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4. Fixed-Dose Subcutaneous C1-Inhibitor Liquid for Prophylactic Treatment of C1-INH-HAE: SAHARA Randomized Study

Author

Keith, P., Yang, W., Maurer, M., Martinez-Saguer, I., Farkas, H., Reshef, A., Kivity, S., Moldovan, D., Caballero, T., Guilarte, M., Hernandez, M.D., González-Quevedo, M.T., Banerji, A., Bernstein, J., Bewtra, A., Craig, T., Fineman, S., Gower, R., Jacobs, J., Johnston, D., Kashkin, J., Li, H.H., Lumry, W.R., Manning, M., McNeil, D., Melamed, I., Mumneh, N., Nickel, T., Panuto, J., Soteres, D., Tachdjian, R., Offenberger, J., Wedner, J., Lumry, William R., Martinez-Saguer, Inmaculada, Yang, William H., Bernstein, Jonathan A., Jacobs, Joshua, Moldovan, Dumitru, Riedl, Marc A., Johnston, Douglas T., Li, H. Henry, Tang, Yongqiang, Schranz, Jennifer, Lu, Peng, Vardi, Moshe, and Farkas, Henriette

Published
2019
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5. On-chip phenotypic analysis of inflammatory monocytes in atherogenesis and myocardial infarction

Author

Foster, Greg A, Gower, R Michael, Stanhope, Kimber L, Havel, Peter J, Simon, Scott I, and Armstrong, Ehrin J

Subjects
Fluid Mechanics and Thermal Engineering, Biomedical and Clinical Sciences, Engineering, Clinical Research, Atherosclerosis, Heart Disease - Coronary Heart Disease, Heart Disease, Cardiovascular, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Adult, Analysis of Variance, CD11c Antigen, CD18 Antigens, Cell Adhesion, Endothelium, Vascular, Female, Flow Cytometry, Humans, Hypertriglyceridemia, Male, Membrane Glycoproteins, Microfluidic Analytical Techniques, Monocytes, Myocardial Infarction, Phenotype, Platelet Glycoprotein GPIb-IX Complex, Vascular Cell Adhesion Molecule-1, B2-integrin, cell arrest, shear flow
Abstract

Monocyte recruitment to inflamed arterial endothelium initiates plaque formation and drives progression of atherosclerosis. Three distinct monocyte subsets are detected in circulation (CD14(++)CD16(-), CD14(++)CD16(+), and CD14(+)CD16(++)), and each may play distinct roles during atherogenesis and myocardial infarction. We studied a range of subjects that included otherwise healthy patients with elevated serum triglyceride levels to patients presenting with acute myocardial infarction. Our objective was to correlate an individual's risk with the activation state of each monocyte subset as a function of changes in adhesion receptor expression using flow cytometric quantitation of integrins and l-selectin membrane expression. A microfluidic-based laboratory-on-a-chip was developed to quantify the adhesion efficiency of monocytes sheared in whole blood on vascular cell adhesion molecule-1, while characterizing adhesion receptor expression and topography on captured monocytes. CD14(++)CD16(+) monocytes adhered with sevenfold higher efficiency than other subsets, and in patients with myocardial infarction the capture efficiency of this subset was double that for healthy subjects. In patients with hypertriglyceridemia, this increase in monocyte adhesion was attributable to CD14(++)CD16(+) uptake of triglyceride-rich lipoproteins and subsequent signaling via a Phospholipase C-dependent mechanism to increase CD11c expression, very late antigen-4 function, and integrin coclustering within focal adhesive sites on vascular cell adhesion molecule-1. In summary, we introduce a unique laboratory-on-a-chip method for quantifying the activation state of monocyte subsets. These experiments reveal that CD11c/CD18 is an inducible integrin whose expression correlates with a monocyte inflammatory state in subjects at risk for atherogenesis and in patients with myocardial infarction.

Published
2013

13. Exporting Australian Architectural 'Expertise' as a Matter of Policy

Author

Wyatt, VJ, Stickells, L, Leech, A, Gower, R, Wyatt, VJ, Stickells, L, Leech, A, and Gower, R

Abstract

As highlighted by Jennifer Taylor and James Connor in Architecture in theSouth Pacific: The Ocean of Islands (2014) and subsequently discussed by Philip Goad in “Importing Expertise: Australian-US Architects and the Large Scale 1945-1990,” the exportation of Australian architectural “expertise” across the second half of the twentieth century was primarily driven by individual practices gaining private and institutional commissions in the Asia-Pacific region. Devised under the Gorton administration the “Australian Policy” however, would, for the first time, prioritise the appointment of Australian architects for overseas work at a government level, opening the doors for Australian architects to design diplomatic buildings for the government’s extensive construction programme announced by Gough Whitlam in 1973.The employment of Australian architects to design government buildings abroad came to the fore in 1965 when the Royal Australian Institute of Architects and Robin Boyd lobbied for an Australian architect to replace the Brazilian architect, Henrique Mindlin, to design the new Australian Embassy in Brasilia. This paper will examine this episode of institutional exchange and its significance for the local architectural profession and its future involvement in the foreign building program of the Federal Government. It will link this activity to the formation of the “Australian Policy” and posit that while this internal government policy was significant in encouraging the exportation of Australian design it was also wielded as a political weapon by the Department of External Affairs to diminish the role of the Commonwealth Department of Works which also had the skills to successfully “export” Australian expertise to the world.

Published
2020

14. Definition, aims, and implementation of GA2LEN/HAEi Angioedema Centers of Reference and Excellence

Author

Maurer, M. (Marcus), Aberer, W. (W.), Agondi, R. (Rosana), Al-Ahmad, M. (Mona), Al-Nesf, M.A. (Maryam Ali), Ansotegui, I.J. (I.), Arnaout, R. (Rand), Arruda, L.K. (Luisa Karla), Asero, R. (Riccardo), Aygören-Pürsü, E. (Emel), Banerji, A. (Aleena), Bauer, A. (Andrea), Ben-Shoshan, M. (Moshe), Berardi, A. (Alejandro), Bernstein, J.A. (Jonathan A.), Betschel, S. (Stephen), Bindslev-Jensen, C. (Carsten), Bizjak, M. (Mojca), Boccon-Gibod, I. (Isabelle), Bork, K. (Konrad), Bouillet, L. (Laurence), Boysen, H.B. (Henrik Balle), Brodszki, N. (N.), Broesby-Olsen, S. (Sigurd), Busse, P. (Paula), Buttgereit, T. (Thomas), Bygum, A. (Anette), Caballero, T. (Teresa), Campos, R.A. (Régis A.), Cancian, M. (Mauro), Cherrez-Ojeda, I. (Ivan), Cohn, D.M. (Danny M.), Costa, C. (Célia), Craig, T., Criado, P.R. (Paulo Ricardo), Criado, R.F. (Roberta F.), Csuka, D. (Dorottya), Dissemond, J. (Joachim), Du-Thanh, A. (Aurélie), Ensina, L.F. (Luis Felipe), Ertaş, R. (Ragıp), Fabiani, J.E. (José E.), Fantini, C. (Claudio), Farkas, H. (Henriette), Ferrucci, S.M. (Silvia Mariel), Figueras-Nart, I. (Ignasi), Fili, N.L. (Natalia L.), Fomina, D. (Daria), Fukunaga, A. (Atsushi), Gelincik, A. (Asli), Giménez-Arnau, A., Godse, K., Gompels, M. (Mark), Gonçalo, M. (Margarida), Gotua, M. (M.), Gower, R. (Richard), Grumach, A.S. (Anete S.), Guidos-Fogelbach, G. (Guillermo), Hide, M. (Michihiro), Ilina, N. (Natalia), Inomata, N. (Naoko), Jakob, T. (Thilo), Josviack, D.O. (Dario O.), Kang, H.-R. (Hye-Ryun), Kaplan, A. (Allen), Kasperska-Zając, A. (Alicja), Katelaris, C. (Constance), Kessel, A. (Aharon), Kleinheinz, A. (Andreas), Kocatürk, E., Košnik, M. (Mitja), Krasowska, D. (Dorota), Kulthanan, K. (Kanokvalai), Kumaran, M.S. (M. Sendhil), Larco Sousa, J.I. (José Ignacio), Longhurst, H.J. (Hilary J.), Lumry, W. (William), MacGinnitie, A. (Andrew), Magerl, M. (Markus), Makris, M.P. (Michael P.), Malbrán, A. (Alejandro), Marsland, A. (Alexander), Martinez-Saguer, I. (Inmaculada), Medina, I.V. (Iris V.), Meshkova, R. (Raisa), Metz, M. (Martin), Nasr, I. (Iman), Nicolay, J. (Jan), Nishigori, C. (Chikako), Ohsawa, I. (Isao), Özyurt, K. (Kemal), Papadopoulos, N., Parisi, C.A.S. (Claudio A. S.), Peter, J.G. (Jonathan Grant), Pfützner, W. (W.), Popov, T.A., Prior, N. (Nieves), Ramon, G.D. (German D.), Reich, A. (Adam), Reshef, A. (Avner), Riedl, M.A. (Marc A.), Ritchie, B. (Bruce), Röckmann-Helmbach, H. (Heike), Rudenko, M. (Michael), Salman, A. (Andaç), Sanchez-Borges, M. (Mario), Schmid-Grendelmeier, P. (Peter), Serpa, F.S. (Faradiba S.), Serra-Baldrich, E. (Esther), Sheikh, F.R. (Farrukh R.), Smith, W. (William), Soria, A. (Angèle), Staubach, P. (Petra), Steiner, U.C. (Urs C.), Stobiecki, M. (Marcin), Sussman, G. (Gordon), Tagka, A. (Anna), Thomsen, S.F. (Simon Francis), Treudler, R. (Regina), Valle, S. (Solange), Doorn, M.B.A. (Martijn) van, Varga, L. (Lilian), Vázquez, D.O. (Daniel O.), Wagner, N. (Nicola), Wang, L. (Liangchun), Weber-Chrysochoou, C. (Christina), Ye, Y.-M. (Young-Min), Zalewska-Janowska, A. (Anna), Zanichelli, A. (Andrea), Zhao, Z. (Zuotao), Zhi, Y. (Yuxiang), Zuberbier, T. (Torsten), Zwiener, R.D. (Ricardo D.), Castaldo, A. (Anthony), Maurer, M. (Marcus), Aberer, W. (W.), Agondi, R. (Rosana), Al-Ahmad, M. (Mona), Al-Nesf, M.A. (Maryam Ali), Ansotegui, I.J. (I.), Arnaout, R. (Rand), Arruda, L.K. (Luisa Karla), Asero, R. (Riccardo), Aygören-Pürsü, E. (Emel), Banerji, A. (Aleena), Bauer, A. (Andrea), Ben-Shoshan, M. (Moshe), Berardi, A. (Alejandro), Bernstein, J.A. (Jonathan A.), Betschel, S. (Stephen), Bindslev-Jensen, C. (Carsten), Bizjak, M. (Mojca), Boccon-Gibod, I. (Isabelle), Bork, K. (Konrad), Bouillet, L. (Laurence), Boysen, H.B. (Henrik Balle), Brodszki, N. (N.), Broesby-Olsen, S. (Sigurd), Busse, P. (Paula), Buttgereit, T. (Thomas), Bygum, A. (Anette), Caballero, T. (Teresa), Campos, R.A. (Régis A.), Cancian, M. (Mauro), Cherrez-Ojeda, I. (Ivan), Cohn, D.M. (Danny M.), Costa, C. (Célia), Craig, T., Criado, P.R. (Paulo Ricardo), Criado, R.F. (Roberta F.), Csuka, D. (Dorottya), Dissemond, J. (Joachim), Du-Thanh, A. (Aurélie), Ensina, L.F. (Luis Felipe), Ertaş, R. (Ragıp), Fabiani, J.E. (José E.), Fantini, C. (Claudio), Farkas, H. (Henriette), Ferrucci, S.M. (Silvia Mariel), Figueras-Nart, I. (Ignasi), Fili, N.L. (Natalia L.), Fomina, D. (Daria), Fukunaga, A. (Atsushi), Gelincik, A. (Asli), Giménez-Arnau, A., Godse, K., Gompels, M. (Mark), Gonçalo, M. (Margarida), Gotua, M. (M.), Gower, R. (Richard), Grumach, A.S. (Anete S.), Guidos-Fogelbach, G. (Guillermo), Hide, M. (Michihiro), Ilina, N. (Natalia), Inomata, N. (Naoko), Jakob, T. (Thilo), Josviack, D.O. (Dario O.), Kang, H.-R. (Hye-Ryun), Kaplan, A. (Allen), Kasperska-Zając, A. (Alicja), Katelaris, C. (Constance), Kessel, A. (Aharon), Kleinheinz, A. (Andreas), Kocatürk, E., Košnik, M. (Mitja), Krasowska, D. (Dorota), Kulthanan, K. (Kanokvalai), Kumaran, M.S. (M. Sendhil), Larco Sousa, J.I. (José Ignacio), Longhurst, H.J. (Hilary J.), Lumry, W. (William), MacGinnitie, A. (Andrew), Magerl, M. (Markus), Makris, M.P. (Michael P.), Malbrán, A. (Alejandro), Marsland, A. (Alexander), Martinez-Saguer, I. (Inmaculada), Medina, I.V. (Iris V.), Meshkova, R. (Raisa), Metz, M. (Martin), Nasr, I. (Iman), Nicolay, J. (Jan), Nishigori, C. (Chikako), Ohsawa, I. (Isao), Özyurt, K. (Kemal), Papadopoulos, N., Parisi, C.A.S. (Claudio A. S.), Peter, J.G. (Jonathan Grant), Pfützner, W. (W.), Popov, T.A., Prior, N. (Nieves), Ramon, G.D. (German D.), Reich, A. (Adam), Reshef, A. (Avner), Riedl, M.A. (Marc A.), Ritchie, B. (Bruce), Röckmann-Helmbach, H. (Heike), Rudenko, M. (Michael), Salman, A. (Andaç), Sanchez-Borges, M. (Mario), Schmid-Grendelmeier, P. (Peter), Serpa, F.S. (Faradiba S.), Serra-Baldrich, E. (Esther), Sheikh, F.R. (Farrukh R.), Smith, W. (William), Soria, A. (Angèle), Staubach, P. (Petra), Steiner, U.C. (Urs C.), Stobiecki, M. (Marcin), Sussman, G. (Gordon), Tagka, A. (Anna), Thomsen, S.F. (Simon Francis), Treudler, R. (Regina), Valle, S. (Solange), Doorn, M.B.A. (Martijn) van, Varga, L. (Lilian), Vázquez, D.O. (Daniel O.), Wagner, N. (Nicola), Wang, L. (Liangchun), Weber-Chrysochoou, C. (Christina), Ye, Y.-M. (Young-Min), Zalewska-Janowska, A. (Anna), Zanichelli, A. (Andrea), Zhao, Z. (Zuotao), Zhi, Y. (Yuxiang), Zuberbier, T. (Torsten), Zwiener, R.D. (Ricardo D.), and Castaldo, A. (Anthony)

Published
2020
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15. Safety, Effectiveness, and Pharmacokinetics of Crisaborole in Infants Aged 3 to < 24 Months with Mild-to-Moderate Atopic Dermatitis: A Phase IV Open-Label Study (CrisADe CARE 1)

Author

Schlessinger, J, Shepard, JS, Gower, R, Su, JC, Lynde, C, Cha, A, Ports, WC, Purohit, V, Takiya, L, Werth, JL, Zang, C, Vlahos, B, Schlessinger, J, Shepard, JS, Gower, R, Su, JC, Lynde, C, Cha, A, Ports, WC, Purohit, V, Takiya, L, Werth, JL, Zang, C, and Vlahos, B

Abstract

BACKGROUND: Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD). OBJECTIVES: The aim of this study was to evaluate the safety, effectiveness, and pharmacokinetics (PK) of crisaborole in infants aged 3 to < 24 months with mild-to-moderate AD in an open-label study. METHODS: Infants (3 to < 24 months) with Investigator's Static Global Assessment (ISGA) of mild (2) or moderate (3) and percentage of treatable body surface area (%BSA) ≥ 5 received crisaborole twice daily for 28 days; a cohort with moderate AD per ISGA and %BSA ≥ 35 were included in a PK analysis. Endpoints included safety (primary), efficacy, and PK (exploratory). RESULTS: Included were 137 infants total (mean age [SD], 13.6 months [6.42]), with 21 in the PK cohort (12.7 months [6.58]). Treatment-emergent adverse events (TEAEs) were reported for 88 (64.2%) patients (98.9% rated as mild/moderate). TEAEs were considered treatment-related for 22 patients (16.1%); most frequently reported were application site pain (3.6%), application site discomfort (2.9%), and erythema (2.9%). ISGA clear/almost clear with ≥ 2-grade improvement at day 29 was achieved by 30.2% of patients. From baseline to day 29, mean percentage change in Eczema Area and Severity Index score was - 57.5%, and mean change in Patient-Oriented Eczema Measure total score was - 8.5. Crisaborole systemic exposures in infants were characterized and, based on nonlinear regression analysis, were comparable with that in patients aged ≥ 2 years. CONCLUSIONS: In this open-label study, crisaborole was well tolerated and effective in infants (3 to < 24 months) with mild-to-moderate AD with systemic exposures similar to patients aged ≥ 2 years. CLINICAL TRIAL REGISTRATION: NCT03356977.

Published
2020

23. Fixed-Dose Subcutaneous C1-Inhibitor Liquid for Prophylactic Treatment of C1-INH-HAE: SAHARA Randomized Study

Author

Lumry, William R., primary, Martinez-Saguer, Inmaculada, additional, Yang, William H., additional, Bernstein, Jonathan A., additional, Jacobs, Joshua, additional, Moldovan, Dumitru, additional, Riedl, Marc A., additional, Johnston, Douglas T., additional, Li, H. Henry, additional, Tang, Yongqiang, additional, Schranz, Jennifer, additional, Lu, Peng, additional, Vardi, Moshe, additional, Farkas, Henriette, additional, Keith, P., additional, Yang, W., additional, Maurer, M., additional, Martinez-Saguer, I., additional, Farkas, H., additional, Reshef, A., additional, Kivity, S., additional, Moldovan, D., additional, Caballero, T., additional, Guilarte, M., additional, Hernandez, M.D., additional, González-Quevedo, M.T., additional, Banerji, A., additional, Bernstein, J., additional, Bewtra, A., additional, Craig, T., additional, Fineman, S., additional, Gower, R., additional, Jacobs, J., additional, Johnston, D., additional, Kashkin, J., additional, Li, H.H., additional, Lumry, W.R., additional, Manning, M., additional, McNeil, D., additional, Melamed, I., additional, Mumneh, N., additional, Nickel, T., additional, Panuto, J., additional, Soteres, D., additional, Tachdjian, R., additional, Offenberger, J., additional, and Wedner, J., additional

Published
2019
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26. Modulation of adipocyte size and fat pad weight via resveratrol releasing scaffolds implanted into the epididymal adipose tissue.

Author

Murphy, Kendall P., Hendley, Michael A., Patterson, Alexandra T., Hall, Hayley E., Carter, Griffin J., Isely, Christopher, and Gower, R. Michael

Abstract

Lipid overload of the adipose tissue, which can be caused by overnutrition, underlies metabolic disease. We hypothesized that increasing the energy demand of adipose tissue is a promising strategy to combat excessive lipid accumulation. Resveratrol, a natural polyphenol, activates lipid catabolism in fat tissue; however, its clinical success is hindered by poor bioavailability. Here, we implanted resveratrol releasing poly(lactide‐co‐glycolide) scaffolds into epididymal fat to overcome its poor bioavailability with the goal of enhancing local lipid catabolism. In lean mice, resveratrol scaffolds decreased adipocyte size relative to scaffolds with no drug, a response that correlated with AMP kinase activation. Immunohistochemistry indicated that macrophages and multinucleated giant cells within the scaffold expressed carnitine palmitoyltransferase 1 (CPT1) at higher levels than other cells in the adipose tissue. Furthermore, resveratrol increased CPT1 levels in cultured macrophages. Taken together, we propose that resveratrol scaffolds decrease adipocyte size because resveratrol increases lipid utilization in scaffold‐infiltrating immune cells, possibly through elevating CPT1 levels or activity. In a follow‐up study, mice that received resveratrol scaffolds 28‐day prior to a high‐fat diet exhibited decreased weight gain, adipose tissue expansion, and adipocyte hypertrophy compared to mice with control scaffolds. Notably, this scaffold‐based strategy required a single resveratrol administration compared to the daily regiment generally needed for oral administration. These results indicate that localized delivery of metabolism modulating agents to the adipose tissue may overcome issues with bioavailability and that the role of biomaterials should be further investigated in this therapeutic strategy for metabolic disease. [ABSTRACT FROM AUTHOR]

Published
2021
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30. Image Building: A Study of Australia's Domestic and Foreign Policy in Relation to Embassy Architecture

Author

Ting, J, Hartoonian, G, Gower, R, Ting, J, Hartoonian, G, and Gower, R

Abstract

The study of embassy architecture has predominately focused on the United States and to a lesser extent the United Kingdom. In particular this research has been conducted by Jane Loeffler as captured in her book The Architecture of Diplomacy: Building America’s Embassies (2011) and by Ron Robin in Enclaves of America: The Rhetoric of American Political Architecture Abroad, 1900-1965 (1992). Both studies establish that embassy buildings can be utilised as historical references to establish a viewpoint into a nation’s political and cultural history. This is no different in Australia, where Australian embassy buildings allow us insight into the directions taken in government policy, international relations, architecture and society. In order to begin to comprehend the complex nature of this building typology, archival research must initially be conducted into the government departments that were responsible for driving embassy design since the opening of Australia House in London in 1918. By correlating this research with domestic and foreign policies that were implemented as a response to changing world events, it becomes clear that a number of bureaucratic forces are behind the development of Australia’s embassy buildings. This paper will focus on the influence these forces had on embassy design during the 1970’s, when the Overseas Property Bureau was created and Australia developed several high profile embassies under the Whitlam Government.

Published
2017

31. International consensus on the diagnosis and management of pediatric patients with hereditary angioedema with C1 inhibitor deficiency

Author

Farkas, H, Martinez Saguer, I, Bork, K, Bowen, T, Craig, T, Frank, M, Germenis, Ae, Grumach, As, Luczay, A, Varga, L, Zanichelli, A, Aberer, W, Andrejevic, S, Aygoeren Pürsün, E, Banerji, A, Bara, Na, Bas, M, Bernstein, J, Betschel, S, Björkander, J, Boccon Gibod, I, Bouillet, L, Bova, M, Boysen, Hh, Branco Ferreira, M, Bygum, A, Caballero, T, Cancian, M, Castaldo, A, Christiansen, S, Cicardi, M, Drouet, C, Fabiani, J, Gompels, M, Gonzalez Quevedo MT, Gooi, J, Gower, R, Gökmen, Nm, Grivcheva Panovska, V, Guilarte, M, Gülbahar, O, Hack, E, Hakl, R, Harmat, G, Mjeseňák, M, Jolles, S, Kaplan, A, Katelaris, C, Kosnik, M, Kőhalmi, Kv, Leibovich, I, Levi, M, Li, H, Longhurst, Hj, Lumry, W, Magerl, M, Malbran, A, Martin, L, Maurer, M, Mihály, E, Moldovan, D, Murdjeva, M, Nagy, Ib, Nielsen, Ew, Nieto, S, Nordenfelt, P, Obtulowitzc, K, Pedrosa, M, Porębski, G, Prior, N, Reshef, A, Riedl, Ma, Rosenkranz, B, Schmid Grendelmeier, P, Péter, S, Speletas, M, Staevska, M, Stobiecki, M, Triggiani, Massimo, Veszeli, N, Wuillemin, W, Xiang, Zy, Yamamoto, B, and Zuraw, B.

Subjects
Male, Abdominal pain, Pediatrics, diagnosis, Comorbidity, Disease, Severity of Illness Index, Ecallantide, 0302 clinical medicine, Risk Factors, Diagnosis, Immunology and Allergy, heterocyclic compounds, 030212 general & internal medicine, Hereditary angioedema, Pediatric, Hereditary Angioedema Types I and II, Age Factors, Disease Management, Combined Modality Therapy, Immunodeficiencies, Management, Female, Original Article, Symptom Assessment, medicine.symptom, management, Algorithms, medicine.drug, medicine.medical_specialty, C1 inhibitor deficiency, Immunology, 03 medical and health sciences, Meta-Analysis as Topic, medicine, Humans, Mucous Membrane, Adult patients, business.industry, Original Articles, bacterial infections and mycoses, medicine.disease, hereditary angioedema, respiratory tract diseases, Clinical trial, pediatric, 030228 respiratory system, Differential diagnosis, business, Biomarkers
Abstract

BACKGROUND: The consensus documents published to date on hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) have focused on adult patients. Many of the previous recommendations have not been adapted to pediatric patients. We intended to produce consensus recommendations for the diagnosis and management of pediatric patients with C1-INH-HAE.METHODS: During an expert panel meeting that took place during the 9th C1 Inhibitor Deficiency Workshop in Budapest, 2015 (www.haenet.hu), pediatric data were presented and discussed and a consensus was developed by voting.RESULTS: The symptoms of C1-INH-HAE often present in childhood. Differential diagnosis can be difficult as abdominal pain is common in pediatric C1-INH-HAE, but also commonly occurs in the general pediatric population. The early onset of symptoms may predict a more severe subsequent course of the disease. Before the age of 1 year, C1-INH levels may be lower than in adults; therefore, it is advisable to confirm the diagnosis after the age of one year. All neonates/infants with an affected C1-INH-HAE family member should be screened for C1-INH deficiency. Pediatric patients should always carry a C1-INH-HAE information card and medicine for emergency use. The regulatory approval status of the drugs for prophylaxis and for acute treatment is different in each country. Plasma-derived C1-INH, recombinant C1-INH, and ecallantide are the only agents licensed for the acute treatment of pediatric patients. Clinical trials are underway with additional drugs. It is recommended to follow up patients in an HAE comprehensive care center.CONCLUSIONS: The pediatric-focused international consensus for the diagnosis and management of C1-INH-HAE patients was created.

Published
2016
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33. Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group

Author

Cicardi, M, Bork, K, Caballero, T, Craig, T, Hh, L, Longhurst, H, Reshef, A, Zuraw, B, Aberer, W, Aygören Pürsün, E, Banerji, A, Bjorkander, J, Boccon Gibod, I, Bouillet, L, Grenoble, F, Bova, M, Bowen, T, Calgary, C, Branco, F, Bygum, A, Cancian, M, Castel Branco, M, de Carolis, C, Mihály, E, Fabiani, J, Farkas, H, Gompels, M, Gower, R, Groffik, A, Grumach, A, Guillarte, M, Hack, E, Hernandez, L, Kaplan, A, Lara, A, Leibovich, I, Li, H, Lock, B, Lumry, W, Malbran, A, Martinez Saguer, I, Matta, C, Maurer, M, Moldovan, D, Montinaro, V, Nieto, S, Nordenfelt, P, Obtulovicz, K, Perricone, R, Prior, N, Riedl, M, Rodrigues do, V, Savoca, C, Spaeth, P, Staubach Renz, P, Stobiecki, M, Triggiani, M, Vacchini, R, Varga, L, Zanichelli, A, Zarchi, K, Zeerleder, S, and Zingale, L

Subjects
C1 inhibitor, Immunology, Angioedemas, Hereditary, Angioedemas, Complement C1 Inactivator Proteins, bradykinin receptor antagonist, Bradykinin, hereditary angioedema, Settore MED/16 - Reumatologia, kallikrein inhibitor, Hereditary, consensus document, Bradykinin Receptor Antagonists, Complement C1 Inhibitor Protein, Humans, Kallikreins, Peptides, Immunology and Allergy
Abstract

Angioedema owing to hereditary deficiency of C1 inhibitor (HAE) is a rare, life-threatening, disabling disease. In the last 2 years, the results of well-designed and controlled trials with existing and new therapies for this condition have been published, and new treatments reached the market. Current guidelines for the treatment for HAE were released before the new trials and before the new treatments became available and were essentially based on observational studies and expert opinion. To provide evidence-based HAE treatment guidelines supported by the new studies, a conference was held in Gargnano del Garda, Italy, from September 26 to 29, 2010. The meeting hosted 58 experienced HAE expert physicians, representatives of pharmaceutical companies and representatives of HAE patients' associations. Here, we report the topics discussed during the meeting and evidence-based consensus about management approaches for HAE in adult/adolescent patients.

Published
2012

34. CD11c/CD18 expression is upregulated on blood monocytes during hypertriglyceridemia and enhances adhesion to VCAM-1

Author

Gower, R. Michael, Wu, Huaizhu, Foster, Greg A., Devaraj, Sridevi, Jialal, Ishwarlal, Ballantyne, Christie M., Knowlton, Anne A., and Simon, Scott I.

Subjects
Hypertriglyceridemia, Inflammation, Male, Time Factors, Lipoproteins, Vascular Cell Adhesion Molecule-1, Biological Transport, Microfluidic Analytical Techniques, Flow Cytometry, Postprandial Period, Dietary Fats, Article, Monocytes, CD11c Antigen, Up-Regulation, CD18 Antigens, Cell Adhesion, Humans, Female, Low Density Lipoprotein Receptor-Related Protein-1, Triglycerides
Abstract

Atherosclerosis is associated with monocyte adhesion to the arterial wall that involves integrin activation and emigration across inflamed endothelium. Involvement of β(2)-integrin CD11c/CD18 in atherogenesis was recently shown in dyslipidemic mice, which motivates our study of its inflammatory function during hypertriglyceridemia in humans.Flow cytometry of blood from healthy subjects fed a standardized high-fat meal revealed that at 3.5 hours postprandial, monocyte CD11c surface expression was elevated, and the extent of upregulation correlated with blood triglycerides. Monocytes from postprandial blood exhibited an increased light scatter profile, which correlated with elevated CD11c expression and uptake of lipid particles. Purified monocytes internalized triglyceride-rich lipoproteins isolated from postprandial blood through low-density lipoprotein-receptor-related protein-1, and this also elicited CD11c upregulation. Laboratory-on-a-chip analysis of whole blood showed that monocyte arrest on a vascular cell adhesion molecule-1 (VCAM-1) substrate under shear flow was elevated at 3.5 hours and correlated with blood triglyceride and CD11c expression. At 7 hours postprandial, blood triglycerides decreased and monocyte CD11c expression and arrest on VCAM-1 returned to fasting levels.During hypertriglyceridemia, monocytes internalize lipids, upregulate CD11c, and increase adhesion to VCAM-1. These data suggest that analysis of monocyte inflammation may provide an additional framework for evaluating individual susceptibility to cardiovascular disease.

Published
2010

36. Vav1 is essential for mechanotactic crawling and migration of neutrophils out of the inflamed microvasculature

Author

Phillipson, Mia, Heit, Bryan, Parsons, Sean A, Petri, Björn, Mullaly, Sarah C, Colarusso, Pina, Gower, R Michael, Neely, Gregory, Simon, Scott I, Kubes, Paul, Phillipson, Mia, Heit, Bryan, Parsons, Sean A, Petri, Björn, Mullaly, Sarah C, Colarusso, Pina, Gower, R Michael, Neely, Gregory, Simon, Scott I, and Kubes, Paul

Abstract

Mac-1-dependent crawling is a new step in the leukocyte recruitment cascade that follows LFA-1-dependent adhesion and precedes emigration. Neutrophil adhesion via LFA-1 has been shown to induce cytoskeletal reorganization through Vav1-dependent signaling, and the current study investigates the role of Vav1 in the leukocyte recruitment process in vivo with particular attention to the events immediately downstream of LFA-1-dependent adhesion. Intravital and spinning-disk-confocal microscopy was used to investigate intravascular crawling in relation to endothelial junctions in vivo in wild-type and Vav1(-/-) mice. Adherent wild-type neutrophils almost immediately began crawling perpendicular to blood flow via Mac-1 until they reached an endothelial junction where they often changed direction. This pattern of perpendicular, mechanotactic crawling was recapitulated in vitro when shear was applied. In sharp contrast, the movement of Vav1(-/-) neutrophils was always in the direction of flow and appeared more passive as if the cells were dragged in the direction of flow in vivo and in vitro. More than 80% of Vav1(-/-) neutrophils moved independent of Mac-1 and could be detached with LFA-1 Abs. An inability to release the uropod was frequently noted for Vav1(-/-) neutrophils, leading to greatly elongated tails. The Vav1(-/-) neutrophils failed to stop or follow junctions and ultimately detached, leading to fewer emigrated neutrophils. The Vav1(-/-) phenotype resulted in fewer neutrophils recruited in a relevant model of infectious peritonitis. Clearly, Vav1 is critical for the complex interplay between LFA-1 and Mac-1 that underlies the programmed intravascular crawling of neutrophils.

Published
2009
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48. RESCUING ACCESS TO PATENTED ESSENTIAL MEDICINES: PHARMACEUTICAL COMPANIES AS TORTFEASORS.

Author

Gower, R. Cameron

Subjects
*PATENT law, *MEDICAL patents, *DRUGS, *PHARMACEUTICAL industry, *DOCTRINE of equivalents (Patent law)
Abstract

Despite some difficulties, state tort law can be argued to create a unique exception to patent law. Specifically, the prevented rescue doctrine suggests that charities and others can circumvent patents on certain critical medications when such actions are necessary to save individuals from death or serious harm. Although this Article finds that the prevented rescue tort doctrines is preempted by federal patent law, all hope is not lost. A federal substantive due process claim may be brought that uses the common law to demonstrate a fundamental right that has long been protected by our Nation's legal traditions. Moreover, this Article argues that even if this legal argument for such an exception ultimately fails, the near success of the argument should give us pause to think about whether patent law should be so untouchable that lives must be lost just to uphold it. [ABSTRACT FROM AUTHOR]

Published
2014

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