Targeting eosinophils: severe asthma and beyond

Recent research in the field of bronchial asthma has mainly focused on eosinophilic disease phenotype. Several trials proved the efficacy and safety profile of eosinophils and interleukin (IL)-5 targeting molecules, currently approved for severe asthma and available on the market. They include mepolizumab and reslizumab, IL-5 blocking molecules, and benralizumab, targeting the IL-5 receptor and eliciting a NK cell-mediated antibody-dependent cellular cytotoxicity against eosinophils. Eosinophilic inflammation represents the common pathophysiological background of several conditions, providing the rationale for the use of the same biologics beyond asthma. Although with different evidence grade, from clinical trials to case reports, anti-IL-5 biologics have been investigated in eosinophilic granulomatosis with polyangitis, allergic bronchopulmonary aspergillosis, chronic eosinophilic pneumonia, nasal polyposis, hypereosinophilic syndrome, and eosinophilic esophagitis. However, non-negligible differences between asthma and other eosinophilic diseases, particularly in eosinophils homing (blood and/or tissues), target organs and thus clinical features, probably account for the different response to the same drug in different clinical conditions and highlights the need for tailoring the therapeutic approach by modulating the drug dose and/or by combination therapy with multiple drugs. The optimal safety and tolerability profile of anti-IL-5 drugs warrants further and larger experimental and real-life investigations, which are needed especially in the field of non-asthma eosinophilic diseases. This review aims at summarizing the rationale for the use of biologics in eosinophilic diseases and their mechanisms of action. The current efficacy and safety evidence about eosinophils and IL-5 targeting molecules in asthma and in eosinophilic conditions beyond bronchi is also discussed

Endothelin-1 Drives Epithelial-Mesenchymal Transition In Hypertensive Nephroangiosclerosis

BACKGROUND: Tubulointerstitial fibrosis, the final outcome of most kidney diseases, involves activation of epithelial mesenchymal transition (EMT). Endothelin‐1 (ET‐1) activates EMT in cancer cells, but it is not known whether it drives EMT in the kidney. We therefore tested the hypothesis that tubulointerstitial fibrosis involves EMT driven by ET‐1. METHODS AND RESULTS: Transgenic TG[mRen2]27 (TGRen2) rats developing fulminant angiotensin II–dependent hypertension with prominent cardiovascular and renal damage were submitted to drug treatments targeted to ET‐1 and/or angiotensin II receptor or left untreated (controls). Expressional changes of E‐cadherin and α‐smooth muscle actin (αSMA) were examined as markers of renal EMT. In human kidney HK‐2 proximal tubular cells expressing the ET(B) receptor subtype, the effects of ET‐1 with or without ET‐1 antagonists were also investigated. The occurrence of renal fibrosis was associated with EMT in control TGRen2 rats, as evidenced by decreased E‐cadherin and increased αSMA expression. Irbesartan and the mixed ET‐1 receptor antagonist bosentan prevented these changes in a blood pressure–independent fashion (P < 0.001 for both versus controls). In HK‐2 cells ET‐1 blunted E‐cadherin expression, increased αSMA expression (both P < 0.01), collagen synthesis, and metalloproteinase activity (P < 0.005, all versus untreated cells). All changes were prevented by the selective ET(B) receptor antagonist BQ‐788. Evidence for involvement of the Rho‐kinase signaling pathway and dephosphorylation of Yes‐associated protein in EMT was also found. CONCLUSIONS: In angiotensin II–dependent hypertension, ET‐1 acting via ET(B) receptors and the Rho‐kinase and Yes‐associated protein induces EMT and thereby renal fibrosis

Case Report: Microangiopathic Hemolytic Anemia With Normal ADAMTS13 Activity

Thrombotic microangiopathies (TMAs) include a heterogeneous group of diseases characterized by abnormalities in the vessel walls of arterioles and capillaries resulting in microvascular thrombosis that typically presents with a microangiopathic hemolytic anemia (MAHA) and severe thrombocytopenia. We describe here the case of an 82-year-old woman, who came to our attention for a clinical condition consistent with thrombotic microangiopathy. Even if initially highly suggestive for a thrombotic thrombocytopenic purpura (TTP), the elevated ADAMTS13 activity together with the alteration of the main coagulation parameters (D-dimer elevation, fibrinogen consumption, slightly prolonged prothrombin time), induced us to consider several other diseases in the differential diagnostic process. The case evolved toward a suspected overlapped secondary hemophagocytic syndrome, though the hyperferritinemia was finally interpreted within the frame of a cytokine storm. After a complex diagnostic workup, the clinical and biochemical parameters guided us toward the diagnosis of a cancer-related microangiopathic hemolytic anemia (CR-MAHA) secondary to a relapsing breast cancer with multiple metastatic localizations. Prednisone 1 mg/kg body weight was started, and several units of fresh frozen plasma were infused, obtaining a good control of the hemolysis. No specific oncological therapies were, however, possible, due to the older age and the critically compromised general condition of the patient; therefore, after clinical stabilization, the patient was discharged for treatment in a palliative care Hospital

Resensitization in suspected penicillin allergy

Background The diagnosis of allergic reactions to penicillins (AR-PEN) is very complex as there is a loss of sensitization over time, which leads to negative skin tests (STs) and specific IgE in serum, and even to tolerance to the drug involved. However, STs may become positive after subsequent exposure to the culprit drug (resensitization), with the risk of inducing potentially severe reactions. The exact rate of resensitization to penicillins is unknown, ranging from 0% to 27.9% in published studies. Objectives To analyze the rate of resensitization in patients with suggestive AR-PEN by repeating STs (retest) after an initial evaluation (IE). Material and Methods Patients with suspected AR-PEN were prospectively evaluated between 2017 and 2020. They underwent STs, and a randomized group also underwent a drug provocation test (DPT) with the culprit. Only patients with negative STs and/or DPT were included. All included cases were retested by STs at 2–8 weeks. Results A total of 545 patients were included: 296 reporting immediate reactions (IRs) and 249 non-immediate reactions (NIRs). Eighty (14.7%) cases had positive results in retest (RT+): 63 (21.3%) IRs and 17 (6.8%) NIRs (p < 0.0001). The rate of RT+ was higher in anaphylaxis compared with all other reactions (45.8% vs 9.1%, p < 0.0001). The risk of RT+ was higher from the fifth week after IE (OR: 4.64, CI: 2.1–11.6; p < 0.001) and increased with the patient's age (OR: 1.02; CI: 1.01–1.04; p = 0.009). Conclusions Due to the high rate of resensitization, retest should be included in the diagnostic algorithm of IRs to penicillins after an initial negative study, especially in anaphylaxis, to avoid potentially severe reactions after subsequent prescriptions of these drugs.he present study has been supported by Institute of Health “Carlos III” of the Ministry of Economy and Competitiveness (grants cofunded by European Regional Development Fund (ERDF): PI18/00095, RETIC ARADYAL RD16/0006/0001). Andalusian Regional Ministry of Economy and Knowledge (grants cofunded by European Regional Development Fund (ERDF): CTS-06603); Andalusian Regional Ministry Health (grants PI-0241-2016 and PE-0172-2018). GB holds a “Juan Rodes” (JR18/00054), Institute of Health “Carlos III” of the Ministry of Economy and Competitiveness (grants cofunded by European Social Fund [ESF]). ID is a Clinical Investigator (B-0001-2017), Andalusian Regional Ministry Health

Endothelin-1 (ET-1) modulates epithelial-mesenchymal transition (EMT), which contributes to kidney tubulo-interstitial fibrosis in angiotensin II-dependent hypertension

The origin of myofibroblasts remains uncertain, but studies suggest that the epithelial cells may acquire a fibroblast-like phenotype via epithelial-mesenchymal transition (EMT). Objective of the study was to investigate whether EMT may contribute to the development of kidney fibrosis in a model of angiotensin II-dependent hypertension and to identify the role of ET-1 via ETA/ETB receptors. Transgenic rats TGRen2 (n=35) received for 4 weeks one of the following treatments a) irbesartan, b) bosentan, non selective ETA /ETB receptor antagonist, c) BMS-182874, selective ETA,antagonist, d) BMS+irbesartan, e) placebo. EMT was assessed by investigating coexpression of a marker of epithelial cell (E-cadherin) and one of myofibroblast (S100A4 or alfa-SMA) with double immunofluorescence. Specific immunoreactivity was measured using QWinStandard Leica ImageTMsoftware. A reduction in blood pressure was found only with irbesartan, whereas both bosentan and irbesartan significantly lowered tubulo-interstitial fibrosis. Coexpression of E-cadherin and S100A4, or E-cadherin and alfa-SMA, markedly decreased in the tubular cells of TGRen2 treated with irbesartan or bosentan. Alfa-SMA expression decreased after irbesartan, bosentan and BMS+irbesartan, but not after BMS. S100A4 expression was reduced after irbesartan, bosentan and BMS+irbesartan. E-cadherin increased only after irbesartan. Coexpression of the markers of myofibroblasts and kidney epithelial cells, by demonstrating the development of EMT during the onset of kidney hypertension-induced damage, suggests a crucial role of EMT in the pathogenesis of Ang II-mediated fibrosis. The reduction of myofibroblast markers not only after irbesartan, but also after blockade of ETA/ETB receptors, suggests an involvement of ET-1 in the development of Ang II-mediated EMT

Endothelin-1 (ET-1) modulates epithelial-mesenchymal transition (EMT), which contributes to kidney tubulo-interstitial fibrosis in angiotensin II-dependent hypertension

The origin of myofibroblasts remains uncertain, but studies suggest that the epithelial cells may acquire a fibroblast-like phenotype via epithelial-mesenchymal transition (EMT). Objective of the study was to investigate whether EMT may contribute to the development of kidney fibrosis in a model of angiotensin II-dependent hypertension and to identify the role of ET-1 via ETA/ETB receptors. Transgenic rats TGRen2 (n=35) received for 4 weeks one of the following treatments a) irbesartan, b) bosentan, non selective ETA /ETB receptor antagonist, c) BMS-182874, selective ETA,antagonist, d) BMS+irbesartan, e) placebo. EMT was assessed by investigating coexpression of a marker of epithelial cell (E-cadherin) and one of myofibroblast (S100A4 or alfa-SMA) with double immunofluorescence. Specific immunoreactivity was measured using QWinStandard Leica ImageTMsoftware. A reduction in blood pressure was found only with irbesartan, whereas both bosentan and irbesartan significantly lowered tubulo-interstitial fibrosis. Coexpression of E-cadherin and S100A4, or E-cadherin and alfa-SMA, markedly decreased in the tubular cells of TGRen2 treated with irbesartan or bosentan. Alfa-SMA expression decreased after irbesartan, bosentan and BMS+irbesartan, but not after BMS. S100A4 expression was reduced after irbesartan, bosentan and BMS+irbesartan. E-cadherin increased only after irbesartan. Coexpression of the markers of myofibroblasts and kidney epithelial cells, by demonstrating the development of EMT during the onset of kidney hypertension-induced damage, suggests a crucial role of EMT in the pathogenesis of Ang II-mediated fibrosis. The reduction of myofibroblast markers not only after irbesartan, but also after blockade of ETA/ETB receptors, suggests an involvement of ET-1 in the development of Ang II-mediated EMT

Um olhar territorial para o desenvolvimento: Sul

Inclui bibliografias.Prefácio / Luciano Coutinho -- Apresentação / José Eduardo Pessoa de Andrade, Maria Lúcia de Oliveira Falcón, Walsey de Assis Magalhães, Cristina Lemos, Marcelo Machado da Silva e Helena Maria Martins Lastres -- Introdução / Maria Lúcia de Oliveira Falcón, Walsey de Assis Magalhães, Guilherme Castanho Franco Montoro e Ana Paula Bernardino Paschoini -- Parte 1. A contribuição do BNDES para o desenvolvimento da região. Capítulo 1. Contexto socioeconômico e atuação do BNDES na Região Sul / Guilherme Castanho Franco Montoro, Ana Paula Bernardino Paschoini, Fernão de Souza Vale, Marco Antonio Silvestre Leite, Pablo Barrio Arconada, Rafael Petrocelli, Ricardo Camacho Bologna Garcia, Roger Vocos, Silvia Maria Guidolin e Vera Lúcia Guedes Teixeira Vieira -- Capítulo 2. A atuação da Área Industrial do BNDES na Região Sul / Bruno Plattek de Araújo, Fernanda Menezes Balbi, Bernardo Hauch Ribeiro de Castro, Fabrício Brollo Dunham, Rangel Galinari, Fernanda Milne-Jones Náder Garavini, Osmar Cervieri Junior, Job Rodrigues Teixeira Junior, Ricardo Rivera de Sousa Lima, Artur Yabe Milanez, Mauricio dos Santos Neves, Diego Nyko, João Paulo Pieroni, Vitor Paiva Pimentel, Luiz Daniel Willcox de Souza e Luiz Edmundo Del Negro Sutter -- Capítulo 3. A atuação da Área de Insumos Básicos na Região Sul / Rodrigo Matos Huet de Bacellar e Marcelo Gonçalves Tavares -- Capítulo 4. O BNDES e a questão energética e logística da Região Sul / Nelson Fontes Siffert Filho, Dalmo dos Santos Marchetti, Andre Daud Cardoso, André Luiz Zanette, Bruno D'assis Rocha, Edson José Dalto, Gabriela de Faria Gomes Valadão, Marcus Cardoso Santiago, Nelson Tucci, Paula Seara Arraes de Oliveira, Rafael Rotenstroch e Vanessa Mesquita Braga -- Capítulo 5. Parcerias para o desenvolvimento: o apoio do BNDES para a Região Sul por meio da Área de Operações Indiretas e instituições financeiras credenciadas, 2008-2013 / Alcidina Magalhães da Cunha Costa, Andrea Varela Ramos Fuchsloch, Andresa Michelle Falcão Ribeiro de Gusmão e Thiago Alessandro Soares de Paula -- Capítulo 6. Atuação da Área de Infraestrutura Social do BNDES na Região Sul do Brasil / Ricardo Luiz de Souza Ramos e Rafael Coutinho Quaresma Pimentel -- Capítulo 7. Apoio à agropecuária sustentável e à inclusão socioprodutiva na Região Sul / Marcelo Porteiro Cardoso, Geraldo Smith, Joaquim Pedro de Vasconcelos Cordeiro, Paulo Fernandes Montano E Rodrigo Cesar Vilas Boas Cardoso -- Capítulo 8. Região Sul: desenvolvimento econômico e sustentabilidade / Gabriel Rangel Visconti, Morena Correa Santos e Raphael Duarte Stein -- Capítulo 9. Ações de fomento do BNDES em renda variável via fundos de investimento à Região Sul / Fernando Ceschin Rieche e Rafael Campos de Mattos -- Parte 2. Atuação dos agentes locais para o desenvolvimento e perspectivas para a Região Sul. Capítulo 10. Território, participação e planejamento: Agenda de Desenvolvimento Territorial e o caso do Rio Grande do Sul / Esther Bemerguy de Albuquerque e Leandro Freitas Couto -- Capítulo 11. XXI: o século das cidades no Brasil / João Basilio Pereima -- Capítulo 12. Desenvolvimento da Região Sul do Brasil / Gilberto Montibeller Filho e Sérgio Luiz Gargioni -- Capítulo 13. Novos paradigmas do desenvolvimento catarinense / Tatiana Borges e Murilo Xavier Flores -- Capítulo 14. Programa de desenvolvimento industrial catarinense 2022: uma rota para o futuro / Carlos Henrique Ramos Fonseca, Carolina Silvestri Cândido, Fernanda Steiner Perin, Flávia Renata Souza, Sidnei Manoel Rodrigues e Juliano Anderson Pacheco -- Capítulo 15. Produtividade, capacitação, inovação e desenvolvimento: um olhar sobre a situação atual brasileira / Moacyr Rogério Sens -- Capítulo 16. O Badesul e a Política Industrial do Rio Grande do Sul / Marcelo de Carvalho Lopes -- Capítulo 17. Os arranjos produtivos locais, extensão produtiva e inovação: (re)construindo a política pública de desenvolvimento / Sérgio Roberto Kapron -- Capítulo 18. BNDES e Itaipu: novas bases para o desenvolvimento sustentável / Nelton Miguel Friedrich -- Capítulo 19. Cooperativismo e o desenvolvimento da Região Sul / John Tadayuki Sato -- Capítulo 20. O BNDES e as cooperativas de crédito: uma parceria para os pequenos municípios no Sul do Brasil / Cláudio Risson e Affonso Augusto Bulcão Flac

COLOCALIZATION OF LOW-AFFINITY AND HIGH-AFFINITY NGF RECEPTORS ON PC12 CELLS, C6 GLIOMA-CELLS AND DORSAL-ROOT GANGLION NEURONS

The biological responsiveness of neural cells to nerve growth factor (NGF) appears to require expression and ligand binding to both the low-affinity NGF receptor (LNGFR) and the proto-oncogene product trk, the latter being a receptor tyrosine kinase. Immunolocalization of the LNGFR and the high-affinity component of the NGF receptor, trk (HNGFR) was studied by electron microscopic morphometric analysis on cultured PC12 pheochromocytoma cells, C6 glioma cells and neonatal rat dorsal root ganglia neurons using a double immunogold labeling technique. Two receptor-specific antibodies, anti-LNGFR monoclonal antibody 192-IgG and a polyclonal antibody against the 14 carboxy-terminal amino acids of the Trk protein, were utilized in conjunction with immunoglobulin conjugated to colloidal gold particles of different sizes. All cells treated with NGF (50 ng/ml) displayed significant colocalization of LNGFR/HNGFR-like immunoreactivity. Gold particles associated with LNGFR (LNGFR-like immunoreactivity) were frequently seen near 2 or 3 (or more) particles delineating the HNGFR on all cell surfaces. Positive Trk-like immunoreactivity (HNGFR) thus seems to localize in close proximity to LNGFRs in at least these cell types

Il trattamento di gruppo per i pazienti affetti da lombalgia cronica: risultati di uno studio longitudinale.

Le osservazioni indicano una prevalenza annuale dei sintomi nel 50% degli adulti in et\ue0 lavorativa, dei quali il 15-20% ricorre a cure mediche. I dolori alla schiena sono la pi\uf9 frequente causa di disabilit\ue0 nei soggetti d\u2019et\ue0 inferiore ai 45 anni e, per quanto si viva in un\u2019epoca post \u2013 industriale, il lavoro continua a richiedere, in modalit\ue0 nuove, un alto impegno all\u2019apparato osteoarticolare. La richiesta nei nostri ambulatori fisiatrici di un trattamento per la lombalgia \ue8 davvero continua e pressante e impegna fisiatri e fisioterapisti, oltre a costituire, come \ue8 ovvio, un alto costo sociale. Solitamente il trattamento riabilitativo del paziente con lombalgia cronica prevede un ciclo di trattamento in gruppo della durata di 10 sedute. Vi sono per\uf2 iniziali indicazioni della letteratura da cui emerge la raccomandazione di allungare i tempi di trattamento riabilitativo . Scopo di questo studio longitudinale \ue8 stato quello di verificare l\u2019efficacia di un nuovo programma di trattamento di gruppo per pazienti lombalgici cronici. Quello che vogliamo verificare, in particolare, \ue8 se le nostre sedute di trattamento in gruppo sono efficaci a aumentare le performances dei pazienti, come misura indiretta della loro condizione di salute, per usare i termini dell\u2019ICF. Valutiamo gli effetti sul dolore e la disabilit\ue0 tramite due questionari il Back Ill e il Roland Morris Disability Questionnaire, in italiano