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5. High cerebrospinal fluid levels of interleukin-10 attained by AAV in dogs

Author

Pleticha, J, Malkmus, SA, Heilmann, LF, Veesart, SL, Rezek, R, Xu, Q, Yaksh, TL, and Beutler, AS

Subjects
Medical Biotechnology, Biomedical and Clinical Sciences, Neurosciences, Biotechnology, Gene Therapy, Pain Research, Genetics, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Animals, Chronic Pain, Dependovirus, Dogs, Genetic Therapy, Green Fluorescent Proteins, Humans, Injections, Spinal, Interleukin-10, Male, Transduction, Genetic, Viral Tropism, Biological Sciences, Medical and Health Sciences, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Intrathecal (IT) gene transfer using adeno-associated virus (AAV) may be clinically promising as a treatment for chronic pain if it can produce sufficiently high levels of a transgene product in the cerebrospinal fluid (CSF). Although this strategy was developed in rodents, no studies investigating CSF levels of an analgesic or antiallodynic protein delivered by IT AAV have been performed in large animals. Interleukin-10 (IL-10) is an antiallodynic cytokine for which target therapeutic levels have been established in rats. The present study tested IT AAV8 encoding either human IL-10 (hIL-10) or enhanced green fluorescent protein (EGFP) in a dog model of IT drug delivery. AAV8/hIL-10 at a dose of 3.5 × 10(12) genome copies induced high hIL-10 levels in the CSF, exceeding the target concentration previously found to be antiallodynic in rodents by >1000-fold. AAV8/EGFP targeted the primary sensory and motor neurons and the meninges. hIL-10, a xenogeneic protein in dogs, induced anti-hIL-10 antibodies detectable in the CSF and serum of dogs. The high hIL-10 levels demonstrate the efficacy of AAV for delivery of secreted transgenes into the IT space of large animals, suggesting a strong case for further development toward clinical testing.

Published
2015

6. Understanding pharmaceutical exposure and the potential for effects in marine biota: A survey of bonefish (Albula vulpes) across the Caribbean Basin

Author

Castillo, N.A., primary, James, W.R., additional, Santos, R.O., additional, Rezek, R., additional, Cerveny, D., additional, Boucek, R.E., additional, Adams, A.J., additional, Goldberg, T., additional, Campbell, L., additional, Perez, A.U., additional, Schmitter-Soto, J.J., additional, Lewis, J.P., additional, Fick, J., additional, Brodin, T., additional, and Rehage, J.S., additional

Published
2023
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7. Global Impact of COVID-19 on Stroke Care and IV Thrombolysis

Author

Nogueira, R.G. Qureshi, M.M. Abdalkader, M. Martins, S.O. Yamagami, H. Qiu, Z. Mansour, O.Y. Sathya, A. Czlonkowska, A. Tsivgoulis, G. Aguiar de Sousa, D. Demeestere, J. Mikulik, R. Vanacker, P. Siegler, J.E. Kõrv, J. Biller, J. Liang, C.W. Sangha, N.S. Zha, A.M. Czap, A.L. Holmstedt, C.A. Turan, T.N. Ntaios, G. Malhotra, K. Tayal, A. Loochtan, A. Ranta, A. Mistry, E.A. Alexandrov, A.W. Huang, D.Y. Yaghi, S. Raz, E. Sheth, S.A. Mohammaden, M.H. Frankel, M. Bila Lamou, E.G. Aref, H.M. Elbassiouny, A. Hassan, F. Menecie, T. Mustafa, W. Shokri, H.M. Roushdy, T. Sarfo, F.S. Alabi, T.O. Arabambi, B. Nwazor, E.O. Sunmonu, T.A. Wahab, K. Yaria, J. Mohammed, H.H. Adebayo, P.B. Riahi, A.D. Sassi, S.B. Gwaunza, L. Ngwende, G.W. Sahakyan, D. Rahman, A. Ai, Z. Bai, F. Duan, Z. Hao, Y. Huang, W. Li, G. Li, W. Liu, G. Luo, J. Shang, X. Sui, Y. Tian, L. Wen, H. Wu, B. Yan, Y. Yuan, Z. Zhang, H. Zhang, J. Zhao, W. Zi, W. Leung, T.W. Chugh, C. Huded, V. Menon, B. Pandian, J.D. Sylaja, P.N. Usman, F.S. Farhoudi, M. Hokmabadi, E.S. Horev, A. Reznik, A. Sivan Hoffmann, R. Ohara, N. Sakai, N. Watanabe, D. Yamamoto, R. Doijiri, R. Tokuda, N. Yamada, T. Terasaki, T. Yazawa, Y. Uwatoko, T. Dembo, T. Shimizu, H. Sugiura, Y. Miyashita, F. Fukuda, H. Miyake, K. Shimbo, J. Sugimura, Y. Yagita, Y. Takenobu, Y. Matsumaru, Y. Yamada, S. Kono, R. Kanamaru, T. Yamazaki, H. Sakaguchi, M. Todo, K. Yamamoto, N. Sonoda, K. Yoshida, T. Hashimoto, H. Nakahara, I. Kondybayeva, A. Faizullina, K. Kamenova, S. Zhanuzakov, M. Baek, J.-H. Hwang, Y. Lee, J.S. Lee, S.B. Moon, J. Park, H. Seo, J.H. Seo, K.-D. Sohn, S.I. Young, C.J. Ahdab, R. Wan Zaidi, W.A. Aziz, Z.A. Basri, H.B. Chung, L.W. Ibrahim, A.B. Ibrahim, K.A. Looi, I. Tan, W.Y. Yahya, N.W. Groppa, S. Leahu, P. Al Hashmi, A.M. Imam, Y.Z. Akhtar, N. Pineda-Franks, M.C. Co, C.O. Kandyba, D. Alhazzani, A. Al-Jehani, H. Tham, C.H. Mamauag, M.J. Venketasubramanian, N. Chen, C.-H. Tang, S.-C. Churojana, A. Akil, E. Aykaç, Ö. Ozdemir, A.O. Giray, S. Hussain, S.I. John, S. Le Vu, H. Tran, A.D. Nguyen, H.H. Nhu Pham, T. Nguyen, T.H. Nguyen, T.Q. Gattringer, T. Enzinger, C. Killer-Oberpfalzer, M. Bellante, F. De Blauwe, S. Vanhooren, G. De Raedt, S. Dusart, A. Lemmens, R. Ligot, N. Pierre Rutgers, M. Yperzeele, L. Alexiev, F. Sakelarova, T. Bedeković, M.R. Budincevic, H. Cindric, I. Hucika, Z. Ozretic, D. Saric, M.S. Pfeifer, F. Karpowic, I. Cernik, D. Sramek, M. Skoda, M. Hlavacova, H. Klecka, L. Koutny, M. Vaclavik, D. Skoda, O. Fiksa, J. Hanelova, K. Nevsimalova, M. Rezek, R. Prochazka, P. Krejstova, G. Neumann, J. Vachova, M. Brzezanski, H. Hlinovsky, D. Tenora, D. Jura, R. Jurák, L. Novak, J. Novak, A. Topinka, Z. Fibrich, P. Sobolova, H. Volny, O. Krarup Christensen, H. Drenck, N. Klingenberg Iversen, H. Simonsen, C.Z. Truelsen, T.C. Wienecke, T. Vibo, R. Gross-Paju, K. Toomsoo, T. Antsov, K. Caparros, F. Cordonnier, C. Dan, M. Faucheux, J.-M. Mechtouff, L. Eker, O. Lesaine, E. Ondze, B. Peres, R. Pico, F. Piotin, M. Pop, R. Rouanet, F. Gubeladze, T. Khinikadze, M. Lobjanidze, N. Tsiskaridze, A. Nagel, S. Ringleb, P.A. Rosenkranz, M. Schmidt, H. Sedghi, A. Siepmann, T. Szabo, K. Thomalla, G. Palaiodimou, L. Sagris, D. Kargiotis, O. Klivenyi, P. Szapary, L. Tarkanyi, G. Adami, A. Bandini, F. Calabresi, P. Frisullo, G. Renieri, L. Sangalli, D. Pirson, A. Uyttenboogaart, M. van den Wijngaard, I. Kristoffersen, E.S. Brola, W. Fudala, M. Horoch-Lyszczarek, E. Karlinski, M. Kazmierski, R. Kram, P. Rogoziewicz, M. Kaczorowski, R. Luchowski, P. Sienkiewicz-Jarosz, H. Sobolewski, P. Fryze, W. Wisniewska, A. Wiszniewska, M. Ferreira, P. Ferreira, P. Fonseca, L. Marto, J.P. Pinho E Melo, T. Nunes, A.P. Rodrigues, M. Tedim Cruz, V. Falup-Pecurariu, C. Krastev, G. Mako, M. de Leciñana, M.A. Arenillas, J.F. Ayo-Martin, O. Cruz Culebras, A. Tejedor, E.D. Montaner, J. Pérez-Sánchez, S. Tola Arribas, M.A. Rodriguez Vasquez, A. Mayza, M. Bernava, G. Brehm, A. Machi, P. Fischer, U. Gralla, J. Michel, P.L. Psychogios, M.-N. Strambo, D. Banerjee, S. Krishnan, K. Kwan, J. Butt, A. Catanese, L. Demchuk, A.M. Field, T. Haynes, J. Hill, M.D. Khosravani, H. Mackey, A. Pikula, A. Saposnik, G. Scott, C.A. Shoamanesh, A. Shuaib, A. Yip, S. Barboza, M.A. Barrientos, J.D. Portillo Rivera, L.I. Gongora-Rivera, F. Novarro-Escudero, N. Blanco, A. Abraham, M. Alsbrook, D. Altschul, D. Alvarado-Ortiz, A.J. Bach, I. Badruddin, A. Barazangi, N. Brereton, C. Castonguay, A. Chaturvedi, S. Chaudry, S.A. Choe, H. Choi, J.H. Dharmadhikari, S. Desai, K. Devlin, T.G. Doss, V.T. Edgell, R. Etherton, M. Farooqui, M. Frei, D. Gandhi, D. Grigoryan, M. Gupta, R. Hassan, A.E. Helenius, J. Kaliaev, A. Kaushal, R. Khandelwal, P. Khawaja, A.M. Khoury, N.N. Kim, B.S. Kleindorfer, D.O. Koyfman, F. Lee, V.H. Leung, L.Y. Linares, G. Linfante, I. Lutsep, H.L. Macdougall, L. Male, S. Malik, A.M. Masoud, H. McDermott, M. Mehta, B.P. Min, J. Mittal, M. Morris, J.G. Multani, S.S. Nahab, F. Nalleballe, K. Nguyen, C.B. Novakovic-White, R. Ortega-Gutierrez, S. Rahangdale, R.H. Ramakrishnan, P. Romero, J.R. Rost, N. Rothstein, A. Ruland, S. Shah, R. Sharma, M. Silver, B. Simmons, M. Singh, A. Starosciak, A.K. Strasser, S.L. Szeder, V. Teleb, M. Tsai, J.P. Voetsch, B. Balaguera, O. Pujol Lereis, V.A. Luraschi, A. Almeida, M.S. Cardoso, F.B. Conforto, A. De Deus Silva, L. Varrone Giacomini, L. Oliveira Lima, F. Longo, A.L. Magalhães, P.S.C. Martins, R.T. Mont'alverne, F. Mora Cuervo, D.L. Costa Rebello, L. Valler, L. Zetola, V.F. Lavados, P.M. Navia, V. Olavarría, V.V. Almeida Toro, J.M. Amaya, P.F.R. Bayona, H. Corredor, A. Rivera Ordonez, C.E. Mantilla Barbosa, D.K. Lara, O. Patiño, M.R. Diaz Escobar, L.F. Dejesus Melgarejo Fariña, D.E. Cardozo Villamayor, A. Zelaya Zarza, A.J. Barrientos Iman, D.M. Rodriguez Kadota, L. Campbell, B. Hankey, G.J. Hair, C. Kleinig, T. Ma, A. Tomazini Martins, R. Sahathevan, R. Thijs, V. Salazar, D. Yuan-Hao Wu, T. Haussen, D.C. Liebeskind, D. Yavagal, D.R. Jovin, T.G. Zaidat, O.O. Nguyen, T.N. SVIN COVID-19 Global Stroke Registry SVIN COVID-19 Global Stroke Registry

Abstract

OBJECTIVE: To measure the global impact of COVID-19 pandemic on volumes of IV thrombolysis (IVT), IVT transfers, and stroke hospitalizations over 4 months at the height of the pandemic (March 1 to June 30, 2020) compared with 2 control 4-month periods. METHODS: We conducted a cross-sectional, observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers. Diagnoses were identified by their ICD-10 codes or classifications in stroke databases. RESULTS: There were 91,373 stroke admissions in the 4 months immediately before compared to 80,894 admissions during the pandemic months, representing an 11.5% (95% confidence interval [CI] -11.7 to -11.3, p < 0.0001) decline. There were 13,334 IVT therapies in the 4 months preceding compared to 11,570 procedures during the pandemic, representing a 13.2% (95% CI -13.8 to -12.7, p < 0.0001) drop. Interfacility IVT transfers decreased from 1,337 to 1,178, or an 11.9% decrease (95% CI -13.7 to -10.3, p = 0.001). Recovery of stroke hospitalization volume (9.5%, 95% CI 9.2-9.8, p < 0.0001) was noted over the 2 later (May, June) vs the 2 earlier (March, April) pandemic months. There was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was noted in 3.3% (1,722/52,026) of all stroke admissions. CONCLUSIONS: The COVID-19 pandemic was associated with a global decline in the volume of stroke hospitalizations, IVT, and interfacility IVT transfers. Primary stroke centers and centers with higher COVID-19 inpatient volumes experienced steeper declines. Recovery of stroke hospitalization was noted in the later pandemic months. © 2021 American Academy of Neurology.

Published
2021

8. In vivo Anticonvulsant and Neurotoxicity Evaluation and Docking Study of Promising Novel [1,5]-Benzodiazepine Derivatives.

Author

El-Gamal, Kamal M., El-Morsy, Ahmed M., Sherbini, Farag F., Elraheim, Adel Saad A., Ayaad, Rezek R., Saad, Ahmed S., Al-Omary, Fatmah A. M., and Mansour, Basem

Subjects
ANTICONVULSANTS, NEUROTOXICOLOGY, BENZODIAZEPINES, CHEMICAL derivatives, GABA receptors
Abstract

Background: Benzodiazepines (BDZs) are predominantly prescribed as sedatives, anxiolytics, and anticonvulsants throughout the world and they act on the GABAA receptor. Objective: New 1,4-BDZ analogues have been designed and synthesized to be evaluated for their anticonvulsant activity. Methods: The newly synthesized compounds have been examined by Maximal electroshock seizure (MES) test, the subcutaneous pentylenetetrazol (scPTZ) seizure test, and rotarod neurotoxicity test. Docking study was performed to justify the activity. Results: The most active compound that showed activity (MES Assay) at both 0.5 h and 4 h at a dose of 30 mg/kg is compound 4b, whereas it has scored protection at a dose level of 100 mg/kg at both 0.5 h and 4 h (scPTZ assay) and did not score any neurotoxicity at maximum dose level unlike phenytoin the reference drug that scored neurotoxicity on mice at dose level of 100 mg/kg. Conclusion: Docking revealed that Compound 4b is active on the three sites of the GABAA isoform a2ß2°. Compared with the reference drug, phenytoin, Compound 4b has more rapid onset and longer duration of action, is more effective, and eventually is safer. Furthermore, we recommend more structural modification studies to come out with much more selective BDZ derivatives to minimize the side effects. [ABSTRACT FROM AUTHOR]

Published
2022
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9. Synthesis and Antiproliferative Activity of 1-(4-(1H-Indol-3-Yl)-6-(4-Methoxyphenyl)Pyrimidin-2-yl)Hydrazine and Its Pyrazolo Pyrimidine Derivatives

Author

Ekhlass Nassar, Yaser A El Badry, Afaf Mm Eltoukhy, and Rezek R Ayyad

Subjects
Chalcone, chemistry.chemical_compound, chemistry, Pyrimidine, 010405 organic chemistry, Hydrazine, 010402 general chemistry, Hydrate, 01 natural sciences, Combinatorial chemistry, Pyrazolopyrimidine, 0104 chemical sciences
Abstract

The target compounds 1-(4-(1H-indol-3-yl)-6-(4-methoxyphenyl)pyrimidin-2-yl)hydrazine (5) was synthesized by reacting 6-(1H-Indol-3-yl)-4-(4-methoxyphenyl)pyrimidine-2(1H)-thione 4 with hydrazine hydrate. Compound 5 was used as a precursor for the synthesis of new pyrazolo pyrimidine derivatives 6-9. Moreover, the 5-amino-1H-pyrazole-4-carbonitrile derivative 6 was then converted into another set of novel compounds 10-14. On the other hand a series of transformations were carried out using the newly synthesized 1-(4-(1H-indol-3-yl)-6-(4-methoxyphenyl) pyrimidin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (11) to afford the pyrazolo pyrimidine derivatives 15-18. Antiproliferatve activities for some of the newly synthesized compounds were evaluated.

Published
2016
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11. Intraneural convection enhanced delivery of AAVrh20 for targeting primary sensory neurons.

Author

Pleticha J, Jeng-Singh C, Rezek R, Zaibak M, and Beutler AS

Subjects
Animals, Convection, Dependovirus genetics, Ganglia, Spinal cytology, Ganglia, Spinal metabolism, Genetic Vectors administration & dosage, Genetic Vectors genetics, Injections methods, Male, Neuralgia metabolism, Rats, Rats, Sprague-Dawley, Sciatic Nerve injuries, Sciatic Nerve metabolism, Gene Transfer Techniques, Genetic Therapy methods, Neuralgia therapy, Sensory Receptor Cells metabolism
Abstract

Gene therapy using adeno-associated virus (AAV) is an attractive strategy to treat disorders of the peripheral nervous system (PNS), such as chronic pain or peripheral neuropathies. Although intrathecal (IT) administration of AAV has been the standard in the field for targeting the PNS, it lacks anatomical specificity and results in wide rostro-caudal distribution of the vector. An alternative approach is to deliver AAV directly to the peripheral nerve axon. The present study employed convection-enhanced delivery (CED) of a novel AAV serotype, AAVrh20, expressing enhanced green fluorescent protein (EGFP) into rat sciatic nerve investigating its efficacy, anatomical selectivity, and safety, compared to the IT route. Intraneural CED resulted in transduction confined to the ipsilateral L4 and L5 DRG while IT administration led to promiscuous DRG transduction encompassing the entire lumbar region bilaterally. The transduction rate for intraneural AAV administration was similar to IT delivery (24% for L4 and 31.5% for L5 DRG versus 50% for L4 and 19.5% for L5 DRG). The use of hyperosmotic diluent did not further improve the transduction efficiency. AAVrh20 was superior to reference serotypes previously described to be most active for each route. Intraneural CED of AAV was associated with transient allodynia that resolved spontaneously. These findings establish intraneural CED as an alternative to IT administration for AAV mediated gene transfer to the PNS and, based on a reference rodent model, suggest AAVrh20 as a superior serotype for targeting the PNS., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Published
2014
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