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1.
Artigo em Inglês | MEDLINE | ID: mdl-34551983

RESUMO

Background and objectives: Membranoproliferative Glomerulonephritis (MPGN) and C3 Glomerulopathy are rare and overlapping disorders associated with dysregulation of the alternative complement pathway. Specific aetiological data for paediatric MPGN/C3 glomerulopathy are lacking, and outcome data are based upon retrospective studies without aetiological data. Design, setting, participants, and measurements: Eighty prevalent pediatric patients with MPGN/C3 glomerulopathy underwent detailed phenotyping and long-term follow-up within the National Registry of Rare Kidney Diseases (RaDaR). Risk factors for kidney survival were determined using COX proportional hazards model. Kidney and transplant graft survival was determined using Kaplan-Meier method. Results: Central histology review determined 39 C3 glomerulopathy, 31 immune-complex MPGN and 10 immune-complex glomerulonephritis (GN) cases. Patients were aged 2-15 (median 9 (IQR 7-11) years. Median complement C3 and C4 levels were 0.31g/L and 0.14g/L respectively; acquired (anti-complement autoantibodies) or genetic alternative pathway abnormalities were detected in 46% and 9% patients respectively, across all groups including immune-complex GN. Median follow-up was 5.18 (IQR 2.13-8.08) years. Eleven patients (14%) progressed to kidney failure with 9 transplants performed in 8 patients, 2 of which failed due to recurrent disease. Presence of >50% crescents on initial biopsy was the sole variable associated with kidney failure in multivariable analysis (Hazard Ratio 6.2, p = 0.045; 95% CI 1.05 to 36.6). Three distinct C3 glomerulopathy prognostic groups were identified according to presenting eGFR and >50% crescents on initial biopsy. Conclusions: Crescentic disease was a key risk factor associated with kidney failure in a national cohort of pediatric MPGN/C3 glomerulopathy and immune-complex GN. Presenting eGFR and crescentic disease help define prognostic groups in pediatric C3 glomerulopathy. Acquired abnormalities of the alternative pathway were commonly identified but not a risk factor for kidney failure.

2.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445337

RESUMO

In fibrotic diseases, myofibroblasts derive from a range of cell types including endothelial-to-mesenchymal transition (EndMT). Increasing evidence suggests that miRNAs are key regulators in biological processes but their profile is relatively understudied in EndMT. In human umbilical vein endothelial cells (HUVEC), EndMT was induced by treatment with TGFß2 and IL1ß. A significant decrease in endothelial markers such as VE-cadherin, CD31 and an increase in mesenchymal markers such as fibronectin were observed. In parallel, miRNA profiling showed that miR-126-3p was down-regulated in HUVECs undergoing EndMT and over-expression of miR-126-3p prevented EndMT, maintaining CD31 and repressing fibronectin expression. EndMT was investigated using lineage tracing with transgenic Cdh5-Cre-ERT2; Rosa26R-stop-YFP mice in two established models of fibrosis: cardiac ischaemic injury and kidney ureteric occlusion. In both cardiac and kidney fibrosis, lineage tracing showed a significant subpopulation of endothelial-derived cells expressed mesenchymal markers, indicating they had undergone EndMT. In addition, miR-126-3p was restricted to endothelial cells and down-regulated in murine fibrotic kidney and heart tissue. These findings were confirmed in patient kidney biopsies. MiR-126-3p expression is restricted to endothelial cells and is down-regulated during EndMT. Over-expression of miR-126-3p reduces EndMT, therefore, it could be considered for miRNA-based therapeutics in fibrotic organs.


Assuntos
Transdiferenciação Celular/genética , Rim/patologia , MicroRNAs/fisiologia , Miocárdio/patologia , Animais , Células Cultivadas , Células Endoteliais/patologia , Células Endoteliais/fisiologia , Fibrose/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Rim/metabolismo , Células-Tronco Mesenquimais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miofibroblastos/metabolismo , Miofibroblastos/patologia
3.
Cancers (Basel) ; 13(14)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34298676

RESUMO

Chemokine receptor CCR7 is implicated in the metastasis of breast cancer to the lymph nodes. Chemokine function is dependent upon their binding to both cell-surface heparan sulphate (HS) and to their specific receptors; thus, the role of HS in CCR7-mediated lymph node metastasis was investigated by creating a non-HS binding chemokine CCL21 (mut-CCL21). Mut-CCL21 (Δ103-134) induced leukocyte chemotaxis in diffusion gradients but did not stimulate trans-endothelial migration of PBMCs (p < 0.001) and 4T1-Luc cells (p < 0.01). Furthermore, the effect of heparin and HS on the chemotactic properties of wild-type (WT) and mut-CCL21 was examined. Interestingly, heparin and HS completely inhibit the chemotaxis mediated by WT-CCL21 at 250 and 500 µg/mL, whereas minimal effect was seen with mut-CCL21. This difference could potentially be attributed to reduced HS binding, as surface plasmon resonance spectroscopy showed that mut-CCL21 did not significantly bind HS compared to WT-CCL21. A murine model was used to assess the potential of mut-CCL21 to prevent lymph node metastasis in vivo. Mice were injected with 4T1-Luc cells in the mammary fat pad and treated daily for a week with 20 µg mut-CCL21. Mice were imaged weekly with IVIS and sacrificed on day 18. Luciferase expression was significantly reduced in lymph nodes from mice that had been treated with mut-CCL21 compared to the control (p = 0.0148), suggesting the potential to target chemokine binding to HS as a therapeutic option.

4.
Nat Commun ; 11(1): 4017, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782292

RESUMO

The thick mucus layer of the gut provides a barrier to infiltration of the underlying epithelia by both the normal microbiota and enteric pathogens. Some members of the microbiota utilise mucin glycoproteins as a nutrient source, but a detailed understanding of the mechanisms used to breakdown these complex macromolecules is lacking. Here we describe the discovery and characterisation of endo-acting enzymes from prominent mucin-degrading bacteria that target the polyLacNAc structures within oligosaccharide side chains of both animal and human mucins. These O-glycanases are part of the large and diverse glycoside hydrolase 16 (GH16) family and are often lipoproteins, indicating that they are surface located and thus likely involved in the initial step in mucin breakdown. These data provide a significant advance in our knowledge of the mechanism of mucin breakdown by the normal microbiota. Furthermore, we also demonstrate the potential use of these enzymes as tools to explore changes in O-glycan structure in a number of intestinal disease states.


Assuntos
Microbioma Gastrointestinal , Hexosaminidases/metabolismo , Glicoproteínas de Membrana/metabolismo , Mucinas/metabolismo , Animais , Bactérias/classificação , Bactérias/enzimologia , Bactérias/genética , Bactérias/metabolismo , Cristalografia por Raios X , Glicosídeo Hidrolases/genética , Glicosídeo Hidrolases/metabolismo , Hexosaminidases/química , Hexosaminidases/genética , Humanos , Glicoproteínas de Membrana/química , Estrutura Molecular , Mucinas/química , Filogenia , Polissacarídeos/química , Polissacarídeos/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato
5.
Pharmacy (Basel) ; 8(1)2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32019094

RESUMO

Medication review (MR) is a vital part of the pharmacist's role in hospital. However, in the South Infirmary Victoria University Hospital (SIVUH), Cork, Ireland, this has not been fully implemented due to resource issues. In addition, the cost of providing this service has not been evaluated. Moreover, it is not clear how other members of the multidisciplinary team e.g. Nurses, value any interventions made as a result of the MR. This mixed methods study assessed the impact of MR in terms of (i) potential clinical harm, (ii) cost avoidance and (iii) the views of nursing staff on the role of the pharmacist. The setting is a 192-bed, voluntary, acute hospital, in the Munster region of Ireland. Study I: The pharmacist provided MR to patients conventionally once a week. Any interventions were then assessed for potential clinical harm and to calculate cost avoidance. Study II: Semi-structured interviews, guided by a topic guide were completed with 12 nurses (11 female). Thematic analysis was used to code the main themes. Main outcome measure: To estimate the cost, cost avoidance, and the net cost benefit ratio of MR provided by pharmacists. Study I: Of 128 patients who received the MR, 113 interventions were made. The estimated cost of providing the MR was €2,559 (senior pharmacist). Using €1084 as the cost of an adverse drug event (ADE), the cost avoidance was calculated at €42,330. This led to a net cost benefit of €39,771 (senior pharmacist) which equated to a net cost benefit ratio of 16.5:1. Study II: The main themes were (i) perceptions of pharmacy services, (ii) the role of the pharmacist-past, present and future, and (iii) teamwork and communication. Nurses expressed a desire to have more pharmacists present on the wards.

6.
Clin Breast Cancer ; 19(3): e440-e451, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30853347

RESUMO

BACKGROUND: Two large acute Irish University teaching hospitals changed the manner in which they treated human epidermal growth factor receptor (HER)2-positive breast cancer patients by implementing the administration of trastuzumab via the subcutaneous (SC) route into their clinical practice. The study objective is to compare the trastuzumab SC and trastuzuamb intravenous (IV) treatment pathways in both hospitals and assess which route is more cost-effective and time saving in relation to active health care professional (HCP) time. MATERIALS AND METHODS: A prospective observational study in the form of cost minimization analysis constituted the study design. Active HCP time for trastuzumab SC- and IV-related tasks were recorded. Staff costs were calculated using fully loaded salary costs. Loss of productivity costs for patients were calculated using the human capital method. RESULTS: On average, the total HCP time saved per trastuzumab SC treatment cycle relative to trastuzumab IV treatment cycle was 59.21 minutes. Time savings in favor of trastuzumab SC resulted from quicker drug reconstitution, no IV catheter installation/removal, and less HCP monitoring. Over a full treatment course of 17 cycles, average HCP time saved accumulates to 16.78 hours, with an estimated direct cost saving of €1609.99. Loss of productivity for patients receiving trastuzumab IV (2.15 days) was greater than that of trastuzumab SC (0.60 days) for a full treatment course. CONCLUSION: Trastuzumab SC treatment has proven to be a more cost-effective option than trastuzumab IV treatment that generated greater HCP time savings in both study sites. Healthcare policymakers should consider replacing trastuzumab IV with trastuzumab SC treatment in all eligible patients.


Assuntos
Administração Intravenosa/economia , Antineoplásicos Imunológicos/economia , Neoplasias da Mama/tratamento farmacológico , Análise Custo-Benefício , Pessoal de Saúde/economia , Injeções Subcutâneas/economia , Trastuzumab/economia , Administração Intravenosa/métodos , Adulto , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/patologia , Feminino , Seguimentos , Pessoal de Saúde/estatística & dados numéricos , Recursos em Saúde , Humanos , Injeções Subcutâneas/métodos , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Tempo , Trastuzumab/uso terapêutico
7.
Biochim Biophys Acta Gen Subj ; 1863(5): 839-848, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30794825

RESUMO

One of the main feature of chronic kidney disease is the development of renal fibrosis. Heparan Sulfate (HS) is involved in disease development by modifying the function of growth factors and cytokines and creating chemokine gradients. In this context, we aimed to understand the function of HS sulfation in renal fibrosis. Using a mouse model of renal fibrosis, we found that total HS 2-O-sulfation was increased in damaged kidneys, whilst, tubular staining of HS 3-O-sulfation was decreased. The expression of HS modifying enzymes significantly correlated with the development of fibrosis with HS3ST1 demonstrating the strongest correlation. The pro-fibrotic factors TGFß1 and TGFß2/IL1ß significantly downregulated HS3ST1 expression in both renal epithelial cells and renal fibroblasts. To determine the implication of HS3ST1 in growth factor binding and signalling, we generated an in vitro model of renal epithelial cells overexpressing HS3ST1 (HKC8-HS3ST1). Heparin Binding EGF like growth factor (HB-EGF) induced rapid, transient STAT3 phosphorylation in control HKC8 cells. In contrast, a prolonged response was demonstrated in HKC8-HS3ST1 cells. Finally, we showed that both HS 3-O-sulfation and HB-EGF tubular staining were decreased with the development of fibrosis. Taken together, these data suggest that HS 3-O-sulfation is modified in fibrosis and highlight HS3ST1 as an attractive biomarker of fibrosis progression with a potential role in HB-EGF signalling.


Assuntos
Rim Fundido/tratamento farmacológico , Heparitina Sulfato/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Sulfotransferases/antagonistas & inibidores , Animais , Células Cultivadas , Rim Fundido/metabolismo , Rim Fundido/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Sulfotransferases/genética , Sulfotransferases/metabolismo
8.
J Clin Invest ; 129(3): 1061-1075, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30714990

RESUMO

Atypical hemolytic uremic syndrome (aHUS) is frequently associated in humans with loss-of-function mutations in complement-regulating proteins or gain-of-function mutations in complement-activating proteins. Thus, aHUS provides an archetypal complement-mediated disease with which to model new therapeutic strategies and treatments. Herein, we show that, when transferred to mice, an aHUS-associated gain-of-function change (D1115N) to the complement-activation protein C3 results in aHUS. Homozygous C3 p.D1115N (C3KI) mice developed spontaneous chronic thrombotic microangiopathy together with hematuria, thrombocytopenia, elevated creatinine, and evidence of hemolysis. Mice with active disease had reduced plasma C3 with C3 fragment and C9 deposition within the kidney. Therapeutic blockade or genetic deletion of C5, a protein downstream of C3 in the complement cascade, protected homozygous C3KI mice from thrombotic microangiopathy and aHUS. Thus, our data provide in vivo modeling evidence that gain-of-function changes in complement C3 drive aHUS. They also show that long-term C5 deficiency is not accompanied by development of other renal complications (such as C3 glomerulopathy) despite sustained dysregulation of C3. Our results suggest that this preclinical model will allow testing of novel complement inhibitors with the aim of developing precisely targeted therapeutics that could have application in many complement-mediated diseases.


Assuntos
Síndrome Hemolítico-Urêmica Atípica , Ativação do Complemento , Complemento C3 , Complemento C5 , Rim , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Animais , Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/imunologia , Síndrome Hemolítico-Urêmica Atípica/patologia , Complemento C3/genética , Complemento C3/imunologia , Complemento C5/genética , Complemento C5/imunologia , Complemento C9/genética , Complemento C9/imunologia , Modelos Animais de Doenças , Glomerulonefrite Membranosa/genética , Glomerulonefrite Membranosa/imunologia , Glomerulonefrite Membranosa/patologia , Rim/imunologia , Rim/patologia , Camundongos , Camundongos Transgênicos
9.
Am J Speech Lang Pathol ; 27(3S): 1152-1163, 2018 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-30347060

RESUMO

Purpose: The aim of this article was to identify what school-aged children who stutter consider to be the most important outcomes from therapy. Method: A Delphi approach was employed for the study. Eighteen participants aged 9-13 years completed a survey, generating 90 statements that would constitute successful therapy outcomes. After categorization and reduction, 79 statements were sent to participants in a second survey to seek consensus on their importance. Fifteen participants aged 8-14 years completed this second survey. Statements with the highest median ratings and smallest standard deviations were retained. Results: Twenty-one statements were retained after analysis. These reflected hopes for affective and behavioral change in the young person and in other people after therapy. Important outcomes included, but are not limited to, increased fluency, greater independence, increased confidence at school, others knowing how to support the individual, and communication situations feeling easier. Conclusions: Participants identified a range of outcomes that were important to achieve as a result of speech and language therapy. The findings suggest a need for a more holistic view of what is meant by successful therapy, incorporating improvements in the ability to communicate and participate in daily situations. The findings suggest that an integrated or holistic approach to intervention would be required to achieve these goals and should include significant others from the child's environment. The important statements identified in this study could be used to inform the content of therapy and to evaluate change over time. Supplemental Material: https://doi.org/10.23641/asha.7144205.


Assuntos
Comportamento do Adolescente , Comportamento Infantil , Acústica da Fala , Gagueira/psicologia , Gagueira/terapia , Qualidade da Voz , Adaptação Psicológica , Adolescente , Fatores Etários , Criança , Consenso , Efeitos Psicossociais da Doença , Técnica Delfos , Feminino , Humanos , Masculino , Participação do Paciente , Qualidade de Vida , Inteligibilidade da Fala , Gagueira/diagnóstico , Gagueira/fisiopatologia , Resultado do Tratamento
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