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1.
BJUI Compass ; 5(5): 465-475, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38751954

RESUMO

Background: Malignant ureteral obstruction (MUO) is a frequent challenge for urologists. Patients have poor prognoses, treatment aims to improve quality-of-life while optimising renal function. Standard practice in the United Kingdom is to use polyurethane stents, which require frequent surgical replacements for blockages and encrustation. More durable metallic stents are available, although these incur an increased initial purchase price. Aims: We aim to assess whether the use of polyurethane double-J (JJ) or metallic stent, Resonance® is more cost-effective for managing MUO in the UK healthcare setting. Methods: A Markov model was parameterised to 5 years with costs and health-related quality-of-life consequences for treating MUO with Resonance metallic stent (Cook Medical), versus standard JJ stents, from the UK care system perspective, with 3.5% discounting. Deterministic and probabilistic sensitivity analyses were undertaken to assess the effect of uncertainty. Results: Over 5 years, approximately four fewer repeat surgical interventions were estimated in the metallic stent arm compared with the JJ stent, driving a 23.4% reduction in costs. The mean estimates of costs and benefits indicate that treatment of MUO with Resonance for 5 years is dominant over JJ stents. Over 5 years a cost-saving of £2164.74 and a health gain of +0.046 quality-adjusted life years (QALYs) per patient is estimated. With a maximum willingness to pay of £20 k per QALY, a net monetary benefit (NMB) of £3077.83 is estimated. Probabilistic sensitivity analysis at a willingness to pay threshold of £20 000 indicates an 89.3% probability of Resonance being cost-effective over JJ stents. Within 1-year savings of £726.53 are estimated driven by a reduction of two fewer repeat surgical interventions when using the metallic stent. Conclusions: Resonance metallic stents for the treatment of MUO reduce the number of repeat procedures and could be a cost-effective option for the treatment, potentially offering efficiencies to the healthcare system.

2.
J Tissue Viability ; 32(2): 262-269, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36990897

RESUMO

BACKGROUND: Wounds cost £8.3 billion per year in the United Kingdom (UK) annually. Venous leg ulcers (VLUs) account for 15% of wounds and can be complicated to heal, increasing nurse visits and resource costs. Recent wound bed preparation consensus recommends wound cleansing and biofilm disrupting agents. However, inert cleansers such as tap water or saline are inexpensive, an evaluation of evidence is required to justify the higher upfront costs of treatment with active cleansers. We undertook a cost-effectiveness analysis of the use of a biofilm disrupting and cleansing solution and gel, Prontosan® Solution and Gel X, (PSGX) (B Braun Medical), as compared to the standard practice of using saline solution, for treating VLUs. METHODS: A Markov model was parameterised to one-year costs and health-related quality of life consequences of treating chronic VLUs with PSGX versus saline solution. Costs are viewed from a UK healthcare payer perspective, include routine care and management of complications. A systematic literature search was performed to inform the clinical parameters of the economic model. Deterministic univariate sensitivity analysis (DSA) and probabilistic sensitivity analysis (PSA) were undertaken. RESULTS: For PSGX an Incremental Net Monetary Benefit (INMB) of £1,129.65 to £1,042.39 per patient (with a Maximum Willingness to Pay of £30k and £20k per QALY respectively), of which cost savings are £867.87 and 0.0087 quality-adjusted life years (QALYs) gain per patient. PSA indicates a 99.3% probability of PSGX being cost-effective over saline. CONCLUSIONS: PSGX for the treatment of VLUs is dominant compared with saline solution in the UK with expected cost-savings within a year and improved patient outcomes.


Assuntos
Betaína , Úlcera Varicosa , Humanos , Análise Custo-Benefício , Betaína/farmacologia , Betaína/uso terapêutico , Qualidade de Vida , Solução Salina/uso terapêutico , Úlcera Varicosa/tratamento farmacológico , Reino Unido
3.
J Wound Care ; 29(7): 380-386, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32654602

RESUMO

OBJECTIVE: The burden of wound care within the NHS is estimated at a cost of £5.3 billion per year and is set to rise annually by 30%. This case series describes the results of using polyhexanide (PHMB) and betaine wound irrigation solution and gels (Prontosan, B.Braun Medical Ltd., UK) across the UK in hard-to-heal (also described as chronic) wounds up to 20 years' duration, with an observation period of greater than one month. Over half of the hard-to-heal wounds were healed and vast improvements to all other wounds were observed. Improvements to wound bed condition were reported as early as two days after commencing initial treatment, with decreases in malodour, exudate, slough and pain reported across the case series. In addition to wound bed improvements, a reduction in dressing change frequency of 55% was observed in hard-to-heal wounds under the new treatment regime.


Assuntos
Betaína/administração & dosagem , Biguanidas/administração & dosagem , Úlcera por Pressão/terapia , Administração Cutânea , Géis , Humanos , Medicina Estatal , Irrigação Terapêutica , Reino Unido , Cicatrização
4.
Eur Respir Rev ; 28(153)2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31554704

RESUMO

Airborne particulate matter (PM) is a leading driver of premature mortality and cardiopulmonary morbidity, associated with exacerbations of asthma and chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and lung cancer. The airway epithelium, as the principal site of PM deposition, is critical to the effects of, and initial response to, PM. A key mechanism by which PM exerts its effects is the generation of reactive oxygen species (ROS), inducing antioxidant and inflammatory responses in exposed epithelial cells. However, much of what is known about the effects of PM is based on research using particulates from urban air. PM from underground railways is compositionally highly distinct from urban PM, being rich in metals associated with wheel, rail and brake wear and electrical arcing and component wear, which endows underground PM with potent ROS-generating capacity. In addition, underground PM appears to be more inflammogenic than urban PM in epithelial cells, but there is a lack of research into effects on exposed individuals, especially those with underlying health conditions. This review summarises current knowledge about the effects of PM on the airway epithelium, how the effects of underground PM may be different to urban PM and the potential health consequences and mitigation strategies for commuters and workers in underground railways.


Assuntos
Poluentes Ocupacionais do Ar/efeitos adversos , Poluentes Atmosféricos/efeitos adversos , Poluição do Ar/efeitos adversos , Exposição por Inalação/efeitos adversos , Exposição Ocupacional/efeitos adversos , Material Particulado/efeitos adversos , Ferrovias , Mucosa Respiratória/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Saúde Ocupacional , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Medição de Risco , Fatores de Risco
5.
PLoS One ; 8(4): e61187, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23593426

RESUMO

Aedes aegypti is the principal vector of Dengue viruses worldwide. We identified field collected insects with differential susceptibility to Dengue-2 virus (DENv-2) and used isofemale selection to establish susceptible and refractory strains based on midgut infection barriers. Previous experiments had identified higher expression of apoptosis-related genes in the refractory strain. To identify potential molecular mechanisms associated with DENv susceptibility, we evaluated the differential expression of Caspase-16, Aedronc, Aedredd, Inhibitor of apoptosis (AeIAP1) and one member of the RNAi pathway, Argonaute-2 in the midguts and fat body tissues of the selected strains at specific times post blood feeding or infection with DENv-2. In the refractory strain there was significantly increased expression of caspases in midgut and fatbody tissues in the presence of DENv-2, compared to exposure to blood alone, and significantly higher caspase expression in the refractory strain compared with the susceptible strain at timepoints when DENv was establishing in these tissues. We used RNAi to knockdown gene expression; knockdown of AeIAP1 was lethal to the insects. In the refractory strain, knockdown of the pro-apoptotic gene Aedronc increased the susceptibility of refractory insects to DENv-2 from 53% to 78% suggesting a contributing role of this gene in the innate immune response of the refractory strain.


Assuntos
Aedes/genética , Apoptose/genética , Vírus da Dengue/patogenicidade , Aedes/virologia , Animais , Sequência de Bases , Primers do DNA , Técnicas de Silenciamento de Genes , Interferência de RNA , Reação em Cadeia da Polimerase em Tempo Real
6.
PLoS One ; 6(6): e21484, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21760880

RESUMO

Granzyme K (GrK) is a trypsin-like serine protease that is elevated in patients with sepsis and acute lung inflammation. While GrK was originally believed to function exclusively as a pro-apoptotic protease, recent studies now suggest that GrK may possess other non-cytotoxic functions. In the context of acute lung inflammation, we hypothesized that GrK induces pro-inflammatory cytokine release through the activation of protease-activated receptors. The direct effect of extracellular GrK on PAR activation, intracellular signaling and cytokine was assessed using cultured human lung fibroblasts. Extracellular GrK induced secretion of IL-6, IL-8 and MCP-1 in a dose- and time-dependent manner in lung fibroblasts. Heat-inactivated GrK did not induce cytokine release indicating that protease activity is required. Furthermore, GrK induced activation of both the ERK1/2 and p38 MAP kinase signaling pathways, and significantly increased fibroblast proliferation. Inhibition of ERK1/2 abrogated the GrK-mediated cytokine release. Through the use of PAR-1 and PAR-2 neutralizing antibodies, it was determined that PAR-1 is essential for GrK-induced IL-6, IL-8 and MCP-1 release. In summary, extracellular GrK is capable of activating PAR-1 and inducing fibroblast cytokine secretion and proliferation.


Assuntos
Granzimas/farmacologia , Receptor PAR-1/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Quimiocina CCL2/biossíntese , Quimiocina CCL2/metabolismo , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/enzimologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Inflamação/metabolismo , Interleucina-6/biossíntese , Interleucina-6/metabolismo , Interleucina-8/biossíntese , Interleucina-8/metabolismo , Pulmão/citologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Trombina/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
Am J Pathol ; 176(2): 1038-49, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20035050

RESUMO

Granzyme B (GZMB) is a serine protease that is abundantly expressed in advanced human atherosclerotic lesions and may contribute to plaque instability. Perforin is a pore-forming protein that facilitates GZMB internalization and the induction of apoptosis. Recently a perforin-independent, extracellular role for GZMB has been proposed. In the current study, the role of GZMB in abdominal aortic aneurysm (AAA) was assessed. Apolipoprotein E (APOE)(-/-) x GZMB(-/-) and APOE(-/-) x perforin(-/-) double knockout (GDKO, PDKO) mice were generated to test whether GZMB exerted a causative role in aneurysm formation. To induce aneurysm, mice were given angiotensin II (1000 ng/kg/min) for 28 days. GZMB was found to be abundant in both murine and human AAA specimens. GZMB deficiency was associated with a decrease in AAA and increased survival compared with APOE-KO and PDKO mice. Although AAA rupture was observed frequently in APOE-KO (46.7%; n = 15) and PDKO (43.3%; n = 16) mice, rupture was rarely observed in GDKO (7.1%; n = 14) mice. APOE-KO mice exhibited reduced fibrillin-1 staining compared with GDKO mice, whereas in vitro protease assays demonstrated that fibrillin-1 is a substrate of GZMB. As perforin deficiency did not affect the outcome, our results suggest that GZMB contributes to AAA pathogenesis via a perforin-independent mechanism involving extracellular matrix degradation and subsequent loss of vessel wall integrity.


Assuntos
Aneurisma da Aorta Abdominal/genética , Granzimas/metabolismo , Perforina/fisiologia , Angiotensina II/farmacologia , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/mortalidade , Apolipoproteínas E/genética , Espaço Extracelular/metabolismo , Fibrilina-1 , Fibrilinas , Granzimas/genética , Granzimas/fisiologia , Humanos , Sistema Imunitário/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas dos Microfilamentos/metabolismo , Perforina/genética , Perforina/metabolismo , Processamento de Proteína Pós-Traducional/genética , Distribuição Tecidual
8.
Apoptosis ; 14(3): 247-56, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19212814

RESUMO

Developmental and tissue homeostasis is a delicate balance between cell proliferation and cell death. The activation of caspases, a conserved family of cysteine proteases, is a main event in the initiation and execution of programmed cell death. While caspases have been characterized from many organisms, comparatively little is known about insect caspases. In Drosophila melanogaster, seven caspases have been characterized; three initiators and four effectors. In mosquitoes, several putative caspases have been identified in the genomes of Aedes aegypti and Anopheles gambiae. A small number of caspases have been identified in the Lepidoptera, the flour beetle, Tribolium castaneum, and the pea aphid, Acyrthosiphon pisum. The availability of new insect genome sequences will provide a unique opportunity to examine the caspase family across an evolutionarily diverse phylum and will provide valuable insights into their function and regulation.


Assuntos
Apoptose , Caspases/metabolismo , Genes de Insetos/fisiologia , Insetos/enzimologia , Animais , Caspases/genética , Evolução Molecular , Genes de Insetos/genética , Insetos/genética , Insetos/fisiologia , Mutação/genética , Mutação/fisiologia , Filogenia
9.
Insect Biochem Mol Biol ; 39(1): 47-54, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18977438

RESUMO

Microbial infections in insects activate a series of immune responses that culminate in the production of antimicrobial peptides (AMPs). In Drosophila, two signaling pathways, govern the challenge-dependent expression of AMPs; the Toll and IMD pathways. While AMPs have been the subject of much research in mosquitoes, the regulation of the pathways required for AMP expression remains largely unknown. We report here the identification of Aedes FADD (AeFADD), a death domain protein in Aedes aegypti. AeFadd is expressed in all immune-competent tissues and all developmental stages examined. At the transcriptional level, AeFadd transcripts increased when challenged with Escherichia coli but not Micrococcus luteus. In both cases, we observed the induction of two AMP genes; cecropin and defensin. Loss of AeFadd function by dsRNA interference impaired the inducible expression of both AMPs, and rendered adult mosquitoes susceptible to both types of bacteria. Identifying molecules that regulate mosquito immunity may help elucidate the factors that contribute to the vectorial capacity and provide insights into general mechanisms that regulate innate immunity.


Assuntos
Aedes/imunologia , Aedes/microbiologia , Peptídeos Catiônicos Antimicrobianos/genética , Proteína de Domínio de Morte Associada a Fas/imunologia , Proteínas de Insetos/imunologia , Aedes/genética , Aedes/crescimento & desenvolvimento , Sequência de Aminoácidos , Animais , Peptídeos Catiônicos Antimicrobianos/imunologia , Proteína de Domínio de Morte Associada a Fas/química , Proteína de Domínio de Morte Associada a Fas/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Imunidade Inata , Proteínas de Insetos/química , Proteínas de Insetos/genética , Masculino , Dados de Sequência Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Homologia de Sequência de Aminoácidos , Febre Amarela/parasitologia
10.
Insect Biochem Mol Biol ; 37(6): 559-69, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17517333

RESUMO

Caspases play an essential role during programmed cell death in all metazoans. These enzymes are cysteine proteases and comprise a multi-gene family with more than a dozen mammalian family members. Although caspases have been characterized in many animals, including Drosophila melanogaster, little is known about the caspases that exist in mosquitoes. Here we describe the identification and characterization of Aedes Dredd (AeDredd), a novel caspase in the yellow fever mosquito, Aedes aegypti. AeDredd contains two N-terminal death effector domains and the well conserved caspase catalytic domain. Multiple sequence alignments and functional substrate assays of recombinant protein suggest that AeDredd is an orthologue of Drosophila Dredd and human caspase-8, both central effectors of the death receptor-mediated apoptotic pathway. AeDredd exhibits substrate specificity most similar to human caspase-8. AeDredd transcripts were found in all developmental stages with highest expression in early pupae. Within adults, AeDredd was found in all the tissues examined, with the highest transcript levels detected in fat body tissues. This is the first functional characterization of a death domain-containing caspase in an insect vector of human disease, and will initiate studies on the role of apoptosis in the innate immune response of vectors towards intracellular parasites such as viruses.


Assuntos
Aedes/enzimologia , Caspases/genética , Caspases/metabolismo , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Aedes/metabolismo , Sequência de Aminoácidos , Animais , Apoptose , Caspases/química , Ecdisona/metabolismo , Expressão Gênica/efeitos da radiação , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Insetos/química , Modelos Moleculares , Dados de Sequência Molecular , Especificidade de Órgãos , Conformação Proteica , Alinhamento de Sequência , Especificidade por Substrato , Raios Ultravioleta
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