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  1. Article ; Online: Development of a clinician worn device for the evaluation of abnormal muscle tone.

    Brokaw, Elizabeth B / Heldman, Dustin A / Plott, Robert J / Rapp, Edward J / Montgomery, Erwin B / Giuffrida, Joseph P

    Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference

    2015  Volume 2014, Page(s) 4091–4094

    Abstract: Neurological disorders such as cerebral palsy commonly result in abnormal muscle hyperactivity that negatively effects functional use of the affected limbs. Individuals with cerebral palsy often present with a mix of spasticity and dystonia, and it can ... ...

    Abstract Neurological disorders such as cerebral palsy commonly result in abnormal muscle hyperactivity that negatively effects functional use of the affected limbs. Individuals with cerebral palsy often present with a mix of spasticity and dystonia, and it can be difficult to distinguish between the effects of these types of abnormal tone. Different types of abnormal tone respond differently to treatments such as deep brain stimulation and baclofen. Conventional clinical evaluation techniques provide minimal information for distinguishing abnormal tone characteristics and changes from treatment. Devices that quantify abnormal tone characteristics can help distinguish between the effects of different types of abnormal muscle tone, and help to quantify treatment effects. This paper discusses the development and initial evaluation of MyoSense(TM), a clinician worn device for the quantification and differentiation of abnormal muscle tone. MyoSense evaluates the orientation, speed, and force during clinician manipulation of the affected limbs with a protocol that is similar to conventional practice for evaluating abnormal tone. Evaluation of the MyoSense device, using a mechanical apparatus to simulate abnormal muscle tone, showed good resolution of abnormal tone characteristics. Using a procedure directly modeled after conventional clinical evaluation of abnormal tone, MyoSense data showed good correlation with simulated profiles, 0.8 for spasticity and 0.93 for hypertonia. Evaluation of average change across different limb manipulation speeds, to mitigate acceleration and mechanical effects, resulted in MyoSense data correlations to simulated profiles of 0.99 for spasticity, spasticity with a catch, and dystonia. Overall these results show promise for future clinical evaluation of the MyoSense device.
    MeSH term(s) Acceleration ; Accelerometry/methods ; Cerebral Palsy/diagnosis ; Cerebral Palsy/physiopathology ; Computer Simulation ; Deep Brain Stimulation ; Equipment Design ; Fingers/physiology ; Hand/physiology ; Humans ; Monitoring, Ambulatory/methods ; Muscle Spasticity/physiopathology ; Muscle Tonus/physiology ; Signal Processing, Computer-Assisted
    Language English
    Publishing date 2015-01-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 2694-0604
    ISSN (online) 2694-0604
    DOI 10.1109/EMBC.2014.6944523
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Drug delivery and in vitro models of the blood-brain barrier.

    Cucullo, Luca / Aumayr, Barbara / Rapp, Edward / Janigro, Damir

    Current opinion in drug discovery & development

    2005  Volume 8, Issue 1, Page(s) 89–99

    Abstract: An understanding of the physiology of the blood-brain barrier (BBB) is crucial when addressing complex issues such as drug delivery, pathogenesis of chronic neurological diseases and bio-defense. Rational central nervous system (CNS) drug design cannot ... ...

    Abstract An understanding of the physiology of the blood-brain barrier (BBB) is crucial when addressing complex issues such as drug delivery, pathogenesis of chronic neurological diseases and bio-defense. Rational central nervous system (CNS) drug design cannot entirely and exclusively rely upon the physicochemical properties of putative neurotherapeutics, since lipophilicity alone is a poor predictor for drug penetration into the CNS. This is particularly true for three large families of CNS drugs: antineoplastics, antivirals and anti-epileptics. For these drugs, in contrast to peripheral acting drugs (eg, antihistamines), negligible penetration across the BBB is preferable in order to avoid CNS side effects. Studies performed using small animals such as rodents cannot be directly extrapolated to human brain tissue, as demonstrated by both clinical and in vitro studies. Furthermore, most of the promising CNS drugs that proved effective in vitro have failed in clinical trials due to misleading predictive permeability data extrapolated from models that were not capable of fully reproducing the functional properties of the BBB in vivo. Therefore, a great effort has been made to develop new in vitro models able to reproduce the physiological, anatomical and functional characteristics of the BBB allowing for a better prediction of drug penetration across the BBB, and enabling the design of new pharmaceutical strategies to bypass the shielding of brain parenchyma. Herein we provide a detailed review and discussion of currently employed in vitro BBB models along with probable future developments.
    MeSH term(s) Animals ; Blood-Brain Barrier/physiology ; Computer Simulation ; Drug Delivery Systems ; Endothelial Cells/metabolism ; Humans ; Models, Biological
    Language English
    Publishing date 2005-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S. ; Review
    ZDB-ID 1461136-3
    ISSN 2040-3437 ; 1367-6733
    ISSN (online) 2040-3437
    ISSN 1367-6733
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Is phosphorylated tau unique to chronic traumatic encephalopathy? Phosphorylated tau in epileptic brain and chronic traumatic encephalopathy.

    Puvenna, Vikram / Engeler, Madeline / Banjara, Manoj / Brennan, Chanda / Schreiber, Peter / Dadas, Aaron / Bahrami, Ashkon / Solanki, Jesal / Bandyopadhyay, Anasua / Morris, Jacqueline K / Bernick, Charles / Ghosh, Chaitali / Rapp, Edward / Bazarian, Jeffrey J / Janigro, Damir

    Brain research

    2016  Volume 1630, Page(s) 225–240

    Abstract: Repetitive traumatic brain injury (rTBI) is one of the major risk factors for the abnormal deposition of phosphorylated tau (PT) in the brain and chronic traumatic encephalopathy (CTE). CTE and temporal lobe epilepsy (TLE) affect the limbic system, but ... ...

    Abstract Repetitive traumatic brain injury (rTBI) is one of the major risk factors for the abnormal deposition of phosphorylated tau (PT) in the brain and chronic traumatic encephalopathy (CTE). CTE and temporal lobe epilepsy (TLE) affect the limbic system, but no comparative studies on PT distribution in TLE and CTE are available. It is also unclear whether PT pathology results from repeated head hits (rTBI). These gaps prevent a thorough understanding of the pathogenesis and clinical significance of PT, limiting our ability to develop preventative and therapeutic interventions. We quantified PT in TLE and CTE to unveil whether a history of rTBI is a prerequisite for PT accumulation in the brain. Six postmortem CTE (mean 73.3 years) and age matched control samples were compared to 19 surgically resected TLE brain specimens (4 months-58 years; mean 27.6 years). No history of TBI was present in TLE or control; all CTE patients had a history of rTBI. TLE and CTE brain displayed increased levels of PT as revealed by immunohistochemistry. No age-dependent changes were noted, as PT was present as early as 4 months after birth. In TLE and CTE, cortical neurons, perivascular regions around penetrating pial vessels and meninges were immunopositive for PT; white matter tracts also displayed robust expression of extracellular PT organized in bundles parallel to venules. Microscopically, there were extensive tau-immunoreactive neuronal, astrocytic and degenerating neurites throughout the brain. In CTE perivascular tangles were most prominent. Overall, significant differences in staining intensities were found between CTE and control (P<0.01) but not between CTE and TLE (P=0.08). pS199 tau analysis showed that CTE had the most high molecular weight tangle-associated tau, whereas epileptic brain contained low molecular weight tau. Tau deposition may not be specific to rTBI since TLE recapitulated most of the pathological features of CTE.
    MeSH term(s) Adolescent ; Adult ; Aged ; Aged, 80 and over ; Brain/metabolism ; Brain/pathology ; Brain/surgery ; Brain Injury, Chronic/metabolism ; Brain Injury, Chronic/pathology ; Child ; Child, Preschool ; Enzyme-Linked Immunosorbent Assay ; Epilepsy/metabolism ; Epilepsy/pathology ; Epilepsy/surgery ; Female ; Humans ; Immunohistochemistry ; Infant ; Male ; Middle Aged ; Phosphorylation ; Young Adult ; tau Proteins/metabolism
    Chemical Substances MAPT protein, human ; tau Proteins
    Language English
    Publishing date 2016-01-01
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1200-2
    ISSN 1872-6240 ; 0006-8993
    ISSN (online) 1872-6240
    ISSN 0006-8993
    DOI 10.1016/j.brainres.2015.11.007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 161: Show issues Location:
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  4. Article: Side by side comparison between dynamic versus static models of blood-brain barrier in vitro: a permeability study.

    Santaguida, Stefano / Janigro, Damir / Hossain, Mohammed / Oby, Emily / Rapp, Edward / Cucullo, Luca

    Brain research

    2006  Volume 1109, Issue 1, Page(s) 1–13

    Abstract: Endothelial cells in vivo are continuously exposed to shear stress, a tangential force generated by the flow of blood across their apical surfaces that affects endothelial cell structure and function. By contrast, the Transwell apparatus cannot reproduce ...

    Abstract Endothelial cells in vivo are continuously exposed to shear stress, a tangential force generated by the flow of blood across their apical surfaces that affects endothelial cell structure and function. By contrast, the Transwell apparatus cannot reproduce the presence of intraluminal blood flow that is essential for the formation and differentiation of the BBB. In contrast, the dynamic in vitro model of the BBB (DIV-BBB) mimics both functionally and anatomically the brain microvasculature, creating quasi-physiological conditions for co-culturing human and non-human endothelial cells and astrocytes in a capillary-like structure. We used intraluminal bovine aortic endothelial cells (BAEC) co-cultured with extraluminal glial cells (C6) to obtain elevated trans-endothelial electrical resistance (TEER) and selective permeability to sucrose and phenytoin. The experiments were performed in parallel using Transwell systems DIV-BBB models and data were then cross compared. By contrast with Transwell, C6 and BAEC co-cultured in the DIV-BBB demonstrated predominantly aerobic metabolism evidenced by a robust increase in glucose consumption that was paralleled by a similar change in lactate production. BAEC exposed to glia under dynamic conditions grow in a monolayer fashion and developed a more stringent barrier as demonstrated by high TEER values and a selective permeability to [14C] phenytoin and the well-known paracellular marker [3H] sucrose. In conclusion, these data demonstrate that the exposure to intraluminal flow plays an essential role in promoting endothelial cell differentiation and increasing BBB tightness, thus making the use of the DIV-BBB well suited for pharmacological studies.
    MeSH term(s) Animals ; Aorta/cytology ; Blood-Brain Barrier/physiology ; Capillary Permeability/physiology ; Carbon Isotopes/pharmacology ; Cattle ; Cells, Cultured ; Coculture Techniques/methods ; Diffusion Chambers, Culture/methods ; Electric Impedance ; Endothelial Cells/metabolism ; Glucose/metabolism ; Lactase/metabolism ; Models, Animal ; Phenytoin/metabolism ; Sucrose/metabolism ; Tritium/pharmacology
    Chemical Substances Carbon Isotopes ; Tritium (10028-17-8) ; Sucrose (57-50-1) ; Phenytoin (6158TKW0C5) ; Lactase (EC 3.2.1.108) ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2006-09-13
    Publishing country Netherlands
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1200-2
    ISSN 1872-6240 ; 0006-8993
    ISSN (online) 1872-6240
    ISSN 0006-8993
    DOI 10.1016/j.brainres.2006.06.027
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Immortalized human brain endothelial cells and flow-based vascular modeling: a marriage of convenience for rational neurovascular studies.

    Cucullo, Luca / Couraud, Pierre-Olivier / Weksler, Babette / Romero, Ignacio-Andres / Hossain, Mohammed / Rapp, Edward / Janigro, Damir

    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

    2008  Volume 28, Issue 2, Page(s) 312–328

    Abstract: In evaluating drugs that enter or are excluded from the brain, novel pharmaceutical strategies are needed. For this reason, we have developed a humanized Dynamic In vitro Blood-Brain Barrier model (hDIV-BBB) based on a novel human brain vascular ... ...

    Abstract In evaluating drugs that enter or are excluded from the brain, novel pharmaceutical strategies are needed. For this reason, we have developed a humanized Dynamic In vitro Blood-Brain Barrier model (hDIV-BBB) based on a novel human brain vascular endothelial cell line (HCMEC/D3), which closely mimics the BBB in vivo. In this system, HCMEC/D3 was grown in the lumen of hollow microporous fibers and exposed to a physiological pulsatile flow. Comparison with well-established humanized DIV-BBB models (based on human brain and non-brain vascular endothelial cells co-cultured with abluminal astrocytes) demonstrated that HCMEC/D3 cells cultured under flow conditions maintain in vitro physiological permeability barrier properties of the BBB in situ even in the absence of abluminal astrocytes. Measurements of glucose metabolism demonstrated that HCMEC/D3 cells retain an aerobic metabolic pathway. Permeability to sucrose and two relevant central nervous system drugs showed that the HCMEC/D3 cells grown under dynamic conditions closely mimic the physiological permeability properties of the BBB in situ (slope=0.93). Osmotic disruption of the BBB was also successfully achieved. Peak BBB opening in the DIV-BBB lasted from 20 to 30 mins and was completely reversible. Furthermore, the sequence of flow cessation/reperfusion in the presence of leukocytes led to BBB failure as demonstrated by a biphasic decrease in transendothelial electrical resistance. Additionally, BBB failure was paralleled by the intraluminal release of proinflammatory factors (interleukin-6 and interleukin-1beta) and matrix metalloproteinase-9 (MMP-9). Pretreatment with ibuprofen (0.125 mmol/L) prevented BBB failure by decreasing the inflammatory response after flow cessation/reperfusion.
    MeSH term(s) Animals ; Blood-Brain Barrier/physiology ; Brain Ischemia/pathology ; Capillaries/cytology ; Cells, Cultured ; Cerebrovascular Circulation ; Cytokines/biosynthesis ; Cytological Techniques ; Diuretics/pharmacology ; Electrophysiology ; Endothelial Cells/physiology ; Endothelium, Vascular/physiology ; Glucose/metabolism ; Humans ; Inflammation/pathology ; Lactic Acid/metabolism ; Leukocytes/physiology ; Mannitol/pharmacology ; Matrix Metalloproteinase 9/biosynthesis ; Models, Biological ; Neurons/physiology ; Osmolar Concentration ; Pharmaceutical Preparations/metabolism ; Rats ; Reperfusion Injury/pathology ; Sucrose/metabolism
    Chemical Substances Cytokines ; Diuretics ; Pharmaceutical Preparations ; Lactic Acid (33X04XA5AT) ; Mannitol (3OWL53L36A) ; Sucrose (57-50-1) ; Matrix Metalloproteinase 9 (EC 3.4.24.35) ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2008-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 604628-9
    ISSN 1559-7016 ; 0271-678X
    ISSN (online) 1559-7016
    ISSN 0271-678X
    DOI 10.1038/sj.jcbfm.9600525
    Database MEDical Literature Analysis and Retrieval System OnLINE

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