng Gang; Dai Zhongming; Zhang Wenbin; Chen Yaoming; Chen Jingyuan

    2007-01-01

    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 FeSO 4 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

  20. Design and validation of a microfluidic device for blood-brain barrier monitoring and transport studies

    Science.gov (United States)

    Ugolini, Giovanni Stefano; Occhetta, Paola; Saccani, Alessandra; Re, Francesca; Krol, Silke; Rasponi, Marco; Redaelli, Alberto

    2018-04-01

    In vitro blood-brain barrier models are highly relevant for drug screening and drug development studies, due to the challenging task of understanding the transport mechanism of drug molecules through the blood-brain barrier towards the brain tissue. In this respect, microfluidics holds potential for providing microsystems that require low amounts of cells and reagent and can be potentially multiplexed for increasing the ease and throughput of the drug screening process. We here describe the design, development and validation of a microfluidic device for endothelial blood-brain barrier cell transport studies. The device comprises of two microstructured layers (top culture chamber and bottom collection chamber) sandwiching a porous membrane for the cell culture. Microstructured layers include two pairs of physical electrodes, embedded into the device layers by geometrically defined guiding channels with computationally optimized positions. These electrodes allow the use of commercial electrical measurement systems for monitoring trans-endothelial electrical resistance (TEER). We employed the designed device for performing preliminary assessment of endothelial barrier formation with murine brain endothelial cells (Br-bEnd5). Results demonstrate that cellular junctional complexes effectively form in the cultures (expression of VE-Cadherin and ZO-1) and that the TEER monitoring systems effectively detects an increase of resistance of the cultured cell layers indicative of tight junction formation. Finally, we validate the use of the described microsystem for drug transport studies demonstrating that Br-bEnd5 cells significantly hinder the transport of molecules (40 kDa and 4 kDa dextran) from the top culture chamber to the bottom collection chamber.

  1. Focused ultrasound delivery of Raman nanoparticles across the blood-brain barrier: Potential for targeting experimental brain tumors

    Science.gov (United States)

    Diaz, Roberto Jose; McVeigh, Patrick Z.; O’Reilly, Meaghan A.; Burrell, Kelly; Bebenek, Matthew; Smith, Christian; Etame, Arnold; Zadeh, Gelareh; Hynynen, Kullervo; Wilson, Brian C.; Rutka, James T.

    2014-01-01

    Spectral mapping of nanoparticles with surface enhanced Raman scattering (SERS) capability in the near-infrared range is an emerging molecular imaging technique. We used magnetic resonance image-guided transcranial focused ultrasound (TcMRgFUS) to reversibly disrupt the blood-brain barrier (BBB) adjacent to brain tumor margins in rats. Glioma cells were found to internalize SERS capable nanoparticles of 50 nm or 120 nm physical diameter. Surface coating with anti-epidermal growth factor receptor antibody or non-specific human immunoglobulin G, resulted in enhanced cell uptake of nanoparticles in-vitro compared to nanoparticles with methyl terminated 12-unit polyethylene glycol surface. BBB disruption permitted the delivery of SERS capable spherical 50 or 120 nm gold nanoparticles to the tumor margins. Thus, nanoparticles with SERS imaging capability can be delivered across the BBB non-invasively using TcMRgFUS and have the potential to be used as optical tracking agents at the invasive front of malignant brain tumors. PMID:24374363

  2. Energy harvesting from arterial blood pressure for powering embedded micro sensors in human brain

    Science.gov (United States)

    Nanda, Aditya; Karami, M. Amin

    2017-03-01

    This manuscript investigates energy harvesting from arterial blood pressure via the piezoelectric effect for the purpose of powering embedded micro-sensors in the human brain. One of the major hurdles in recording and measuring electrical data in the human nervous system is the lack of implantable and long term interfaces that record neural activity for extended periods of time. Recently, some authors have proposed micro sensors implanted deep in the brain that measure local electrical and physiological data which are then communicated to an external interrogator. This paper proposes a way of powering such interfaces. The geometry of the proposed harvester consists of a piezoelectric, circular, curved bimorph that fits into the blood vessel (specifically, the Carotid artery) and undergoes bending motion because of blood pressure variation. In addition, the harvester thickness is constrained such that it does not modify arterial wall dynamics. This transforms the problem into a known strain problem and the integral form of Gauss's law is used to obtain an equation relating arterial wall motion to the induced voltage. The theoretical model is validated by means of a Multiphysics 3D-FEA simulation comparing the harvested power at different load resistances. The peak harvested power achieved for the Carotid artery (proximal to Brain), with PZT-5H, was 11.7 μW. The peak power for the Aorta was 203.4 μW. Further, the variation of harvested power with variation in the harvester width and thickness, arterial contractility, and pulse rate is investigated. Moreover, potential application of the harvester as a chronic, implantable and real-time Blood pressure sensor is considered. Energy harvested via this mechanism will also have applications in long-term, implantable Brain Micro-stimulation.

  3. 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), ...

  4. /GD-Tracker/ A software for blood-brain barrier permeability assessment\

    Czech Academy of Sciences Publication Activity Database

    Kala, David; Svoboda, Jan; Litvinec, Andrej; Pošusta, Antonín; Lisý, J.; Šulc, V.; Tomek, A.; Marusič, P.; Jiruška, Přemysl; Otáhal, Jakub

    2017-01-01

    Roč. 47, č. 2 (2017), s. 43-48 ISSN 0301-5491 R&D Projects: GA MZd(CZ) NV15-33115A; GA MŠk(CZ) LM2015062 Institutional support: RVO:67985823 Keywords : blood-brain barrier * MRI * Gd-DTPA * permeability * stroke * epileptogenesis * MATLAB * freeware * Gd-Tracker Subject RIV: FH - Neurology OBOR OECD: Neurosciences (including psychophysiology

  5. Comparison between PVHIS on the MRI and the permeability of brain blood vessels in elderly patients

    International Nuclear Information System (INIS)

    Yamaguchi, Katsuhiko; Tanaka, Yuriko; Kubo, Hideki; Takagi, Yasushi; Tachikawa, Shinzo; Katsunuma, Hideyo.

    1989-01-01

    The degree of PVHIS (periventricular high intensity signal) on the MRI was composed with the permeability of brain blood vessels using the cerebrospinal fluid (CSF)/serum ratio for albumin, and the CSF/serum ratio for IgG in elderly patients. The 47 elderly patients (mean age=79.9) were divided into three groups: (1) Mild group (20 cases, M:6, F:14, mean age=75.8), (2) Moderate group (18 cases, M:7, F:11, mean age=82.6), (3) Severe group (9 cases, M:2, F:7, mean age=82.9), in accordance with the degree of PVHIS on the MRI. The MRI was operated at a field strength of 0.22 tesla. The pulse sequence (used on all patients) had a repetition times (TR) of 2,000 msec and a time to echo (TE) of 40 msec. The levels of albumin and IgG in the serum and CSF were measured. The CSF/serum ratio for albumin was used of analyze the permeability of the brain blood vessels in each group. There was no significant difference in the level of the serum albumin, the CSF albumin, the serum IgG, the CSF IgG and the CSF/serum ratio for IgG among the three groups. The same was found to be true for the IgG index which indicates the synthesis of immunoglobulin in the central nervous system. However, there was a statistically significant difference (p<0.05) in the CSF/serum ratio for albumin between groups (1) and (3). The increased CSF/serum ratio for albumin in the severe group indicated there were confluent lesions involving the entire extent of the periventriular white matter on the MRI. This suggested an increased permeability of brain blood vessels which revealed the dysfunction of the blood brain barrier due to affected cerebral endothelial cells in capillaries. (author)

  6. Role of cerebral blood volume changes in brain specific-gravity measurements

    International Nuclear Information System (INIS)

    Picozzi, P.; Todd, N.V.; Crockard, A.H.

    1985-01-01

    Cerebral blood volume (CBV) was calculated in gerbils from specific-gravity (SG) changes between normal and saline-perfused brains. Furthermore, changes in CBV were investigated during ischemia using carbon-14-labeled dextran (MW 70,000) as an intravascular marker. Both data were used to evaluate the possible error due to a change in CBV on the measurement of ischemic brain edema by the SG method. The methodological error found was 0.0004 for a 100% CBV change. This error is insignificant, being less than the standard deviation in the SG measured for the gerbil cortex. Thus, CBV changes are not responsible for the SG variations observed during the first phase of ischemia. These variations are better explained as an increase of brain water content during ischemia

  7. Tryps and trips: cell trafficking across the 100-year-old blood-brain barrier.

    Science.gov (United States)

    Bentivoglio, Marina; Kristensson, Krister

    2014-06-01

    One hundred years ago, Edwin E. Goldmann discovered the blood-brain barrier (BBB) using trypan dyes. These dyes were developed and named by Paul Ehrlich during his search for drugs to kill African trypanosomes (extracellular parasites that cause sleeping sickness) while sparing host cells. For Ehrlich, this was the first strategy based on the 'chemotherapy' concept he had introduced. The discovery of the BBB revealed, however, the difficulties in drug delivery to the brain. Mechanisms by which parasites enter, dwell, and exit the brain currently provide novel views on cell trafficking across the BBB. These mechanisms also highlight the role of pericytes and endocytosis regulation in BBB functioning and in disrupted BBB gating, which may be involved in the pathogenesis of neurodegeneration. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  8. Are blood flow and lipolysis in subcutaneous adipose tissue influenced by contractions in adjacent muscles in humans?

    DEFF Research Database (Denmark)

    Stallknecht, Bente; Dela, Flemming; Helge, Jørn Wulff

    2006-01-01

    Aerobic exercise increases whole body adipose tissue lipolysis, but is lipolysis higher in subcutaneous adipose tissue (SCAT) adjacent to contracting muscles than in SCAT adjacent to resting muscles? Ten healthy, overnight-fasted males performed one-legged knee extension exercise at 25% of maximal...... workload (W(max)) for 30 min followed by exercise at 55% W(max) for 120 min with the other leg and finally exercised at 85% W(max) for 30 min with the first leg. Subjects rested for 30 min between exercise periods. Femoral SCAT blood flow was estimated from washout of (133)Xe, and lipolysis was calculated...... from femoral SCAT interstitial and arterial glycerol concentrations and blood flow. In general, blood flow and lipolysis were higher in femoral SCAT adjacent to contracting than adjacent to resting muscle (time 15-30 min; blood flow: 25% W(max) 6.6 +/- 1.0 vs. 3.9 +/- 0.8 ml x 100 g(-1) x min(-1), P...

  9. Muscle fatigue in fibromyalgia is in the brain, not in the muscles: a case-control study of perceived versus objective muscle fatigue.

    Science.gov (United States)

    Bandak, Elisabeth; Amris, Kirstine; Bliddal, Henning; Danneskiold-Samsøe, Bente; Henriksen, Marius

    2013-06-01

    To investigate relationships between perceived and objectively measured muscle fatigue during exhausting muscle contractions in women with fibromyalgia (FM) compared with healthy controls (HC). Women with FM and HC completed an isometric muscle exhaustion task at 90° shoulder abduction. Surface electromyographic (EMG) activity in the deltoid muscle was recorded together with self-reported level of muscle fatigue. 25 participants with FM and 23 HC were included. Average time to exhaustion was 254 s shorter in participants with FM than in HC. Participants with FM did not exhibit the same level of objective signs of muscle fatigue, seen as fewer changes in the EMG activity, as the HC during the exhaustion task. The task did not provoke pain in the HC, while participants with FM reported a doubling of pain. Women with FM had shorter exhaustion times and showed fewer objective signs of muscle fatigue during an exhausting isometric shoulder abduction compared with younger HC. This indicates that perceived muscle fatigue may be of central origin and supports the notion of central nervous dysfunction as basic pathological changes in FM.

  10. Hypomyelination, memory impairment, and blood-brain barrier permeability in a model of sleep apnea.

    Science.gov (United States)

    Kim, Lenise Jihe; Martinez, Denis; Fiori, Cintia Zappe; Baronio, Diego; Kretzmann, Nélson Alexandre; Barros, Helena Maria Tannhauser

    2015-02-09

    We investigated the effect of intermittent hypoxia, mimicking sleep apnea, on axonal integrity, blood-brain barrier permeability, and cognitive function of mice. Forty-seven C57BL mice were exposed to intermittent or sham hypoxia, alternating 30s of progressive hypoxia and 30s of reoxigenation, during 8h/day. The axonal integrity in cerebellum was evaluated by transmission electron microscopy. Short- and long-term memories were assessed by novel object recognition test. The levels of endothelin-1 were measured by ELISA. Blood-brain barrier permeability was quantified by Evans Blue dye. After 14 days, animals exposed to intermittent hypoxia showed hypomyelination in cerebellum white matter and higher serum levels of endothelin-1. The short and long-term memories in novel object recognition test was impaired in the group exposed to intermittent hypoxia as compared to controls. Blood-brain barrier permeability was similar between the groups. These results indicated that hypomyelination and impairment of short- and long-term working memories occurred in C57BL mice after 14 days of intermittent hypoxia mimicking sleep apnea. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Extraction of [99mTc]-d,l-HM-PAO across the blood-brain barrier

    DEFF Research Database (Denmark)

    Andersen, A R; Friberg, H; Knudsen, K B

    1988-01-01

    The initial extraction (E) across the blood-brain barrier (BBB) of [99mTc]-d,l-HM-PAO after intracarotid injection was measured in 14 Wistar rats and 6 patients using the double indicator, single injection method with Na-24 as the cotracer. In both series, cerebral blood flow (CBF) was measured...... was increased from 20 to 120 microliters, while using a 120 microliters bolus containing 10% albumin resulted in a decrease in E. This suggests that HM-PAO binding to albumin is not totally and rapidly reversible during a single passage through brain capillaries and that binding to blood elements may reduce...... the apparent extraction across brain capillaries. In patients using a bolus of 1 ml saline, E decreased linearly with increasing CBF (r = -0.81, p less than 0.001). For a CBF of 0.59 ml/g/min and an average apparent E of 0.72, an apparent PS product of 0.76 ml/g/min was calculated.(ABSTRACT TRUNCATED AT 250...

  12. Microfluidic organ-on-chip technology for blood-brain barrier research.

    Science.gov (United States)

    van der Helm, Marinke W; van der Meer, Andries D; Eijkel, Jan C T; van den Berg, Albert; Segerink, Loes I

    2016-01-01

    Organs-on-chips are a new class of microengineered laboratory models that combine several of the advantages of current in vivo and in vitro models. In this review, we summarize the advances that have been made in the development of organ-on-chip models of the blood-brain barrier (BBBs-on-chips) and the challenges that are still ahead. The BBB is formed by specialized endothelial cells and separates blood from brain tissue. It protects the brain from harmful compounds from the blood and provides homeostasis for optimal neuronal function [corrected]. Studying BBB function and dysfunction is important for drug development and biomedical research. Microfluidic BBBs-on-chips enable real-time study of (human) cells in an engineered physiological microenvironment, for example incorporating small geometries and fluid flow as well as sensors. Examples of BBBs-on-chips in literature already show the potential of more realistic microenvironments and the study of organ-level functions. A key challenge in the field of BBB-on-chip development is the current lack of standardized quantification of parameters such as barrier permeability and shear stress. This limits the potential for direct comparison of the performance of different BBB-on-chip models to each other and existing models. We give recommendations for further standardization in model characterization and conclude that the rapidly emerging field of BBB-on-chip models holds great promise for further studies in BBB biology and drug development.

  13. Effects of insulin on hexose transport across blood-brain barrier in normoglycemia

    International Nuclear Information System (INIS)

    Namba, H.; Lucignani, G.; Nehlig, A.; Patlak, C.; Pettigrew, K.; Kennedy, C.; Sokoloff, L.

    1987-01-01

    The effects of insulin on 3-O-[ 14 C] methylglucose transport across the blood-brain barrier (BBB) were studied in conscious rats under steady-state normoglycemic conditions. The [ 14 C]methylglucose was infused intravenously at a constant rate, and animals were killed at various times between 5 and 30 min after the initiation of the infusion. The time course of the arterial plasma concentration of [ 14 C]methylglucose was determined in timed arterial blood samples taken during the infusion. Local cerebral tissue concentrations of [ 14 C]methylglucose at the time of killing were determined by quantitative autoradiography of brain sections. The rate constants for inward and outward transport of [ 14 C]methylglucose across the BBB, K 1 , and k 2 , respectively, were estimated by a least-squares, best-fit of a kinetic equation to the measured time courses of plasma and tissue concentrations. The equilibrium distribution ration, K 1 /k 2 , for [ 14 C]methylglucose in brain increased by ∼ 10-11% in the hyperinsulinemic animals. Because 3-O-[ 14 C]methylglucose shares the same carrier that transports glucose and other hexoses across the BBB, these results suggest that hyperinsulinemia decreases the rate constants for transport but increases the distribution space for hexoses in brain. These effects are, however, quite small and are probably minor or negligible when compared with the major effects of insulin in other tissues

  14. Kinetics of Transferrin and Transferrin-Receptor during Iron Transport through Blood Brain Barrier

    Science.gov (United States)

    Khan, Aminul; Liu, Jin; Dutta, Prashanta

    2017-11-01

    Transferrin and its receptors play an important role during the uptake and transcytosis of iron by blood brain barrier (BBB) endothelial cells to maintain iron homeostasis in BBB endothelium and brain. In the blood side of BBB, ferric iron binds with the apo-transferrin to form holo-transferrin which enters the endothelial cell via transferrin receptor mediated endocytosis. Depending on the initial concentration of iron inside the cell endocytosed holo-transferrin can either be acidified in the endosome or exocytosed through the basolateral membrane. Acidification of holo-transferrin in the endosome releases ferrous irons which may either be stored and used by the cell or transported into brain side. Exocytosis of the holo-transferrin through basolateral membrane leads to transport of iron bound to transferrin into brain side. In this work, kinetics of internalization, recycling and exocytosis of transferrin and its receptors are modeled by laws of mass action during iron transport in BBB endothelial cell. Kinetic parameters for the model are determined by least square analysis. Our results suggest that the cell's initial iron content determines the extent of the two possible iron transport pathways, which will be presented in this talk Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R01GM122081.

  15. Increased blood-brain barrier vulnerability to systemic inflammation in an Alzheimer disease mouse model.

    Science.gov (United States)

    Takeda, Shuko; Sato, Naoyuki; Ikimura, Kazuko; Nishino, Hirohito; Rakugi, Hiromi; Morishita, Ryuichi

    2013-08-01

    Behavioral and psychological problems are often observed in patients with dementia such as that associated with Alzheimer disease, and these noncognitive symptoms place an extremely heavy burden on the family and caregivers. Although it is well know that these symptoms often are triggered by infection of peripheral organs, the underlying mechanisms for these pathological conditions are still unclear. In this study, using an Alzheimer amyloid precursor protein (APP)-transgenic mouse, we analyzed behavioral changes and brain inflammatory response induced by peripheral administration of lipopolysaccharide. Application of a unique in vivo microdialysis system revealed that the increase in brain inflammatory cytokine (interleukin-6) level was significantly higher in APP-Tg than in wild-type mice after peripheral lipopolysaccharide injection, which was associated with more severe sickness behaviors. The blood-brain barrier became more permeable in APP-Tg mice during peripherally evoked inflammation, suggesting the increased vulnerability of the blood-brain barrier to inflammation in this animal model of Alzheimer's disease. These findings might provide insight into the pathogenesis of noncognitive symptoms in dementia and a basis to develop new therapeutic treatments for them. Copyright © 2013 Elsevier Inc. All rights reserved.

  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. Aging alters mRNA expression of amyloid transporter genes at the blood-brain barrier.

    Science.gov (United States)

    Osgood, Doreen; Miller, Miles C; Messier, Arthur A; Gonzalez, Liliana; Silverberg, Gerald D

    2017-09-01

    Decreased clearance of potentially toxic metabolites, due to aging changes, likely plays a significant role in the accumulation of amyloid-beta (Aβ) peptides and other macromolecules in the brain of the elderly and in the patients with Alzheimer's disease (AD). Aging is the single most important risk factor for AD development. Aβ transport receptor proteins expressed at the blood-brain barrier are significantly altered with age: the efflux transporters lipoprotein receptor-related protein 1 and P-glycoprotein are reduced, whereas the influx transporter receptor for advanced glycation end products is increased. These receptors play an important role in maintaining brain biochemical homeostasis. We now report that, in a rat model of aging, gene transcription is altered in aging, as measured by Aβ receptor gene messenger RNA (mRNA) at 3, 6, 9, 12, 15, 20, 30, and 36 months. Gene mRNA expression from isolated cerebral microvessels was measured by quantitative polymerase chain reaction. Lipoprotein receptor-related protein 1 and P-glycoprotein mRNA were significantly reduced in aging, and receptor for advanced glycation end products was increased, in parallel with the changes seen in receptor protein expression. Transcriptional changes appear to play a role in aging alterations in blood-brain barrier receptor expression and Aβ accumulation. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Human blood-brain barrier insulin-like growth factor receptor

    International Nuclear Information System (INIS)

    Duffy, K.R.; Pardridge, W.M.; Rosenfeld, R.G.

    1988-01-01

    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 125 I-IGF-1, 125 I-IGF-2, and 125 I-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

  19. Xenon-133 determination of muscle blood flow: Use in evaluating cardioactive drugs

    International Nuclear Information System (INIS)

    Wexler, J.P.; Davis, L.; Mancini, D.; Chadwick, B.; Le Jemtel, T.

    1985-01-01

    Cardioactive drugs may effect both the central and peripheral circulatory systems. The effects on the central and peripheral circulatory systems of chronic Captorpril therapy in 7 pts with severe congestive heart failure (CHF) were evaluated simultaneously. Skeletal muscle blood flow (SMBF) determined using 133-Xe washout and a Cd/Te detector, oxygen consumption (VO/sub 2/), and radial artery and femoral vein O/sub 2/ concentration difference (A-V) were determined at rest and peak upright bicycle exercise before (BT) and after (AT) 6-12 weeks of Captopril therapy. In CI pts there was a significant increase in VO/sub 2/ and SMBF AT vs BT. In contrast, in CNC pts there was no change in VO/sub 2/ and a significant decrease in SMBF AT vs BT. In pts with severe CHF who are CI, there is an apparent fall in peripheral vascular resistance (PVR). In contrast, in CNC pts there is an increase in PVR. This study demonstrates that SMBF determines using 133-Xe is an important method for determining the effects of cardioactive drugs

  20. Muscle Deoxygenation Causes Muscle Fatigue

    Science.gov (United States)

    Murthy, G.; Hargens, A. R.; Lehman, S.; Rempel, D.

    1999-01-01

    Muscle fatigue is a common musculoskeletal disorder in the work place, and may be a harbinger for more disabling cumulative trauma disorders. Although the cause of fatigue is multifactorial, reduced blood flow and muscle oxygenation may be the primary factor in causing muscle fatigue during low intensity muscle exertion. Muscle fatigue is defined as a reduction in muscle force production, and also occurs among astronauts who are subjected to postural constraints while performing lengthy, repetitive tasks. The objectives of this research are to: 1) develop an objective tool to study the role of decreased muscle oxygenation on muscle force production, and 2) to evaluate muscle fatigue during prolonged glovebox work.

  1. Control of abdominal muscles by brain stem respiratory neurons in the cat.

    Science.gov (United States)

    Miller, A D; Ezure, K; Suzuki, I

    1985-07-01

    Control of abdominal musculature by brain stem respiratory neurons was studied in decerebrate unanesthetized cats by determining 1) which brain stem respiratory neurons could be antidromically activated from the lumbar cord, from which the abdominal muscles receive part of their innervation, and 2) if lumbar-projecting respiratory neurons make monosynaptic connections with abdominal motoneurons. A total of 462 respiratory neurons, located between caudal C2 and the retrofacial nucleus (Bötzinger complex), were tested for antidromic activation from the upper lumbar cord. Fifty-eight percent of expiratory (E) neurons (70/121) in the caudal ventral respiratory group (VRG) between the obex and rostral C1 were antidromically activated from contralateral L1. Eight of these neurons were activated at low thresholds from lamina VIII and IX in the L1-2 gray matter. One-third (14/41) of the E neurons that projected to L1 could also be activated from L4-5. Almost all antidromic E neurons had an augmenting firing pattern. Ten scattered inspiratory (I) neurons projected to L1 but could not be activated from L4-5. No neurons that fired during both E and I phases (phase-spanning neurons) were antidromically activated from the lumbar cord. In order to test for possible monosynaptic connections between descending E neurons and abdominal motoneurons, cross-correlations were obtained between 27 VRG E neurons, which were antidromically activated from caudal L2 and contralateral L1 and L2 abdominal nerve activity (47 neuron-nerve combinations). Only two neurons showed a correlation with one of the two nerves tested. Although there is a large projection to the lumbar cord from expiratory neurons in the ventral respiratory group caudal to the obex, cross-correlation analyses suggest that strong monosynaptic connections between these neurons and abdominal motoneurons are scarce.

  2. A Triple Culture Model of the Blood-Brain Barrier Using Porcine Brain Endothelial cells, Astrocytes and Pericytes.

    Science.gov (United States)

    Thomsen, Louiza Bohn; Burkhart, Annette; Moos, Torben

    2015-01-01

    In vitro blood-brain barrier (BBB) models based on primary brain endothelial cells (BECs) cultured as monoculture or in co-culture with primary astrocytes and pericytes are useful for studying many properties of the BBB. The BECs retain their expression of tight junction proteins and efflux transporters leading to high trans-endothelial electric resistance (TEER) and low passive paracellular permeability. The BECs, astrocytes and pericytes are often isolated from small rodents. Larger species as cows and pigs however, reveal a higher yield, are readily available and have a closer resemblance to humans, which make them favorable high-throughput sources for cellular isolation. The aim of the present study has been to determine if the preferable combination of purely porcine cells isolated from the 6 months old domestic pigs, i.e. porcine brain endothelial cells (PBECs) in co-culture with porcine astrocytes and pericytes, would compare with PBECs co-cultured with astrocytes and pericytes isolated from newborn rats with respect to TEER value and low passive permeability. The astrocytes and pericytes were grown both as contact and non-contact co-cultures as well as in triple culture to examine their effects on the PBECs for barrier formation as revealed by TEER, passive permeability, and expression patterns of tight junction proteins, efflux transporters and the transferrin receptor. This syngenic porcine in vitro BBB model is comparable to triple cultures using PBECs, rat astrocytes and rat pericytes with respect to TEER formation, low passive permeability, and expression of hallmark proteins signifying the brain endothelium (tight junction proteins claudin 5 and occludin, the efflux transporters P-glycoprotein (PgP) and breast cancer related protein (BCRP), and the transferrin receptor).

  3. The protective effect of HET0016 on brain edema and blood-brain barrier dysfunction after cerebral ischemia/reperfusion.

    Science.gov (United States)

    Liu, Yu; Wang, Di; Wang, Huan; Qu, Youyang; Xiao, Xingjun; Zhu, Yulan

    2014-01-28

    N-hydroxy-N-(4-butyl-2-methylphenyl) formamidine (HET0016) is a specific 20-hydroxyeicosatetraenoic acid (20-HETE) inhibitor which was first synthesized in 2001. It has been demonstrated that HET0016 reduces cerebral infarction volume in rat middle cerebral artery occlusion (MCAO) models. However, little is known about the role of HET0016 in the blood-brain barrier (BBB) dysfunction after cerebral ischemia/reperfusion (I/R) injury. The present study was designed to examine the effect of HET0016 in a MCAO and reperfusion rat model to determine whether it protects against brain edema and BBB disruption. Rats were subjected to 90 min MCAO, followed by 4, 24, 48, and 72 h reperfusion. Brain edema was measured according to the wet and dry weight method. BBB permeability based on the extravasation of Evans blue and sodium fluorescein was detected. BBB ultrastructure alterations were presented through transmission electron microscope. Superoxide production in ischemic tissue was also measured by dihydroethidium fluorescent probe. Western blot was used to analyze the expression of Claudin-5, ZO-1, MMP-9, and JNK pathway. At 24h after reperfusion, HET0016 reduced brain edema and BBB leakage. Ultrastructural damage of BBB and the increase of superoxide production were attenuated by HET0016 treatment. Western blot showed that HET0016 suppressed the activation of MMP-9 and JNK pathway but restored the expression of Claudin-5 and ZO-1. In conclusion, these results suggest that HET0016 protects BBB dysfunction after I/R by regulating the expression of MMP-9 and tight junction proteins. Furthermore, inhibition of oxidative stress and JNK pathway may be involved in this protecting effect. © 2013 Published by Elsevier B.V.

  4. Permeability of PEGylated immunoarsonoliposomes through in vitro blood brain barrier-medulloblastoma co-culture models for brain tumor therapy.

    Science.gov (United States)

    Al-Shehri, Abdulghani; Favretto, Marco E; Ioannou, Panayiotis V; Romero, Ignacio A; Couraud, Pierre-Olivier; Weksler, Babette Barbash; Parker, Terry L; Kallinteri, Paraskevi

    2015-03-01

    Owing to restricted access of pharmacological agents into the brain due to blood brain barrier (BBB) there is a need: 1. to develop a more representative 3-D-co-culture model of tumor-BBB interaction to investigate drug and nanoparticle transport into the brain for diagnostic and therapeutic evaluation. 2. to address the lack of new alternative methods to animal testing according to replacement-reduction-refinement principles. In this work, in vitro BBB-medulloblastoma 3-D-co-culture models were established using immortalized human primary brain endothelial cells (hCMEC/D3). hCMEC/D3 cells were cultured in presence and in absence of two human medulloblastoma cell lines on Transwell membranes. In vitro models were characterized for BBB formation, zonula occludens-1 expression and permeability to dextran. Transferrin receptors (Tfr) expressed on hCMEC/D3 were exploited to facilitate arsonoliposome (ARL) permeability through the BBB to the tumor by covalently attaching an antibody specific to human Tfr. The effect of anticancer ARLs on hCMEC/D3 was assessed. In vitro BBB and BBB-tumor co-culture models were established successfully. BBB permeability was affected by the presence of tumor aggregates as suggested by increased permeability of ARLs. There was a 6-fold and 8-fold increase in anti-Tfr-ARL uptake into VC312R and BBB-DAOY co-culture models, respectively, compared to plain ARLs. The three-dimensional models might be appropriate models to study the transport of various drugs and nanocarriers (liposomes and immunoarsonoliposomes) through the healthy and diseased BBB. The immunoarsonoliposomes can be potentially used as anticancer agents due to good tolerance of the in vitro BBB model to their toxic effect.

  5. Fatty Acid-Binding Protein 5 at the Blood-Brain Barrier Regulates Endogenous Brain Docosahexaenoic Acid Levels and Cognitive Function.

    Science.gov (United States)

    Pan, Yijun; Short, Jennifer L; Choy, Kwok H C; Zeng, Annie X; Marriott, Philip J; Owada, Yuji; Scanlon, Martin J; Porter, Christopher J H; Nicolazzo, Joseph A

    2016-11-16

    Fatty acid-binding protein 5 (FABP5) at the blood-brain barrier contributes to the brain uptake of docosahexaenoic acid (DHA), a blood-derived polyunsaturated fatty acid essential for maintenance of cognitive function. Given the importance of DHA in cognition, the aim of this study was to investigate whether deletion of FABP5 results in cognitive dysfunction and whether this is associated with reduced brain endothelial cell uptake of exogenous DHA and subsequent attenuation in the brain levels of endogenous DHA. Cognitive function was assessed in male and female FABP5 +/+ and FABP5 -/- mice using a battery of memory paradigms. FABP5 -/- mice exhibited impaired working memory and short-term memory, and these cognitive deficits were associated with a 14.7 ± 5.7% reduction in endogenous brain DHA levels. The role of FABP5 in the blood-brain barrier transport of DHA was assessed by measuring 14 C-DHA uptake into brain endothelial cells and capillaries isolated from FABP5 +/+ and FABP5 -/- mice. In line with a crucial role of FABP5 in the brain uptake of DHA, 14 C-DHA uptake into brain endothelial cells and brain capillaries of FABP5 -/- mice was reduced by 48.4 ± 14.5% and 14.0 ± 4.2%, respectively, relative to those of FABP5 +/+ mice. These results strongly support the hypothesis that FABP5 is essential for maintaining brain endothelial cell uptake of DHA, and that cognitive deficits observed in FABP5 -/- mice are associated with reduced CNS access of DHA. Genetic deletion of fatty acid-binding protein 5 (FABP5) in mice reduces uptake of exogenous docosahexaenoic acid (DHA) into brain endothelial cells and brain capillaries and reduces brain parenchymal levels of endogenous DHA. Therefore, FABP5 in the brain endothelial cell is a crucial contributor to the brain levels of DHA. Critically, lowered brain DHA levels in FABP5 -/- mice occurred in tandem with cognitive deficits in a battery of memory paradigms. This study provides evidence of a critical role for FABP5

  6. An improved in vitro blood-brain barrier model: rat brain endothelial cells co-cultured with astrocytes.

    Science.gov (United States)

    Abbott, N Joan; Dolman, Diana E M; Drndarski, Svetlana; Fredriksson, Sarah M

    2012-01-01

    In vitro blood-brain barrier (BBB) models using primary cultured brain endothelial cells are important for establishing cellular and molecular mechanisms of BBB function. Co-culturing with BBB-associated cells especially astrocytes to mimic more closely the in vivo condition leads to upregulation of the BBB phenotype in the brain endothelial cells. Rat brain endothelial cells (RBECs) are a valuable tool allowing ready comparison with in vivo studies in rodents; however, it has been difficult to obtain pure brain endothelial cells, and few models achieve a transendothelial electrical resistance (TEER, measure of tight junction efficacy) of >200 Ω cm(2), i.e. the models are still relatively leaky. Here, we describe methods for preparing high purity RBECs and neonatal rat astrocytes, and a co-culture method that generates a robust, stable BBB model that can achieve TEER >600 Ω cm(2). The method is based on >20 years experience with RBEC culture, together with recent improvements to kill contaminating cells and encourage BBB differentiation.Astrocytes are isolated by mechanical dissection and cell straining and are frozen for later co-culture. RBECs are isolated from 3-month-old rat cortices. The brains are cleaned of meninges and white matter and enzymatically and mechanically dissociated. Thereafter, the tissue homogenate is centrifuged in bovine serum albumin to separate vessel fragments from other cells that stick to the myelin plug. The vessel fragments undergo a second enzyme digestion to separate pericytes from vessels and break down vessels into shorter segments, after which a Percoll gradient is used to separate capillaries from venules, arterioles, and single cells. To kill remaining contaminating cells such as pericytes, the capillary fragments are plated in puromycin-containing medium and RBECs grown to 50-60% confluence. They are then passaged onto filters for co-culture with astrocytes grown in the bottom of the wells. The whole procedure takes ∼2

  7. Remission spectrometry for blood vessel detection during stereotactic biopsy of brain tumors.

    Science.gov (United States)

    Markwardt, Niklas A; Stepp, Herbert; Franz, Gerhard; Sroka, Ronald; Goetz, Marcus; Zelenkov, Petr; Rühm, Adrian

    2017-08-01

    Stereotactic biopsy is used to enable diagnostic confirmation of brain tumors and treatment planning. Despite being a well-established technique, it is related to significant morbidity and mortality rates mostly caused by hemorrhages due to blood vessel ruptures. This paper presents a method of vessel detection during stereotactic biopsy that can be easily implemented by integrating two side-view fibers into a conventional side-cutting biopsy needle. Tissue within the needle window is illuminated through the first fiber; the second fiber detects the remitted light. By taking the ratio of the intensities at two wavelengths with strongly differing hemoglobin absorption, blood vessels can be recognized immediately before biopsy sampling. Via ray tracing simulations and phantom experiments, the dependency of the remission ratio R = I 578 /I 650 on various parameters (blood oxygenation, fiber-to-vessel and inter-fiber distance, vessel diameter and orientation) was investigated for a bare-fiber probe. Up to 800-1200 µm away from the probe, a vessel can be recognized by a considerable reduction of the remission ratio from the background level. The technique was also successfully tested with a real biopsy needle probe on both optical phantoms and ex-vivo porcine brain tissue, thus showing potential to improve the safety of stereotactic biopsy. Dual-wavelength remission measurement for the detection of blood vessels during stereotactic biopsy. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Autoregulation of spinal cord blood flow: is the cord a microcosm of the brain

    Energy Technology Data Exchange (ETDEWEB)

    Hickey, R.; Albin, M.S.; Bunegin, L.; Gelineau, J.

    1986-11-01

    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.

  9. The Effect of an Experimental Missile Wound to the Brain on Brain Electrolytes, Regional Cerebral Blood Flow and Blood Brain Barrier Permeability.

    Science.gov (United States)

    1987-02-10

    that many brain-wounded soldiers rendered apneac by a missile fragment to a cerebral hemisphere could be saved if early ventilatory support were A...CYCLO --- INHIBITION-ASPIRIN ,, OXYGERASEOXGENASE INDOMETHACIN PGG 2 TXA 2 PI PGE2 PGF PGD p .. Figure 35: Schematic of arachidonic acid metabolism...cyclic AMP. ? coregulator of adrenergic and dopaminergic pathways. PGD 2: depresses sympathetic neurotransmission 3. - PGF2 : hypothalamic secretion

  10. 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.

  11. Evolutionarily Conserved Roles for Blood-Brain Barrier Xenobiotic Transporters in Endogenous Steroid Partitioning and Behavior.

    Science.gov (United States)

    Hindle, Samantha J; Munji, Roeben N; Dolghih, Elena; Gaskins, Garrett; Orng, Souvinh; Ishimoto, Hiroshi; Soung, Allison; DeSalvo, Michael; Kitamoto, Toshihiro; Keiser, Michael J; Jacobson, Matthew P; Daneman, Richard; Bainton, Roland J

    2017-10-31

    Central nervous system (CNS) chemical protection depends upon discrete control of small-molecule access by the blood-brain barrier (BBB). Curiously, some drugs cause CNS side-effects despite negligible transit past the BBB. To investigate this phenomenon, we asked whether the highly BBB-enriched drug efflux transporter MDR1 has dual functions in controlling drug and endogenous molecule CNS homeostasis. If this is true, then brain-impermeable drugs could induce behavioral changes by affecting brain levels of endogenous molecules. Using computational, genetic, and pharmacologic approaches across diverse organisms, we demonstrate that BBB-localized efflux transporters are critical for regulating brain levels of endogenous steroids and steroid-regulated behaviors (sleep in Drosophila and anxiety in mice). Furthermore, we show that MDR1-interacting drugs are associated with anxiety-related behaviors in humans. We propose a general mechanism for common behavioral side effects of prescription drugs: pharmacologically challenging BBB efflux transporters disrupts brain levels of endogenous substrates and implicates the BBB in behavioral regulation. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  12. 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.

  13. Resting state cerebral blood flow with arterial spin labeling MRI in developing human brains.

    Science.gov (United States)

    Liu, Feng; Duan, Yunsuo; Peterson, Bradley S; Asllani, Iris; Zelaya, Fernando; Lythgoe, David; Kangarlu, Alayar

    2018-03-24

    The development of brain circuits is coupled with changes in neurovascular coupling, which refers to the close relationship between neural activity and cerebral blood flow (CBF). Studying the characteristics of CBF during resting state in developing brain can be a complementary way to understand the functional connectivity of the developing brain. Arterial spin labeling (ASL), as a noninvasive MR technique, is particularly attractive for studying cerebral perfusion in children and even newborns. We have collected pulsed ASL data in resting state for 47 healthy subjects from young children to adolescence (aged from 6 to 20 years old). In addition to studying the developmental change of static CBF maps during resting state, we also analyzed the CBF time series to reveal the dynamic characteristics of CBF in differing age groups. We used the seed-based correlation analysis to examine the temporal relationship of CBF time series between the selected ROIs and other brain regions. We have shown the developmental patterns in both static CBF maps and dynamic characteristics of CBF. While higher CBF of default mode network (DMN) in all age groups supports that DMN is the prominent active network during the resting state, the CBF connectivity patterns of some typical resting state networks show distinct patterns of metabolic activity during the resting state in the developing brains. Copyright © 2018 European Paediatric Neurology Society. All rights reserved.

  14. A porcine astrocyte/endothelial cell co-culture model of the blood-brain barrier.

    Science.gov (United States)

    Jeliazkova-Mecheva, Valentina V; Bobilya, Dennis J

    2003-10-01

    A method for the isolation of porcine atrocytes as a simple extension of a previously described procedure for isolation of brain capillary endothelial cells from adolescent pigs [Methods Cell Sci. 17 (1995) 2] is described. The obtained astroglial culture purified through two passages and by the method of the selective detachment was validated by a phase contrast microscopy and through an immunofluorescent assay for the glial fibrillary acidic protein (GFAP). Porcine astrocytes were co-cultivated with porcine brain capillary endothelial cells (PBCEC) for the development of an in vitro blood-brain barrier (BBB) model. The model was visualized by an electron microscopy and showed elevated transendothellial electrical resistance and reduced inulin permeability. To our knowledge, this is the first report for the establishment of a porcine astrocyte/endothelial cell co-culture BBB model, which avoids interspecies and age differences between the two cell types, usually encountered in the other reported co-culture BBB models. Considering the availability of the porcine brain tissue and the close physiological and anatomical relation between the human and pig brain, the porcine astrocyte/endothelial cell co-culture system can serve as a reliable and easily reproducible model for different in vitro BBB studies.

  15. Dimethyl fumarate attenuates cerebral edema formation by protecting the blood-brain barrier integrity.

    Science.gov (United States)

    Kunze, Reiner; Urrutia, Andrés; Hoffmann, Angelika; Liu, Hui; Helluy, Xavier; Pham, Mirko; Reischl, Stefan; Korff, Thomas; Marti, Hugo H

    2015-04-01

    Brain edema is a hallmark of various neuropathologies, but the underlying mechanisms are poorly understood. We aim to characterize how tissue hypoxia, together with oxidative stress and inflammation, leads to capillary dysfunction and breakdown of the blood-brain barrier (BBB). In a mouse stroke model we show that systemic treatment with dimethyl fumarate (DMF), an antioxidant drug clinically used for psoriasis and multiple sclerosis, significantly prevented edema formation in vivo. Indeed, DMF stabilized the BBB by preventing disruption of interendothelial tight junctions and gap formation, and decreased matrix metalloproteinase activity in brain tissue. In vitro, DMF directly sustained endothelial tight junctions, inhibited inflammatory cytokine expression, and attenuated leukocyte transmigration. We also demonstrate that these effects are mediated via activation of the redox sensitive transcription factor NF-E2 related factor 2 (Nrf2). DMF activated the Nrf2 pathway as shown by up-regulation of several Nrf2 target genes in the brain in vivo, as well as in cerebral endothelial cells and astrocytes in vitro, where DMF also increased protein abundance of nuclear Nrf2. Finally, Nrf2 knockdown in endothelial cells aggravated subcellular delocalization of tight junction proteins during ischemic conditions, and attenuated the protective effect exerted by DMF. Overall, our data suggest that DMF protects from cerebral edema formation during ischemic stroke by targeting interendothelial junctions in an Nrf2-dependent manner, and provide the basis for a completely new approach to treat brain edema. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Delivery of Biologics Across the Blood-Brain Barrier with Molecular Trojan Horse Technology.

    Science.gov (United States)

    Pardridge, William M

    2017-12-01

    Biologics are potential new therapeutics for many diseases of the central nervous system. Biologics include recombinant lysosomal enzymes, neurotrophins, decoy receptors, and therapeutic antibodies. These are large molecule drugs that do not cross the blood-brain barrier (BBB). All classes of biologics have been tested, without success, in clinical trials of brain disease over the last 25 years. In none of these past clinical trials was the biologic re-engineered to enable transport across the BBB. If the biologic does not cross the BBB, the drug cannot reach the target site in brain, and success in a clinical trial is not expected. Biologics can be re-engineered for BBB transport with the use of molecular Trojan horse technology. A BBB molecular Trojan horse is a monoclonal antibody (MAb) against an endogenous BBB receptor transporter, such as the insulin receptor or transferrin receptor. The receptor-specific MAb penetrates the brain via transport on the endogenous BBB receptor. The MAb acts as a molecular Trojan horse to deliver across the BBB the biologic pharmaceutical that is genetically fused to the MAb. The lead Trojan horse is a MAb against the human insulin receptor (HIR), and HIRMAb-derived fusion proteins have entered clinical trials for the treatment of brain disease.

  17. Bladder Distension Increases Blood Flow in Pain Related Brain Structures in Subjects with Interstitial Cystitis.

    Science.gov (United States)

    Deutsch, Georg; Deshpande, Hrishikesh; Frölich, Michael A; Lai, H Henry; Ness, Timothy J

    2016-09-01

    In healthy control subjects certain brain regions of interest demonstrate increased regional cerebral blood flow in response to painful stimuli. We examined the effect of bladder distension on arterial spin label functional magnetic resonance imaging measures of regional cerebral blood flow in regions of interest in subjects with interstitial cystitis. A total of 11 female subjects with interstitial cystitis and 11 healthy controls underwent 3 brain perfusion scan studies using arterial spin label functional magnetic resonance imaging, including 1) with a full bladder, 2) with an empty bladder and 3) while experiencing heat pain. Regional cerebral blood flow was calculated using custom software and individual scans were spatially normalized to the MNI (Montreal Neurological Institute) template. Region of interest based, absolute regional cerebral blood flow was determined for each condition and for the within group/within subject regional cerebral blood flow distribution changes induced by each condition. Bladder distension was associated with robust increases in regional cerebral blood flow in subjects with interstitial cystitis. The increases were greater than those in healthy controls in multiple regions of interest, including the supplemental motor area (mainly Brodmann area 6), the motor and sensory cortex, the insula bilaterally, the hippocampal structures bilaterally, and the middle and posterior cingulate areas bilaterally. During heat pain healthy controls had more robust regional cerebral blood flow increases in the amygdala bilaterally. At baseline with an empty bladder there was lower regional cerebral blood flow in the insula, and the mid and posterior cingulate cortex bilaterally in subjects with interstitial cystitis. Compared to healthy controls, subjects with interstitial cystitis have limited differences in regional cerebral blood flow in baseline (empty bladder) conditions as well as during heat pain. However, they had robust regional cerebral

  18. 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......-proteiner bliver påvirkede af dyrkningsmedier med høj bufferkoncentration; karakteriser den transcellulære transport af L-glutamat og involveringen af excitatoriske aminosyre transportører (excitatory amino acid transporter, EAAT) og evaluer om BBB kan spille en rolle i hjernens L-glutamat-homeostase. In vitro...

  19. Mechanisms and regulation of iron trafficking across the capillary endothelial cells of the blood-brain barrier

    Directory of Open Access Journals (Sweden)

    Ryan C. McCarthy

    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.

  20. 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 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 found...

  1. 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.

  2. 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.

  3. 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....

  4. Preparation of Silica Nanoparticles Loaded with Nootropics and Their In Vivo Permeation through Blood-Brain Barrier

    OpenAIRE

    Jampilek, Josef; Zaruba, Kamil; Oravec, Michal; Kunes, Martin; Babula, Petr; Ulbrich, Pavel; Brezaniova, Ingrid; Opatrilova, Radka; 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 i...

  5. Lactate, Glucose and Oxygen Uptake in Human Brain During Recovery from Maximal Exercise

    DEFF Research Database (Denmark)

    Kojiro, I.; Schmalbruch, I.K.; Quistorff, B.

    1999-01-01

    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...

  6. Blood-compatible poly(2-methoxyethyl acrylate) for the adhesion and proliferation of endothelial and smooth muscle cells.

    Science.gov (United States)

    Sato, Chikako; Aoki, Makiko; Tanaka, Masaru

    2016-09-01

    Thrombus formation presents a serious hindrance in the development of functional artificial blood vessels, especially those with a small diameter. Endothelialization can prevent thrombus formation; however, the adhesion of endothelial cells to existing polymer materials is generally weak. Therefore, polymers that have both anti-thrombotic and endothelialization properties do not currently exist. We previously reported that platelets do not adhere to poly(2-methoxyethyl acrylate) (PMEA) or poly(tetrahydrofurfuryl acrylate)(PTHFA). Here, we investigated whether endothelial cells and smooth muscle cells, both of which are blood vessel components, could adhere to these synthetic polymers. Polyethylene terephthalate films were coated with PMEA and PTHFA using a spin-coater. Human umbilical vein endothelial cells or aorta smooth muscle cells were seeded on the polymer surfaces, after which we analyzed the number of adherent cells, their morphologies and vinculin expression. We found that both endothelial and smooth muscle cells adhered to PMEA and PTHFA, while platelets did not. We propose that, by using PMEA and PTHFA with no modifications, it should be possible to develop artificial blood vessels with both anti-thrombotic and endothelialization properties. In addition, we discuss the mechanism of selective cell adhesion in PMEA and PTHFA. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Mercury and selenium levels, and selenium:mercury molar ratios of brain, muscle and other tissues in bluefish (Pomatomus saltatrix) from New Jersey, USA

    Science.gov (United States)

    Burger, Joanna; Jeitner, Christian; Donio, Mark; Pittfield, Taryn; Gochfeld, Michael

    2015-01-01

    A number of contaminants affect fish health, including mercury and selenium, and the selenium: mercury molar ratio. Recently the protective effects of selenium on methylmercury toxicity have been publicized, particularly for consumption of saltwater fish. Yet the relative ameliorating effects of selenium on toxicity within fish have not been examined, nor has the molar ratio in different tissues, (i.e. brain). We examined mercury and selenium levels in brain, kidney, liver, red and white muscle, and skin and scales in bluefish (Pomatomus saltatrix) from New Jersey to determine whether there were toxic levels of either metal, and we computed the selenium: mercury molar ratios by tissues. Total mercury averaged 0.32 ± 0.02 ppm wet weight in edible muscle and 0.09 ± 0.01 ppm in brain. Selenium concentration averaged 0.37 ± 0.03 in muscle and 0.36 ± 0.03 ppm in brain. There were significant differences in levels of mercury, selenium, and selenium: mercury molar ratios, among tissues. Mercury and selenium levels were correlated in kidney and skin/scales. Mercury levels were highest in kidney, intermediate in muscle and liver, and lowest in brain and skin/scales; selenium levels were also highest in kidney, intermediate in liver, and were an order of magnitude lower in the white muscle and brain. Mercury levels in muscle, kidney and skin/scales were positively correlated with fish size (length). Selenium levels in muscle, kidney and liver were positively correlated with fish length, but in brain; selenium levels were negatively correlated with fish length. The selenium: mercury molar ratio was negatively correlated with fish length for white muscle, liver, kidney, and brain, particularly for fish over 50 cm in length, suggesting that older fish experience less protective advantages of selenium against mercury toxicity than smaller fish, and that consumers of bluefish similarly receive less advantage from eating larger fish. PMID:23202378

  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. Synthetic smooth muscle in the outer blood plexus of the rhinarium skin of Lemur catta L.

    Science.gov (United States)

    Elofsson, Rolf; Kröger, Ronald H H

    2017-01-01

    The skin of the lemur nose tip (rhinarium) has arterioles in the outer vascular plexus that are endowed with an unusual coat of smooth muscle cells. Comparison with the arterioles of the same area in a number of unrelated mammalians shows that the lemur pattern is unique. The vascular smooth muscle cells belong to the synthetic type. The function of synthetic smooth muscles around the terminal vessels in the lemur rhinarium is unclear but may have additional functions beyond regulation of vessel diameter.

  10. Global fluctuations of cerebral blood flow indicate a global brain network independent of systemic factors.

    Science.gov (United States)

    Zhao, Li; Alsop, David C; Detre, John A; Dai, Weiying

    2017-01-01

    Global synchronization across specialized brain networks is a common feature of network models and in-vivo electrical measurements. Although the imaging of specialized brain networks with blood oxygenation sensitive resting state functional magnetic resonance imaging (rsfMRI) has enabled detailed study of regional networks, the study of globally correlated fluctuations with rsfMRI is confounded by spurious contributions to the global signal from systemic physiologic factors and other noise sources. Here we use an alternative rsfMRI method, arterial spin labeled perfusion MRI, to characterize global correlations and their relationship to correlations and anti-correlations between regional networks. Global fluctuations that cannot be explained by systemic factors dominate the fluctuations in cerebral blood flow. Power spectra of these fluctuations are band limited to below 0.05 Hz, similar to prior measurements of regional network fluctuations in the brain. Removal of these global fluctuations prior to measurement of regional networks reduces all regional network fluctuation amplitudes to below the global fluctuation amplitude and changes the strength and sign of inter network correlations. Our findings support large amplitude, globally synchronized activity across networks that require a reassessment of regional network amplitude and correlation measures.

  11. The xenoestrogens ethinylestradiol and bisphenol A regulate BCRP at the blood-brain barrier of rats.

    Science.gov (United States)

    Nickel, Sabrina; Mahringer, Anne

    2014-11-01

    1. Breast cancer resistance protein (BCRP) is an ABC-transporter at the blood-brain barrier (BBB) facilitating efflux of xenobiotics into blood. Expression and function are regulated via estrogen-receptors (ERs). 2. 17α-Ethinylestradiol (EE2) and bisphenol A (BPA) represent two prominent xenoestrogens. We studied whether EE2 and BPA regulate BCRP function and expression upon a 6 h treatment in an ER-dependent manner in a rat BBB-ex-vivo-model. 3. Isolated brain capillaries were incubated with EE2 or BPA. BCRP function and expression were analyzed by confocal microscopy and Western-Blot. ERα-antagonist MPP and ER-antagonist ICI182.780 were used to study involvement of ERs. 4. EE2 and BPA down-regulated BCRP transport function and expression. EE2 effects occurred at pharmacologically relevant doses, BPA exhibited only weak influences. Down-regulation by EE2 was reversed by ICI but not MPP. BPA effects were not reversed by either antagonist. 5. EE2 is a potent regulator of BCRP expression and function acting by ERβ-stimulation. Oral contraception could alter uptake of pharmaceuticals to the brain and might thus be considered as an origin of central nervous system (CNS) side-effects. EE2 could also present a novel co-treatment to improve CNS-pharmacotherapy. BPA is a weak modulator of BCRP expression. Its effects appear not to be caused by ERs.

  12. Caloric restriction increases ketone bodies metabolism and preserves blood flow in aging brain.

    Science.gov (United States)

    Lin, Ai-Ling; Zhang, Wei; Gao, Xiaoli; Watts, Lora

    2015-07-01

    Caloric restriction (CR) has been shown to increase the life span and health span of a broad range of species. However, CR effects on in vivo brain functions are far from explored. In this study, we used multimetric neuroimaging methods to characterize the CR-induced changes of brain metabolic and vascular functions in aging rats. We found that old rats (24 months of age) with CR diet had reduced glucose uptake and lactate concentration, but increased ketone bodies level, compared with the age-matched and young (5 months of age) controls. The shifted metabolism was associated with preserved vascular function: old CR rats also had maintained cerebral blood flow relative to the age-matched controls. When investigating the metabolites in mitochondrial tricarboxylic acid cycle, we found that citrate and α-ketoglutarate were preserved in the old CR rats. We suggest that CR is neuroprotective; ketone bodies, cerebral blood flow, and α-ketoglutarate may play important roles in preserving brain physiology in aging. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  13. 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.

  14. 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

    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 exposure......Petroleum products with low content of aromatics have been increasingly used during the past years. This study investigates tissue disposition of dearomatised white spirit. In addition, brain neurotransmitter concentrations were measured. Male rats were exposed by inhalation to 0, 400 (2.29 mg....../l), or 800 p.p.m. (4.58 mg/l) of dearomatised white spirit, 6 hr/day, 5 days/week up to 3 weeks. Five rats from each group were sacrificed immediately after the exposure for 1, 2, or 3 weeks and 2, 4, 6, or 24 hr after the end of 3 weeks' exposure. After 3 weeks of exposure the concentration of total white...

  15. 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

    Petroleum products with low content of aromatics have been increasingly used during the past years. This study investigates tissue disposition of dearomatised white spirit. In addition, brain neurotransmitter concentrations were measured. Male rats were exposed by inhalation to 0, 400 (2.29 mg....../l), or 800 p.p.m. (4.58 mg/l) of dearomatised white spirit, 6 hr/day, 5 days/week up to 3 weeks. Five rats from each group were sacrificed immediately after the exposure for 1, 2, or 3 weeks and 2, 4, 6, or 24 hr after the end of 3 weeks' exposure. After 3 weeks of exposure the concentration of total 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 exposure...

  16. 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

  17. Effects of blood-flow-restricted resistance training on muscle function in a 74-year-old male with sporadic inclusion body myositis

    DEFF Research Database (Denmark)

    Jørgensen, Anders Nørkær; Aagaard, P; Nielsen, J L

    2016-01-01

    Sporadic inclusion body myositis (sIBM) is a systemic disease that is characterized by substantial skeletal muscle weakness and muscle inflammation, leading to impaired physical function. The objective was to investigate the effect of low-load resistance exercise with concurrent partial blood flow...... 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 substantial...

  18. Influence of blood flow occlusion on the development of peripheral and central fatigue during small muscle mass handgrip exercise.

    Science.gov (United States)

    Broxterman, R M; Craig, J C; Smith, J R; Wilcox, S L; Jia, C; Warren, S; Barstow, T J

    2015-09-01

    Critical power represents an important threshold for neuromuscular fatigue development and may, therefore, dictate intensities for which exercise tolerance is determined by the magnitude of fatigue accrued. Peripheral fatigue appears to be constant across O2 delivery conditions for large muscle mass exercise, but this consistency is equivocal for smaller muscle mass exercise. We sought to determine the influence of blood flow occlusion during handgrip exercise on neuromuscular fatigue development and to examine the relationship between neuromuscular fatigue development and W '. Blood flow occlusion influenced the development of both peripheral and central fatigue, thus providing further evidence that the magnitude of peripheral fatigue is not constant across O2 delivery conditions for small muscle mass exercise. W ' appears to be related to the magnitude of fatigue accrued during exercise, which may explain the reported consistency of intramuscular metabolic perturbations and work performed for severe-intensity exercise. The influence of the muscle metabolic milieu on peripheral and central fatigue is currently unclear. Moreover, the relationships between peripheral and central fatigue and the curvature constant (W ') have not been investigated. Six men (age: 25 ± 4 years, body mass: 82 ± 10 kg, height: 179 ± 4 cm) completed four constant power handgrip tests to exhaustion under conditions of control exercise (Con), blood flow occlusion exercise (Occ), Con with 5 min post-exercise blood flow occlusion (Con + Occ), and Occ with 5 min post-exercise blood flow occlusion (Occ + Occ). Neuromuscular fatigue measurements and W ' were obtained for each subject. Each trial resulted in significant peripheral and central fatigue. Significantly greater peripheral (79.7 ± 5.1% vs. 22.7 ± 6.0%) and central (42.6 ± 3.9% vs. 4.9 ± 2.0%) fatigue occurred for Occ than for Con. In addition, significantly greater peripheral (83.0 ± 4.2% vs. 69.0 ± 6.2%) and central

  19. Enhanced muscle blood flow with intermittent pneumatic compression of the lower leg during plantar flexion exercise and recovery.

    Science.gov (United States)

    Zuj, K A; Prince, C N; Hughson, R L; Peterson, S D

    2018-02-01

    This study tested the hypothesis that intermittent compression of the lower limb would increase blood flow during exercise and postexercise recovery. Data were collected from 12 healthy individuals (8 men) who performed 3 min of standing plantar flexion exercise. The following three conditions were tested: no applied compression (NoComp), compression during the exercise period only (ExComp), and compression during 2 min of standing postexercise recovery. Doppler ultrasound was used to determine superficial femoral artery (SFA) blood flow responses. Mean arterial pressure (MAP) and cardiac stroke volume (SV) were assessed using finger photoplethysmography, with vascular conductance (VC) calculated as VC = SFA flow/MAP. Compared with the NoComp condition, compression resulted in increased MAP during exercise [+3.5 ± 4.1 mmHg (mean ± SD)] but not during postexercise recovery (+1.6 ± 5.9 mmHg). SV increased with compression during both exercise (+4.8 ± 5.1 ml) and recovery (+8.0 ± 6.6 ml) compared with NoComp. There was a greater increase in SFA flow with compression during exercise (+52.1 ± 57.2 ml/min) and during recovery (+58.6 ± 56.7 ml/min). VC immediately following exercise was also significantly greater in the ExComp condition compared with the NoComp condition (+0.57 ± 0.42 ml·min -1 ·mmHg -1 ), suggesting the observed increase in blood flow during exercise was in part because of changes in VC. Results from this study support the hypothesis that intermittent compression applied during exercise and recovery from exercise results in increased limb blood flow, potentially contributing to changes in exercise performance and recovery. NEW & NOTEWORTHY Blood flow to working skeletal muscle is achieved in part through the rhythmic actions of the skeletal muscle pump. This study demonstrated that the application of intermittent pneumatic compression during the diastolic phase of the cardiac cycle, to mimic the mechanical

  20. Blood-Brain Barrier Leakage in Patients with Early Alzheimer Disease.

    Science.gov (United States)

    van de Haar, Harm J; Burgmans, Saartje; Jansen, Jacobus F A; van Osch, Matthias J P; van Buchem, Mark A; Muller, Majon; Hofman, Paul A M; Verhey, Frans R J; Backes, Walter H

    2016-11-01

    Purpose To investigate whether the blood-brain barrier (BBB) leaks blood-circulating substances in patients with early forms of Alzheimer disease (AD), and if so, to examine the extent and pattern of leakage. Materials and Methods This study was approved by the local medical ethical committees of the Maastricht University Medical Center and Leiden University Medical Center, and written informed consent was obtained from all subjects. For this pilot study, 16 patients with early AD and 17 healthy age-matched control subjects underwent dynamic contrast material-enhanced magnetic resonance (MR) imaging sequence with dual time resolution for 25 minutes. The Patlak graphical approach was used to quantify the BBB leakage rate and local blood plasma volume. Subsequent histogram analysis was used to determine the volume fraction of the leaking brain tissue. Differences were assessed with linear regression analysis, adjusted for confounding variables. Results The BBB leakage rate was significantly higher in patients compared with that in control subjects in the total gray matter (P cascade of pathologic events that eventually lead to cognitive decline and dementia. © RSNA, 2016 Online supplemental material is available for this article.

  1. C5a alters blood-brain barrier integrity in experimental lupus

    Science.gov (United States)

    Jacob, Alexander; Hack, Bradley; Chiang, Eddie; Garcia, Joe G. N.; Quigg, Richard J.; Alexander, Jessy J.

    2010-01-01

    The blood-brain barrier (BBB) is a crucial anatomic location in the brain. Its dysfunction complicates many neurodegenerative diseases, from acute conditions, such as sepsis, to chronic diseases, such as systemic lupus erythematosus (SLE). Several studies suggest an altered BBB in lupus, but the underlying mechanism remains unknown. In the current study, we observed a definite loss of BBB integrity in MRL/MpJ-Tnfrsf6lpr (MRL/lpr) lupus mice by IgG infiltration into brain parenchyma. In line with this result, we examined the role of complement activation, a key event in this setting, in maintenance of BBB integrity. Complement activation generates C5a, a molecule with multiple functions. Because the expression of the C5a receptor (C5aR) is significantly increased in brain endothelial cells treated with lupus serum, the study focused on the role of C5a signaling through its G-protein-coupled receptor C5aR in brain endothelial cells, in a lupus setting. Reactive oxygen species production increased significantly in endothelial cells, in both primary cells and the bEnd3 cell line treated with lupus serum from MRL/lpr mice, compared with those treated with control serum from MRL+/+ mice. In addition, increased permeability monitored by changes in transendothelial electrical resistance, cytoskeletal remodeling caused by actin fiber rearrangement, and increased iNOS mRNA expression were observed in bEnd3 cells. These disruptive effects were alleviated by pretreating cells with a C5a receptor antagonist (C5aRant) or a C5a antibody. Furthermore, the structural integrity of the vasculature in MRL/lpr brain was maintained by C5aR inhibition. These results demonstrate the regulation of BBB integrity by the complement system in a neuroinflammatory setting. For the first time, a novel role of C5a in the maintenance of BBB integrity is identified and the potential of C5a/C5aR blockade highlighted as a promising therapeutic strategy in SLE and other neurodegenerative diseases

  2. 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

    2009-06-01

    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.

  3. Delivery of dopamine transporter tracer (PE2I) through blood brain barrier with ultrasound and microbubbles

    Science.gov (United States)

    Serrière, Sophie; Escoffre, Jean-Michel; Bodard, Sylvie; Novell, Anthony; Vergote, Jackie; Vercouillie, Johnny; Thiéry, Jean-Claude; Chalon, Sylvie; Bouakaz, Ayache

    2012-10-01

    The blood-brain barrier plays a major role in controlling the delivery of therapeutic and imaging agents to the brain. The aim of this study was to investigate the use of ultrasound and microbubbles to increase its delivery through the BBB and by determining the optimal experimental conditions that achieve a transient and safe BBB disruption. First, we established the ultrasound conditions that achieved a transient BBB disruption in rats using a non-permeant marker, Evans blue. Hence SonoVue® (450 μL/kg) and Evans blue (100 mg/kg) were intravenously administered. BBB leakage was obtained using ultrasound insonation through the rat skull at 1.6 MPa, PRF 1 Hz, duty cycle 12%, burst 10 ms during 120 sec. BBB disruption was observed in all treated animals (N=4) by histological analysis. The same experimental conditions were applied to enhance brain uptake of PE2I. Biological samples were analyzed using a scintillation counter apparatus. The results showed 50% and 20% increase of 125I-PE2I uptake in the striatum and cerebral cortex, respectively, in the treated rats (N=5) versus control (N=4). Similar enhancements were observed using SonoVue® at half concentration. This innovative method provides a great potential for intracerebral delivery of molecular ligands that could be used for the therapy of brain diseases.

  4. Gliotransmitters and cytokines in the control of blood-brain barrier permeability.

    Science.gov (United States)

    Osipova, Elena D; Semyachkina-Glushkovskaya, Oxana V; Morgun, Andrey V; Pisareva, Natalia V; Malinovskaya, Natalia A; Boitsova, Elizaveta B; Pozhilenkova, Elena A; Belova, Olga A; Salmin, Vladimir V; Taranushenko, Tatiana E; Noda, Mami; Salmina, Alla B

    2018-01-08

    The contribution of astrocytes and microglia to the regulation of neuroplasticity or neurovascular unit (NVU) is based on the coordinated secretion of gliotransmitters and cytokines and the release and uptake of metabolites. Blood-brain barrier (BBB) integrity and angiogenesis are influenced by perivascular cells contacting with the abluminal side of brain microvessel endothelial cells (pericytes, astrocytes) or by immune cells existing (microglia) or invading the NVU (macrophages) under pathologic conditions. The release of gliotransmitters or cytokines by activated astroglial and microglial cells is provided by distinct mechanisms, affects intercellular communication, and results in the establishment of microenvironment controlling BBB permeability and neuroinflammation. Glial glutamate transporters and connexin and pannexin hemichannels working in the tight functional coupling with the purinergic system serve as promising molecular targets for manipulating the intercellular communications that control BBB permeability in brain pathologies associated with excessive angiogenesis, cerebrovascular remodeling, and BBB-mediated neuroinflammation. Substantial progress in deciphering the molecular mechanisms underlying the (patho)physiology of perivascular glia provides promising approaches to novel clinically relevant therapies for brain disorders. The present review summarizes the current understandings on the secretory machinery expressed in glial cells (glutamate transporters, connexin and pannexin hemichannels, exocytosis mechanisms, membrane-derived microvesicles, and inflammasomes) and the role of secreted gliotransmitters and cytokines in the regulation of NVU and BBB permeability in (patho)physiologic conditions.

  5. Cold injury, blood-brain barrier changes, and leukotriene synthesis: Inhibition by phenidone

    International Nuclear Information System (INIS)

    Robichaud, L.J.; Marcoux, F.W.

    1990-01-01

    Transcranial cold injury in rats and guinea pigs induced cerebral extravasation of albumin labeled with Evans blue dye or 125 I, respective indicators of the area and amount of blood-brain barrier (BBB) disruption. Radioimmunoassay of brain extracts showed that cold injury induced leukotriene (LT)C4 in rat and guinea pig brains 15 min after injury. In guinea pigs, the LT synthesis inhibitor phenidone (30 mg/kg, i.p.) completely blocked cold-induced LTC4 in brain. Phenidone (30 and 100 mg/kg) also inhibited cerebral tissue accumulation of 125 I-albumin and dye in rats and guinea pigs. Phenidone is reported to show antioxidant properties and selective lipoxygenase inhibition of arachidonic acid metabolism compared to cyclooxygenase inhibitors, meclofenamate sodium, and other nonsteroidal anti-inflammatory agents. Since several oxygen and hydroxyl radical scavengers and the cyclooxygenase inhibitor, meclofenamate sodium, did not inhibit protein extravasation, the findings support a role for LT as a mediator of cold-induced changes in BBB permeability in rats and guinea pigs and suggest that the inhibitory effects of phenidone on BBB permeability may be due to inhibition of LT production

  6. Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder.

    Science.gov (United States)

    Tărlungeanu, Dora C; Deliu, Elena; Dotter, Christoph P; Kara, Majdi; Janiesch, Philipp Christoph; Scalise, Mariafrancesca; Galluccio, Michele; Tesulov, Mateja; Morelli, Emanuela; Sonmez, Fatma Mujgan; Bilguvar, Kaya; Ohgaki, Ryuichi; Kanai, Yoshikatsu; Johansen, Anide; Esharif, Seham; Ben-Omran, Tawfeg; Topcu, Meral; Schlessinger, Avner; Indiveri, Cesare; Duncan, Kent E; Caglayan, Ahmet Okay; Gunel, Murat; Gleeson, Joseph G; Novarino, Gaia

    2016-12-01

    Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched-chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here, we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation, and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Presentation of regional cerebral blood flow in amphetamine abusers by 99Tcm-HMPAO brain SPECT

    International Nuclear Information System (INIS)

    Kao, C.H.; Wang, S.J.; Yeh, S.H.

    1994-01-01

    The aim of this study was to describe the effectiveness of 99 Tc m -hexamethylpropyleneamine oxime ( 99 Tc m -HMPAO) brain single photon emission computed tomography (SPECT) in the assessment of the regional cerebral blood flow (rCBF) in amphetamine abusers. Twenty-one amphetamine abusers were included and 99 Tc m -HMPAO brain SPECT performed to evaluate rCBF. The drug-using periods ranged from 1 month to several years. The demonstrated neuropsychogenic symptoms and signs of the abusers were from normal presentation to various neurologic complications. The brain SPECT scans were interpreted visually as either normal or abnormal. The degree of abnormality was classified into mild or severe. The results revealed that (a) most SPECT studies in abusers show small defects (95%, 20/21 cases); 71% (15/21) of cases revealed multiple defects over both hemispheres (classified as severe); 24% (5/21) of the cases had focal defects (classified as mild); and only one case (5%, 1/21) demonstrated a normal SPECT finding; (b) the degree of abnormality on SPECT scans was not related to the dose and duration of drug use or the severity of the neuropsychiatric symptoms and signs. In conclusion, 99 Tc m -HMPAO brain SPECT is a sensitive but not specific test for neuropsychogenic abnormalities associated with amphetamine abuse. (Author)

  8. Blood-brain barrier disruption induced by diagnostic ultrasound combined with microbubbles in mice.

    Science.gov (United States)

    Zhao, Bingxia; Chen, Yihan; Liu, Jinfeng; Zhang, Li; Wang, Jing; Yang, Yali; Lv, Qing; Xie, Mingxing

    2018-01-12

    To investigate the effects of the microbubble (MB) dose, mechanism index (MI) and sonication duration on blood-brain barrier (BBB) disruption induced by diagnostic ultrasound combined with MBs as well as to investigate the potential molecular mechanism. The extent of BBB disruption increased with MB dose, MI and sonication duration. A relatively larger extent of BBB disruption associated with minimal tissue damage was achieved by an appropriate MB dose and ultrasound exposure parameters with diagnostic ultrasound. Decreased expression of ZO-1, occludin and claudin-5 were correlated with disruption of the BBB, as confirmed by paracellular passage of the tracer lanthanum nitrate into the brain parenchyma after BBB disruption. These findings indicated that this technique is a promising tool for promoting brain delivery of diagnostic and therapeutic agents in the diagnosis and treatment of brain diseases. The extent of BBB disruption was qualitatively assessed by Evans blue (EB) staining and quantitatively analyzed by an EB extravasation measurement. A histological examination was performed to evaluate tissue damage. Expression of tight junction (TJ) related proteins ZO-1, occludin and claudin-5 was determined by western blotting analysis and immunohistofluorescence. Transmission electron microscopy was performed to observe ultrastructure changes of TJs after BBB disruption.

  9. Proximate Mediators of Microvascular Dysfunction at the Blood-Brain Barrier: Neuroinflammatory Pathways to Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Barry W. Festoff

    2017-01-01

    Full Text Available Current projections are that by 2050 the numbers of people aged 65 and older with Alzheimer’s disease (AD in the US may increase threefold while dementia is projected to double every 20 years reaching ~115 million by 2050. AD is clinically characterized by progressive dementia and neuropathologically by neuronal and synapse loss, accumulation of amyloid plaques, and neurofibrillary tangles (NFTs in specific brain regions. The preclinical or presymptomatic stage of AD-related brain changes may begin over 20 years before symptoms occur, making development of noninvasive biomarkers essential. Distinct from neuroimaging and cerebrospinal fluid biomarkers, plasma or serum biomarkers can be analyzed to assess (i the presence/absence of AD, (ii the risk of developing AD, (iii the progression of AD, or (iv AD response to treatment. No unifying theory fully explains the neurodegenerative brain lesions but neuroinflammation (a lethal stressor for healthy neurons is universally present. Current consensus is that the earlier the diagnosis, the better the chance to develop treatments that influence disease progression. In this article we provide a detailed review and analysis of the role of the blood-brain barrier (BBB and damage-associated molecular patterns (DAMPs as well as coagulation molecules in the onset and progression of these neurodegenerative disorders.

  10. Effect of strength training with blood flow restriction on muscle power and submaximal strength in eumenorrheic women.

    Science.gov (United States)

    Gil, Ana L S; Neto, Gabriel R; Sousa, Maria S C; Dias, Ingrid; Vianna, Jeferson; Nunes, Rodolfo A M; Novaes, Jefferson S

    2017-03-01

    Blood flow restriction (BFR) training stimulates muscle size and strength by increasing muscle activation, accumulation of metabolites and muscle swelling. This method has been used in different populations, but no studies have evaluated the effects of training on muscle power and submaximal strength (SS) in accounted for the menstrual cycle. The aim of this study was to analyse the effect of strength training (ST) with BFR on the muscle power and SS of upper and lower limbs in eumenorrheic women. Forty untrained women (18-40 years) were divided randomly and proportionally into four groups: (i) high-intensity ST at 80% of 1RM (HI), (ii) low-intensity ST at 20% of 1RM combined with partial blood flow restriction (LI + BFR), (iii) low-intensity ST at 20% of 1RM (LI) and d) control group (CG). Each training group performed eight training sessions. Tests with a medicine ball (MB), horizontal jump (HJ), vertical jump (VJ), biceps curls (BC) and knee extension (KE) were performed during the 1st day follicular phase (FP), 14th day (ovulatory phase) and 26-28th days (luteal phase) of the menstrual cycle. There was no significant difference among groups in terms of the MB, HJ, VJ or BC results at any time point (P>0·05). SS in the KE exercise was significantly greater in the LI + BFR group compared to the CG group (P = 0·014) during the LP. Therefore, ST with BFR does not appear to improve the power of upper and lower limbs and may be an alternative to improve the SS of lower limbs of eumenorrheic women. © 2015 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.

  11. THE INFLUINCE OF THE STAPHYLOCOCCUS INFECTION TO THE STRUCTURAL ORGANIZATION OF WISTAR RATS BRAIN AND CEREBRAL BLOOD VESSELS

    Directory of Open Access Journals (Sweden)

    Torianik I. I.

    2013-12-01

    Full Text Available In this article there are a dates about the influence of thestaphylococcus infection to the structural organization of Wistar rats brain and cerebral blood vessels in experiment. The purpose of the experiment’s are achieving by the seding staphylococcus infection means of the characterical structures of the brain and cerebralblood damages, that similar with the such in a human in a case of the development of a traditional clinic pathology.The results are evaluated to character of the morphological changes (brain cortex and cerebral blood vessels destructive and degenerative alterations,inflammatory processes.

  12. Mechanisms of restriction of viral neuroinvasion at the blood-brain barrier.

    Science.gov (United States)

    Miner, Jonathan J; Diamond, Michael S

    2016-02-01

    The blood-brain barrier (BBB) consists of highly specialized cells including brain microvascular endothelial cells, astrocytes, microglia, pericytes, and neurons, which act in concert to restrict the entry of pathogens, immune cells, and soluble molecules into the central nervous system (CNS). If pathogens manage to cross the BBB and establish infection within the CNS, the BBB can open in a regulated manner to allow leukocyte transmigration into the CNS so that microbes, infected cells, and debris can be cleared. This review highlights how different inflammatory cytokines or signaling pathways disrupt or enhance BBB integrity in a way that regulates entry of neurotropic viruses into the CNS. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. 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.

  14. 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

  15. Evaluation of [14C] and [13C]Sucrose as Blood-Brain Barrier Permeability Markers.

    Science.gov (United States)

    Miah, Mohammad K; Chowdhury, Ekram A; Bickel, Ulrich; Mehvar, Reza

    2017-06-01

    Nonspecific quantitation of [ 14 C]sucrose in blood and brain has been routinely used as a quantitative measure of the in vivo blood-brain barrier (BBB) integrity. However, the reported apparent brain uptake clearance (K in ) of the marker varies widely (∼100-fold). We investigated the accuracy of the use of the marker in comparison with a stable isotope of sucrose ([ 13 C]sucrose) measured by a specific liquid chromatography-tandem mass spectrometry method. Rats received single doses of each marker, and the K in values were determined. Surprisingly, the K in value of [ 13 C]sucrose was 6- to 7-fold lower than that of [ 14 C]sucrose. Chromatographic fractionation after in vivo administration of [ 14 C]sucrose indicated that the majority of the brain content of radioactivity belonged to compounds other than the intact [ 14 C]sucrose. However, mechanistic studies failed to reveal any substantial metabolism of the marker. The octanol:water partition coefficient of [ 14 C]sucrose was >2-fold higher than that of [ 13 C]sucrose, indicating the presence of lipid-soluble impurities in the [ 14 C]sucrose solution. Our data indicate that [ 14 C]sucrose overestimates the true BBB permeability to sucrose. We suggest that specific quantitation of the stable isotope ( 13 C) of sucrose is a more accurate alternative to the current widespread use of the radioactive sucrose as a BBB marker. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  16. Whole brain C-arm computed tomography parenchymal blood volume measurements.

    Science.gov (United States)

    Kamran, Mudassar; Byrne, James V

    2016-04-01

    C-arm flat detector computed tomography (FDCT) parenchymal blood volume (PBV) imaging in the neuro-interventional suite is a new technique for which detailed whole brain measurements have not been previously reported. This study aims to create a catalogue of PBV measurements for various anatomical regions encompassing the whole brain, using a three-dimensional volume-of-interest (3D-VOI) analysis. We acquired and analysed 30 C-arm FDCT datasets from 26 patients with aneurysmal subarachnoid haemorrhage (SAH), as part of a prospective study comparing C-arm computed tomography (CT) PBV with magnetic resonance perfusion-weighted imaging (MR-PWI). We calculated the PBV values for various brain regions with an automated analysis, using 58 pre-defined atlas-based 3D-VOIs encompassing the whole brain. VOIs partially or completely overlapping regions of magnetic resonance diffusion weighted imaging (MR-DWI) abnormality or magnetic resonance cerebral blood flow (MR-CBF) asymmetry were excluded from the analysis. Of the 30 C-arm CT PBV datasets, 14 (54%; 12 patients) had areas of restricted diffusion, the majority of which were focal. The PBV values for the cerebral cortex and cerebral white matter were 4.01 ± 0.47 (mean ± SD) and 3.01 ± 0.39 ml per 100 ml. Lobar PBV values were: frontal lobe 4.2 ± 0.8, temporal lobe 4.2 ± 0.9, parietal lobe 3.9 ± 0.7 and occipital lobe 4.3 ± 0.8 ml/100 ml. The basal ganglia and brainstem PBV values were 3.4 ± 0.7 and 4.6 ± 0.6 ml/100 ml, respectively. Compared with the typical reference cerebral blood volume (CBV) values reported in the literature for Positron Emission Tomography (PET), the PBV values were relatively high for the white matter and relatively low for the cortical grey matter. The reported catalogue of PBV values for various brain regions would be useful to inform future studies and could be used in clinical practice, when interpreting PBV maps. © The Author(s) 2016.

  17. Resuscitation of Hypotensive Traumatic Brain Injured Animals With Spray-Dried Plasma Does Not Adversely Alter Physiology and Improves Blood-Brain Barrier Function.

    Science.gov (United States)

    McDaniel, Steven; Golla, Stephanie; Moore, Anthony N; DaCorta, Joe; Bode, Arthur; Pati, Shibani; Dash, Pramod K; Zhao, Jing

    2017-07-01

    According to the Defense and Veterans Brain Injury Center and the Armed Forces Health Surveillance Center, the number of soldiers who have sustained a traumatic brain injury (TBI) has risen dramatically over the past decade. Studies have shown that brain damage can be exacerbated if blood loss occurs (often occurring in polytrauma). As blood supply is critical for brain function and survival, TBI patients must be properly resuscitated to maintain blood volume, blood pressure, and cerebral perfusion. Recent studies have suggested that blood loss can damage the vascular endothelium and enhance blood-brain barrier (BBB) permeability. Brain endothelial cells and the tight junctions between them are key structural components of the BBB. As the BBB is critical for isolating the brain from potential pathogens and for regulating the influx of molecules into the brain, evaluation of resuscitation fluids for their efficacy to improve BBB function has clinical relevance. Although whole blood and fresh frozen plasma (FFP) contain the essential coagulation factors, ions, and other factors, the transport and storage of these products in remote, austere environments can be challenging. The use of spray-dried plasma (SDP) has several advantages including storage at ambient temperature, can be readily reconstituted before use, and infectious materials can be inactivated during the drying process. In this study, we compared FFP and SDP for their effects on blood pressure, cerebral blood flow, BBB integrity, and markers of endothelial cells and tight junction proteins, in TBI animals with blood loss. All procedures were reviewed and approved by the UTHealth animal welfare committee. Sprague Dawley rats received controlled cortical impact brain injury followed by removal of 25% blood volume. Animals were resuscitated 40 minutes later with either FFP or concentrated SDP (Resusix) Heart rate and blood pressure were monitored continuously using catheters implanted into the femoral artery

  18. Purinergic receptor P2RY12-dependent microglial closure of the injured blood-brain barrier

    DEFF Research Database (Denmark)

    Lou, Nanhong; Takano, Takahiro; Pei, Yong

    2016-01-01

    Microglia are integral functional elements of the central nervous system, but the contribution of these cells to the structural integrity of the neurovascular unit has not hitherto been assessed. We show here that following blood-brain barrier (BBB) breakdown, P2RY12 (purinergic receptor P2Y, G......-protein coupled, 12)-mediated chemotaxis of microglia processes is required for the rapid closure of the BBB. Mice treated with the P2RY12 inhibitor clopidogrel, as well as those in which P2RY12 was genetically ablated, exhibited significantly diminished movement of juxtavascular microglial processes and failed...

  19. Blood-brain barrier opening by isotonic saline infusion in normotensive and hypertensive animals

    International Nuclear Information System (INIS)

    Rapoport, S.I.

    1978-01-01

    The blood-brain barrier to intravascular Evans blue-albumin was opened in monkeys and rabbits by infusing isotonic saline for 15 s into the common carotid artery, when the external carotid was clamped temporarily and the lingual was catheterized for measuring pressure. Barrier opening correlated better with infusion pressure than with infusion rate, and occurred at carotid artery pressures above 170 mmHg. Systematic hypertension induced by Aramine increased barrier vulnerability by causing a higher net carotid artery pressure to be attained at a given infusion rate. (Auth.)

  20. Gap junction proteins in the blood-brain barrier control nutrient-dependent reactivation of Drosophila neural stem cells.

    Science.gov (United States)

    Spéder, Pauline; Brand, Andrea H

    2014-08-11

    Neural stem cells in the adult brain exist primarily in a quiescent state but are reactivated in response to changing physiological conditions. How do stem cells sense and respond to metabolic changes? In the Drosophila CNS, quiescent neural stem cells are reactivated synchronously in response to a nutritional stimulus. Feeding triggers insulin production by blood-brain barrier glial cells, activating the insulin/insulin-like growth factor pathway in underlying neural stem cells and stimulating their growth and proliferation. Here we show that gap junctions in the blood-brain barrier glia mediate the influence of metabolic changes on stem cell behavior, enabling glia to respond to nutritional signals and reactivate quiescent stem cells. We propose that gap junctions in the blood-brain barrier are required to translate metabolic signals into synchronized calcium pulses and insulin secretion. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Effect of inspiratory muscle training with load compared with sham training on blood pressure in individuals with hypertension: study protocol of a double-blind randomized clinical trial.

    Science.gov (United States)

    Posser, Simone Regina; Callegaro, Carine Cristina; Beltrami-Moreira, Marina; Moreira, Leila Beltrami

    2016-08-02

    Hypertension is a complex chronic condition characterized by elevated arterial blood pressure. Management of hypertension includes non-pharmacologic strategies, which may include techniques that effectively reduce autonomic sympathetic activity. Respiratory exercises improve autonomic control over cardiovascular system and attenuate muscle metaboreflex. Because of these effects, respiratory exercises may be useful to lower blood pressure in subjects with hypertension. This randomized, double-blind clinical trial will test the efficacy of inspiratory muscle training in reducing blood pressure in adults with essential hypertension. Subjects are randomly allocated to intervention or control groups. Intervention consists of inspiratory muscle training loaded with 40 % of maximum inspiratory pressure, readjusted weekly. Control sham intervention consists of unloaded exercises. Systolic and diastolic blood pressures are co-primary endpoint measures assessed with 24 h ambulatory blood pressure monitoring. Secondary outcome measures include cardiovascular autonomic control, inspiratory muscle metaboreflex, cardiopulmonary capacity, and inspiratory muscle strength and endurance. Previously published work suggests that inspiratory muscle training reduces blood pressure in persons with hypertension, but the effectiveness of this intervention is yet to be established. We propose an adequately sized randomized clinical trial to test this hypothesis rigorously. If an effect is found, this study will allow for the investigation of putative mechanisms to mediate this effect, including autonomic cardiovascular control and metaboreflex. ClinicalTrials.gov NCT02275377 . Registered on 30 September 2014.

  2. Laser speckle-imaging of blood microcirculation in the brain cortex of laboratory rats in stress

    Science.gov (United States)

    Vilensky, M. A.; Semyachkina-Glushkovskaya, Oxana V.; Timoshina, P. A.; Kuznetsova, Jana V.; Semyachkin-Glushkovskii, I. A.; Agafonov, Dmitry N.; Tuchin, Valerii V.

    2012-06-01

    The results of experimental approbation of the method of laser full-field speckle-imaging for monitoring the changes in blood microcirculation state of the brain cortex of laboratory rats under the conditions of developing stroke and administration of vasodilating and vasoconstrictive agents are presented. The studies aimed at the choice of the optimal conditions of speckle-image formation and recording were performed and the software implementing an adaptive algorithm for processing the data of measurements was created. The transfer of laser radiation to the probed region of the biotissue was implemented by means of a silica-polymer optical fibre. The problems and prospects of speckle-imaging of cerebral microcirculation of blood in laboratory and clinical conditions are discussed.

  3. RIA examinations of CSF hormones as a method of demonstrating leakage through the blood-brain and brain-CSF barriers

    Energy Technology Data Exchange (ETDEWEB)

    Zaidman, J.L.; Pinto, N.; Czerniak, P.

    1985-12-01

    Radioimmunoassay determinations of the levels of total T3, total T4, TSH, and prolactin in the CSF were performed on samples taken from 36 healthy individuals. The obtained reference values are the first of their kind. It is considered that RIA determinations of CSF hormone levels may provide a sensitive method for demonstrating pathological leakage through the blood-brain and brain-CSF barriers.

  4. The effect of butylphthalide on the brain edema, blood-brain barrier of rats after focal cerebral infarction and the expression of Rho A.

    Science.gov (United States)

    Hu, Jinyang; Wen, Qingping; Wu, Yue; Li, Baozhu; Gao, Peng

    2014-06-01

    The aim of this study was to explore the effect of butylphthalide on the brain edema, blood-brain barrier of rats of rats after focal cerebral infarction and the expression of Rho A. A total of 195 sprague-dawley male rats were randomly divided into control group, model group, and butylphthalide group (40 mg/kg, once a day, by gavage). The model was made by photochemical method. After surgery 3, 12, 24, 72, and 144 h, brain water content was done to see the effect of butylphthalide for the cerebral edema. Evans blue extravasation method was done to see the changes in blood-brain barrier immunohistochemistry, and Western blot was done to see the expression of Rho A around the infarction. Compared with the control group, the brain water content of model group and butylphthalide group rats was increased, the permeability of blood-brain barrier of model group and butylphthalide group rats was increased, and the Rho A protein of model group and butylphthalide group rats was increased. Compared with the model group, the brain water content of butylphthalide group rats was induced (73.67 ± 0.67 vs 74.14 ± 0.46; 74.89 ± 0.57 vs 75.61 ± 0.52; 77.49 ± 0.34 vs 79.33 ± 0.49; 76.31 ± 0.56 vs 78.01 ± 0.48; 72.36 ± 0.44 vs 73.12 ± 0.73; P edema, protect the blood-brain barrier, and decrease the expression of Rho A around the infarction.

  5. Blood flow measurement of brain tumor by sup 123 I-IMP using 3-heads rotating gamma camera SPECT

    Energy Technology Data Exchange (ETDEWEB)

    Ishihara, Makiko; Yui, Nobuharu; Togawa, Takashi; Namba, Hiroki; Kinoshita, Fujimi; Koakutsu, Masaki (Chiba Cancer Center (Japan)); Minoshima, Satoshi; Uchida, Yoshitaka; Arimizu, Noboru

    1991-12-01

    Using 3-heads rotating gamma camera SPECT system, regional blood flow was measured from the super-early image obtained 4 to 6 minutes after the intravenous injection of {sup 123}I-IMP on 11 patients with various brain tumors. Two cases of olfactory groove meningioma and malignant astrocytoma showed significantly high {sup 123}I-IMP uptake by the lesion visualized by MRI compared to the uptake by normal brain cortex on super-early image but {sup 123}I-IMP uptake by the tumor decreased on early image. In both cases, blood flow of the tumor measured from super-early image showed values much higher than those of normal brain cortex. It was thought that usual correction method based on early image did not correctly represent the blood flow of the lesion but that the present method based on super-early image could show the increase of blood flow of the tumor. (author).

  6. Influence of exercise intensity on skeletal muscle blood flow, O2 extraction and O2 uptake on-kinetics

    Science.gov (United States)

    Jones, Andrew M; Krustrup, Peter; Wilkerson, Daryl P; Berger, Nicolas J; Calbet, José A; Bangsbo, Jens

    2012-01-01

    Following the start of low-intensity exercise in healthy humans, it has been established that the kinetics of skeletal muscle O2 delivery is faster than, and does not limit, the kinetics of muscle O2 uptake (). Direct data are lacking, however, on the question of whether O2 delivery might limit kinetics during high-intensity exercise. Using multiple exercise transitions to enhance confidence in parameter estimation, we therefore investigated the kinetics of, and inter-relationships between, muscle blood flow (), a– difference and following the onset of low-intensity (LI) and high-intensity (HI) exercise. Seven healthy males completed four 6 min bouts of LI and four 6 min bouts of HI single-legged knee-extension exercise. Blood was frequently drawn from the femoral artery and vein during exercise and , a– difference and were calculated and subsequently modelled using non-linear regression techniques. For LI, the fundamental component mean response time (MRTp) for kinetics was significantly shorter than kinetics (mean ± SEM, 18 ± 4 vs. 30 ± 4 s; P exercise intensities; however, the MRTp for a– difference was significantly shorter for HI compared with LI (17 ± 3 vs. 28 ± 4 s; P exercise and remained unaltered thereafter, with no differences between LI and HI. These results indicate that bulk O2 delivery does not limit kinetics following the onset of LI or HI knee-extension exercise. PMID:22711961

  7. [Blood distribution in the human leg arteries during orthostasis: role of the hydrostatic factor and posturotonic straining of the anti-gravity muscles].

    Science.gov (United States)

    Modin, A Iu

    2004-01-01

    Ultrasonic visualization and dopplerography were used to study volumetric blood flows along the femoral artery, deep artery of the thigh, and the popliteal and sural arteries in normal volunteers. Active standing test resulted in significant blood redistribution among the arteries with prioritized blood supply to predominantly anti-g muscles but not to predominantly locomotor muscles. Elimination of static loading on the anti-g muscles by weight removal (transfer of the body mass on the other leg) was conducive to the opposite effect, i.e. absolute and relative decreases in the intensity of blood flow along the sural artery and a relatively more marked blood redistribution toward the deep artery of the thigh.

  8. Placental and cord blood brain derived neurotrophic factor levels are decreased in nondiabetic macrosomia.

    Science.gov (United States)

    Cai, Qian-Ying; Zhang, Heng-Xin; Wang, Chen-Chen; Sun, Hao; Sun, Shu-Qiang; Wang, Yu-Huan; Yan, Hong-Tao; Yang, Xin-Jun

    2017-08-01

    To measure levels of placental brain derived neurotrophic factor (BDNF) gene expression and umbilical cord blood BDNF in neonates with nondiabetic macrosomia and determine associations between these levels and macrosomia. This case-control study included 58 nondiabetic macrosomic and 59 normal birth weight mother-infant pairs. Data were collected from interviews and our hospital's database. BDNF gene expression was quantified in placental tissues using quantitative real-time polymerase chain reaction (n = 117). Umbilical cord blood BDNF levels were measured by enzyme-linked immunosorbent assay (n = 90). Multivariate logistic regression models were used to evaluate associations between BDNF levels and macrosomia. Placental BDNF gene expression (P = 0.026) and cord blood BDNF (P = 0.008) were lower in neonates with nondiabetic macrosomia than in normal birth weight controls. Cord blood BDNF was significantly lower in vaginally delivered macrosomic neonates than vaginally delivered controls (P = 0.014), but cord BDNF did not differ between vaginal and cesarean section delivery modes in macrosomic neonates. Cord blood BDNF was positively associated with gestational age in control neonates (r = 0.496, P macrosomia (adjusted odds ratio 0.992; 95% confidence interval 0.986-0.998). Both placental BDNF gene expression and cord blood BDNF were downregulated in neonates with nondiabetic macrosomia compared with normal birth weight neonates. Cord BDNF may partly derive from BDNF secreted by the placenta. Higher cord plasma BDNF levels protected against nondiabetic macrosomia.

  9. The Drosophila surface glia transcriptome: evolutionary conserved blood-brain barrier processes.

    Science.gov (United States)

    DeSalvo, Michael K; Hindle, Samantha J; Rusan, Zeid M; Orng, Souvinh; Eddison, Mark; Halliwill, Kyle; Bainton, Roland J

    2014-01-01

    Central nervous system (CNS) function is dependent on the stringent regulation of metabolites, drugs, cells, and pathogens exposed to the CNS space. Cellular blood-brain barrier (BBB) structures are highly specific checkpoints governing entry and exit of all small molecules to and from the brain interstitial space, but the precise mechanisms that regulate the BBB are not well understood. In addition, the BBB has long been a challenging obstacle to the pharmacologic treatment of CNS diseases; thus model systems that can parse the functions of the BBB are highly desirable. In this study, we sought to define the transcriptome of the adult Drosophila melanogaster BBB by isolating the BBB surface glia with fluorescence activated cell sorting (FACS) and profiling their gene expression with microarrays. By comparing the transcriptome of these surface glia to that of all brain glia, brain neurons, and whole brains, we present a catalog of transcripts that are selectively enriched at the Drosophila BBB. We found that the fly surface glia show high expression of many ATP-binding cassette (ABC) and solute carrier (SLC) transporters, cell adhesion molecules, metabolic enzymes, signaling molecules, and components of xenobiotic metabolism pathways. Using gene sequence-based alignments, we compare the Drosophila and Murine BBB transcriptomes and discover many shared chemoprotective and small molecule control pathways, thus affirming the relevance of invertebrate models for studying evolutionary conserved BBB properties. The Drosophila BBB transcriptome is valuable to vertebrate and insect biologists alike as a resource for studying proteins underlying diffusion barrier development and maintenance, glial biology, and regulation of drug transport at tissue barriers.

  10. The Drosophila surface glia transcriptome: evolutionary conserved blood-brain barrier processes.

    Directory of Open Access Journals (Sweden)

    Michael K DeSalvo

    2014-11-01

    Full Text Available AbstractCentral nervous system (CNS function is dependent on the stringent regulation of metabolites, drugs, cells, and pathogens exposed to the CNS space. Cellular blood-brain barrier (BBB structures are highly specific checkpoints governing entry and exit of all small molecules to and from the brain interstitial space, but the precise mechanisms that regulate the BBB are not well understood. In addition, the BBB has long been a challenging obstacle to the pharmacologic treatment of CNS diseases; thus model systems that can parse the functions of the BBB are highly desirable. In this study, we sought to define the transcriptome of the adult Drosophila melanogaster BBB by isolating the BBB surface glia with FACS and profiling their gene expression with microarrays. By comparing the transcriptome of these surface glia to that of all brain glia, brain neurons, and whole brains, we present a catalog of transcripts that are selectively enriched at the Drosophila BBB. We found that the fly surface glia show high expression of many ABC and SLC transporters, cell adhesion molecules, metabolic enzymes, signaling molecules, and components of xenobiotic metabolism pathways. Using gene sequence-based alignments, we compare the Drosophila and Murine BBB transcriptomes and discover many shared chemoprotective and small molecule control pathways, thus affirming the relevance of invertebrate models for studying evolutionary conserved BBB properties. The Drosophila BBB transcriptome is valuable to vertebrate and insect biologists alike as a resource for studying proteins underlying diffusion barrier development and maintenance, glial biology, and regulation of drug transport at tissue barriers.

  11. Regulation of Reduced Folate Carrier (RFC) by Vitamin D Receptor at the Blood-Brain Barrier.

    Science.gov (United States)

    Alam, Camille; Hoque, Md Tozammel; Finnell, Richard H; Goldman, I David; Bendayan, Reina

    2017-11-06

    Folates are essential for brain development and function. Folate transport in mammalian tissues is mediated by three major folate transport systems, i.e., reduced folate carrier (RFC), proton-coupled folate transporter (PCFT), and folate receptor alpha (FRα), known to be regulated by ligand-activated nuclear receptors, such as vitamin D receptor (VDR). Folate uptake at the choroid plexus, which requires the actions of both FRα and PCFT, is critical to cerebral folate delivery. Inactivating FRα or PCFT mutations cause severe cerebral folate deficiency resulting in early childhood neurodegeneration. The objective of this study was to investigate the role of RFC in folate uptake at the level of the blood-brain barrier (BBB) and its potential regulation by VDR. We detected robust expression of RFC in different in vitro BBB model systems, particularly in immortalized cultures of human cerebral microvascular endothelial cells (hCMEC/D3) and isolated mouse brain capillaries. [ 3 H]-methotrexate uptake by hCMEC/D3 cells at pH 7.4 was inhibited by PT523 and pemetrexed, antifolates with high affinity for RFC. We also showed that activation of VDR through calcitriol (1,25-dihydroxyvitamin D 3 ) exposure up-regulates RFC mRNA and protein expression as well as function in hCMEC/D3 cells and isolated mouse brain capillaries. We further demonstrated that RFC expression could be down-regulated by VDR-targeting siRNA, further confirming the role of VDR in the direct regulation of this folate transporter. Together, these data suggest that augmenting RFC functional expression could constitute a novel strategy for enhancing brain folate delivery for the treatment of neurometabolic disorders caused by loss of FRα or PCFT function.

  12. 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.)

  13. Estimation of center line and diameter of brain blood vessel using three-dimensional blood vessel matching method with head three-dimensional CTA image

    International Nuclear Information System (INIS)

    Maekawa, Masashi; Shinohara, Toshihiro; Nakayama, Masato; Nakasako, Noboru

    2010-01-01

    To support and automate the brain blood vessel disease diagnosis, a novel method to obtain the center line and the diameter of a blood vessel is proposed with a three-dimensional head computed tomographic angiography (CTA) image. Although the line thinning processing with distance transform or gray information is generally used to obtain the blood vessel center line, this method is not essentially one to obtain the center line and tends to yield extra lines depending on CTA images. In this study, the center line of the blood vessel is obtained by tracing the vessel. The blood vessel is traced by sequentially estimating the center point and direction of the blood vessel. The center point and direction of the blood vessel are estimated by taking the correlation between the blood vessel and a solid model of the blood vessel that is designed by considering noise influence. In addition, the vessel diameter is also estimated by correlating the blood vessel and the blood vessel model of which the diameter is variable. The validity of the proposed method is confirmed by experimentally applied the proposed method to an actual three-dimensional head CTA image. (author)

  14. De-coupling of blood flow and metabolism in the rat brain induced by glutamate

    International Nuclear Information System (INIS)

    Hirose, Shinichiro; Momosaki, Sotaro; Sasaki, Kazunari; Hosoi, Rie; Abe, Kohji; Inoue, Osamu; Gee, A.

    2009-01-01

    Glutamate plays an essential role in neuronal cell death in many neurological disorders. In this study, we examined both glucose metabolism and cerebral blood flow in the same rat following infusion of glutamate or ibotenic acid using the dual-tracer technique. The effects of MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, and 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-kainate receptor antagonist, on the changes in the glucose metabolism and cerebral blood flow induced by glutamate were also examined. The rats were microinjected with glutamate (1 μmol/μl, 2 μl) or ibotenic acid (10 μg/μl, 1 μl) into the right striatum, and dual-tracer autoradiograms of [ 18 F]fluorodeoxyglucose (FDG) and [ 14 C]iofetamine (IMP) were obtained. MK-801 and NBQX were injected intravenously about 45 and 30 min, respectively, after the infusion of glutamate. De-coupling of blood flow and metabolism was noted in the glutamate-infused hemisphere (as assessed by no alteration of [ 18 F]FDG uptake and significant decrease of [ 14 C]IMP uptake). Pretreatments with MK-801, NBQX, or combined use of MK-801 and NBQX did not affect the de-coupling of the blood flow and metabolism induced by glutamate. A histochemical study revealed that about 20% neuronal cell death had occurred in the striatum at 105 min after the infusion of glutamate. In addition, a significant increase of the [ 18 F]FDG uptake and decrease of [ 14 C]IMP uptake were also seen in the rat brain infused with ibotenic acid. These results indicate that glutamate and ibotenic acid caused a significant de-coupling of blood flow and glucose metabolism in the intact rat brain during the early phase of neurodegeneration. It is necessary to evaluate the relation between metabotropic glutamate receptors and de-coupling of blood flow and metabolism. (author)

  15. 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

    into the femoral artery at sea level and then after 8-12 days of residence at 4559 m above sea level. At sea level, the infusions were carried out while the subjects breathed room air, acute hypoxia (FI O2 = 0.11) and hyperoxia (FI O2 = 1); and at altitude (FI O2 = 0.21 and 1). Skeletal muscle P2Y2 receptor...... 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 sea level and was unaltered by hyperoxic breathing. Baseline leg vascular conductance was 25% lower...... at altitude than at sea level (P sea level by 24 and 38%, during the low and high ATP doses...

  16. Contrasted study on the opening degree of blood-brain barriier after radiation therapy with SPECT and MRI

    International Nuclear Information System (INIS)

    Zhang Qing; Sun Aihua; Hu Yun; Zhang Li; Ye Hengguang

    2004-01-01

    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)

  17. Age-related decline in cerebral blood flow and brain atrophy

    International Nuclear Information System (INIS)

    Takeda, Shumpei; Matsuzawa, Taiju; Yamada, Kenji

    1987-01-01

    Using computed tomography, the authors studied brain atrophy during aging in 536 men and 529 women with no neurologic disturbances. They measured cerebrospinal fluid (CSF) space volume and cranial cavity volume above the level of the tentorium cerebelli and calculated a brain atrophy index. CFS space volume strated to increase significantly in the group aged from 45 to 54 years, while the BAI started to increase significantly in the group aged from 35 to 44 years in both men and women. The BAI increased exponentially with the increasing age after 25 years, continuing to increase until 75 years or more in both men and women: log BAI = -0.260 + 0.0150 x age, r = 0.707, n = 493, p < 0.001 in men; log BAI = -0.434 + 0.0162 x age, r = 0.757, n = 504, p < 0.001 in women. Using the xenon-133 inhalation method, the authors studied age-related decline in regional cerebral blood flow (regional initial slope index; rISI) in 197 men and 238 women with no neurologic disturbances, ranging in age from 19 to 88 years. The rISI values in women declined almost linearly with the advancing age from the 50s to the 80s except the 70s. The rISI values in men declined with the advancing age from the 40s to the 60s, but remained unchanged thereafter until the 80s, suggesting the existence of a threshold of rISI values. We estimated the rISI values (probable threshold of brain atrophy), the frequency under which is equivalent to the volume of brain tissues atrophying in a decade, and obtained constant values as about 32 for men and about 37 for women in the 50s, 60s and 70s. If the frequency of rISI values in the brain is distributed according to a Gaussian function and mean of rISI values decreases linearly to the increasing age, then brain tissues having rISI values below the thresholds degenerate almost exponentially with the increasing age, leading to the exponential atrophy of the brain. (J.P.N.)

  18. Enhanced therapeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruption for brain tumor treatment: an overview of the current preclinical status.

    Science.gov (United States)

    Liu, Hao-Li; Yang, Hung-Wei; Hua, Mu-Yi; Wei, Kuo-Chen

    2012-01-01

    Malignant glioma is a severe primary CNS cancer with a high recurrence and mortality rate. The current strategy of surgical debulking combined with radiation therapy or chemotherapy does not provide good prognosis, tumor progression control, or improved patient survival. The blood-brain barrier (BBB) acts as a major obstacle to chemotherapeutic treatment of brain tumors by severely restricting drug delivery into the brain. Because of their high toxicity, chemotherapeutic drugs cannot be administered at sufficient concentrations by conventional delivery methods to significantly improve long-term survival of patients with brain tumors. Temporal disruption of the BBB by microbubble-enhanced focused ultrasound (FUS) exposure can increase CNS-blood permeability, providing a promising new direction to increase the concentration of therapeutic agents in the brain tumor and improve disease control. Under the guidance and monitoring of MR imaging, a brain drug-delivery platform can be developed to control and monitor therapeutic agent distribution and kinetics. The success of FUS BBB disruption in delivering a variety of therapeutic molecules into brain tumors has recently been demonstrated in an animal model. In this paper the authors review a number of critical studies that have demonstrated successful outcomes, including enhancement of the delivery of traditional clinically used chemotherapeutic agents or application of novel nanocarrier designs for actively transporting drugs or extending drug half-lives to significantly improve treatment efficacy in preclinical animal models.

  19. Application of optical coherence tomography for in vivo monitoring of the meningeal lymphatic vessels during opening of blood-brain barrier: mechanisms of brain clearing

    Science.gov (United States)

    Semyachkina-Glushkovskaya, Oxana; Abdurashitov, Arkady; Dubrovsky, Alexander; Bragin, Denis; Bragina, Olga; Shushunova, Nataliya; Maslyakova, Galina; Navolokin, Nikita; Bucharskaya, Alla; Tuchin, Valery; Kurths, Juergen; Shirokov, Alexander

    2017-12-01

    The meningeal lymphatic vessels were discovered 2 years ago as the drainage system involved in the mechanisms underlying the clearance of waste products from the brain. The blood-brain barrier (BBB) is a gatekeeper that strongly controls the movement of different molecules from the blood into the brain. We know the scenarios during the opening of the BBB, but there is extremely limited information on how the <