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1.
Malays J Pathol ; 45(3): 457-462, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38155386

RESUMO

Hirschsprung's Disease (HD) is a congenital disorder causing severe constipation in infants and children. Suction rectal biopsy (SRB) is the preferred technique for obtaining tissue samples for histopathological evaluation. In low-resource settings like Malaysia, cost-effective diagnostic approaches are necessary, making single sample SRB valuable. This study evaluates the diagnostic accuracy and sufficiency of a single macroscopically adequate sample in suction rectal biopsies for the histopathological confirmation of HD. We conducted a retrospective study of children who underwent suction rectal biopsies for the diagnosis of HD at Hospital Raja Perempuan Zainab II (HRPZII), Kota Bharu, Kelantan. A total of 68 patients were included in the study. The inadequacy rate for bedside SRB was 14%, comparable to current literature. Our study found no statistically significant association between sample inadequacy and gestational age, gender, birth weight, or weight at biopsy. Complication rates were 0%, consistent with literature reports. Calretinin staining, an additional technique, was performed in 23 biopsy episodes, with a 4.3% inadequacy rate, compared to 20% in specimens not subjected to calretinin staining. The cost of SRB almost doubled with each additional sample taken, significant in low-resource environments. In conclusion, single sample SRBs can be adequately diagnostic and cost-effective in low-resource settings, providing valuable insights for healthcare facilities in Malaysia and other developing countries. The use of adjunctive techniques such as calretinin staining may improve diagnostic accuracy while maintaining cost-effectiveness. Further prospective studies with larger sample sizes are needed to validate these findings.


Assuntos
Doença de Hirschsprung , Lactente , Criança , Humanos , Doença de Hirschsprung/diagnóstico , Doença de Hirschsprung/patologia , Reto/patologia , Calbindina 2 , Estudos Retrospectivos , Sucção , Estudos Prospectivos , Biópsia/métodos
2.
Nat Prod Rep ; 38(4): 682-692, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33021616

RESUMO

Covering: 1951 to 2020Andrographolide is one of the most widely studied plant secondary metabolites, known to display diverse pharmacological actions. Current literature has documented a sizeable list of pharmacological targets for andrographolide, suggesting its multi-targeting nature. Many of these targets are central to the pathophysiology of highly prevalent diseases such as cardiovascular diseases, neurodegenerative disorders, autoimmunity, and even cancer. Despite its well-documented therapeutic efficacy in various disease models, for years, the discrepancies between in vivo bioavailability and bioactivity of andrographolide and the debate surrounding its multi-targeting properties (polypharmacology or promiscuity?) have hindered the development of this versatile molecule into a potential therapeutic agent. Is andrographolide a valuable lead for therapeutic development or a potential invalid metabolic panacea (IMP)? This perspective article aims to discuss this by considering various contributing factors to the polypharmacology of andrographolide.


Assuntos
Diterpenos/farmacologia , Animais , Diterpenos/química , Diterpenos/metabolismo , Diterpenos/farmacocinética , Humanos , Polifarmacologia , Ratos
3.
Pharmacol Res ; 161: 105223, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33017650

RESUMO

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. Cumulative evidence has implicated renin-angiotensin system (RAS) in the pathogenesis of COPD. This study aimed to investigate potential protective effects of angiotensin II type-2 receptor (AT2R) activation in cigarette smoke (CS)-induced COPD models. Compound 21 (C21), a selective and potent non-peptide small molecule AT2R agonist, was evaluated for anti-inflammatory, anti-oxidative and anti-remodeling activities in a two-week (acute) and an eight-week (chronic) CS-induced COPD models. C21 inhibited CS-induced increases in macrophage and neutrophil counts, pro-inflammatory cytokines and oxidative damage markers in bronchoalveolar lavage (BAL) fluid, and TGF-ß1 in lung tissues, from COPD models. C21 restored phosphatase activities and reduced phospho-p38 MAPK, phospho-ERK and p65 subunit of NF-κB levels in CS-exposed lung tissues. C21 also suppressed CS-induced increases in α-Sma, Mmp9, Mmp12 and hydroxyproline levels in lung tissues, and neutrophil elastase activity in BAL fluid. C21 modulated RAS in CS-exposed lungs by downregulating Ang II but upregulating Ang-(1-7) and Mas receptor levels. C21 prevented CS-induced emphysema and improved lung functions in chronic COPD model. We report here for the first time the protective effects of AT2R agonist C21 against CS-induced COPD, and provide strong evidence for further development of AT2R agonist for the treatment of COPD.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Imidazóis/farmacologia , Pulmão/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/prevenção & controle , Enfisema Pulmonar/prevenção & controle , Receptor Tipo 2 de Angiotensina/agonistas , Sistema Renina-Angiotensina/efeitos dos fármacos , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Remodelação das Vias Aéreas/efeitos dos fármacos , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Mediadores da Inflamação/metabolismo , Pulmão/metabolismo , Pulmão/fisiopatologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Camundongos Endogâmicos BALB C , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/fisiopatologia , Receptor Tipo 2 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas G , Transdução de Sinais , Fumaça , Produtos do Tabaco
4.
J Intern Med ; 285(4): 436-445, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30521125

RESUMO

BACKGROUND: A lack of consensus exists amongst national guidelines regarding who should be investigated for haematuria. Type of haematuria and age-specific thresholds are frequently used to guide referral for the investigation of haematuria. OBJECTIVES: To develop and externally validate the haematuria cancer risk score (HCRS) to improve patient selection for the investigation of haematuria. METHODS: Development cohort comprise of 3539 prospectively recruited patients recruited at 40 UK hospitals (DETECT 1; ClinicalTrials.gov: NCT02676180) and validation cohort comprise of 656 Swiss patients. All patients were aged >18 years and referred to hospital for the evaluation of visible and nonvisible haematuria. Sensitivity and specificity of the HCRS in the validation cohort were derived from a cut-off identified from the discovery cohort. RESULTS: Patient age, gender, type of haematuria and smoking history were used to develop the HCRS. HCRS validation achieves good discrimination (AUC 0.835; 95% CI: 0.789-0.880) and calibration (calibration slope = 1.215) with no significant overfitting (P = 0.151). The HCRS detected 11.4% (n = 8) more cancers which would be missed by UK National Institute for Health and Clinical Excellence guidelines. The American Urological Association guidelines would identify all cancers with a specificity of 12.6% compared to 30.5% achieved by the HCRS. All patients with upper tract cancers would have been identified. CONCLUSION: The HCRS offers good discriminatory accuracy which is superior to existing guidelines. The simplicity of the model would facilitate adoption and improve patient and physician decision-making.


Assuntos
Hematúria/etiologia , Medição de Risco , Neoplasias da Bexiga Urinária/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes , Medição de Risco/métodos , Fatores de Risco , Sensibilidade e Especificidade , Fumar/efeitos adversos , Neoplasias da Bexiga Urinária/complicações , Neoplasias da Bexiga Urinária/etiologia , Adulto Jovem
5.
Pharmacol Res ; 144: 1-7, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30953685

RESUMO

Autophagy is an evolutionary conserved process that is responsible for maintaining cellular homeostasis through lysosome-dependent degradation of damaged proteins, lipid and organelles. When autophagy is dysregulated by factors such as cigarette smoking, environmental insults and ageing, it can lead to formation of aggresome-bodies and enhanced production of reactive oxygen species (ROS), of which contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD). This review will aim to decipher the pathogenic process of autophagy that is dysregulated by the various risk factors of COPD, leading to either cell death or senescence and COPD progression. It will also cover potential therapeutics that can be used to augment autophagy for the treatment of COPD. This will help shed light on COPD pathophysiology in the context of autophagy so that novel therapeutics can be developed to provide target-specific treatment.


Assuntos
Autofagia , Doença Pulmonar Obstrutiva Crônica/patologia , Animais , Autofagia/efeitos dos fármacos , Humanos , Mitofagia/efeitos dos fármacos , Terapia de Alvo Molecular , Estresse Oxidativo/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Fatores de Risco
6.
J Immunol ; 199(1): 39-47, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28526682

RESUMO

Exposure to environmental allergens is a major risk factor for asthma development. Allergens possess proteolytic activity that is capable of disrupting the airway epithelium. Although there is increasing evidence pointing to asthma as an epithelial disease, the underlying mechanism that drives asthma has not been fully elucidated. In this study, we investigated the direct DNA damage potential of aeroallergens on human bronchial epithelial cells and elucidated the mechanisms mediating the damage. Human bronchial epithelial cells, BEAS-2B, directly exposed to house dust mites (HDM) resulted in enhanced DNA damage, as measured by the CometChip and the staining of DNA double-strand break marker, γH2AX. HDM stimulated cellular reactive oxygen species production, increased mitochondrial oxidative stress, and promoted nitrosative stress. Notably, expression of nuclear factor erythroid 2-related factor 2-dependent antioxidant genes was reduced immediately after HDM exposure, suggesting that HDM altered antioxidant responses. HDM exposure also reduced cell proliferation and induced cell death. Importantly, HDM-induced DNA damage can be prevented by the antioxidants glutathione and catalase, suggesting that HDM-induced reactive oxygen and nitrogen species can be neutralized by antioxidants. Mechanistic studies revealed that HDM-induced cellular injury is NADPH oxidase (NOX)-dependent, and apocynin, a NOX inhibitor, protected cells from double-strand breaks induced by HDM. Our results show that direct exposure of bronchial epithelial cells to HDM leads to the production of reactive oxygen and nitrogen species that damage DNA and induce cytotoxicity. Antioxidants and NOX inhibitors can prevent HDM-induced DNA damage, revealing a novel role for antioxidants and NOX inhibitors in mitigating allergic airway disease.


Assuntos
Alérgenos/imunologia , Antioxidantes/fisiologia , Brônquios/imunologia , Dano ao DNA , Células Epiteliais/imunologia , Pyroglyphidae/imunologia , Espécies Reativas de Oxigênio/metabolismo , Acetofenonas/imunologia , Acetofenonas/farmacologia , Ar , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Fator de Indução de Apoptose/genética , Fator de Indução de Apoptose/metabolismo , Asma/etiologia , Asma/imunologia , Asma/fisiopatologia , Brônquios/citologia , Brônquios/metabolismo , Catalase/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/metabolismo , Glutationa/farmacologia , Humanos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , NADPH Oxidase 2 , NADPH Oxidase 4 , NADPH Oxidases/genética , NADPH Oxidases/metabolismo
7.
Toxicol Appl Pharmacol ; 360: 120-130, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30291937

RESUMO

Cigarette smoking is the leading cause of chronic obstructive pulmonary disease (COPD). Cigarette smoke heightens oxidative stress and impairs autophagy, advancing COPD progression. Andrographolide is a bioactive diterpenoid lactone isolated from the plant Andrographis paniculata which has been a traditional medicinal herb for respiratory diseases. As airway epithelial cells form the first interface to be exposed to cigarette smoke, this study aimed to explore the modulatory effects of andrographolide on oxidative stress and autophagy in human bronchial epithelial BEAS-2B cells exposed to cigarette smoke extract (CSE). CSE (2%) exposure increased autophagic markers p62 and LC3B-II levels in BEAS-2B cells. Andrographolide alone increased p62 and p-p62 (S349) but not LC3B-II in BEAS-2B cells. However, in the presence of CSE, andrographolide was able to simultaneously increase LC3B-II level and enhance antioxidant defense by decreasing oxidative stress and increasing total antioxidant capacity, through upregulation of nuclear Nrf2 via the p62-Nrf2 positive feedback loop. Using RFP-GFP-LC3B transfected BEAS-2B cells exposed to CSE, andrographolide was found to impair autophagosome fusion with lysosome, which may account for the moderate increase in activated caspase 3/7 and annexin V levels. Our findings revealed for the first time that andrographolide simultaneously upregulated antioxidant defense through the p62-Nrf2 loop and moderately induced apoptosis through impairment of autophagic flux in CSE-exposed bronchial epithelium. Andrographolide facilitated cigarette smoke-induced apoptosis may be a potential toxicological outcome or may protect against chronic inflammation and aberrant DNA repair. Validation of these in-vitro findings in an experimental COPD model by andrographolide is warranted.


Assuntos
Antioxidantes/metabolismo , Autofagia/efeitos dos fármacos , Brônquios/efeitos dos fármacos , Diterpenos/farmacologia , Células Epiteliais/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fumaça/efeitos adversos , Apoptose/efeitos dos fármacos , Brônquios/metabolismo , Linhagem Celular , Células Epiteliais/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Fumar/efeitos adversos , Nicotiana/efeitos adversos , Regulação para Cima/efeitos dos fármacos
8.
J Immunol ; 196(11): 4706-12, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27183596

RESUMO

LPS and IFN-γ alone or in combination have been implicated in the development of steroid resistance. Combined LPS/IFN-γ strongly upregulates IL-27 production, which has been linked to steroid-resistant airway hyperresponsiveness (AHR). Andrographolide, a bioactive molecule isolated from the plant Andrographis paniculata, has demonstrated anti-inflammatory and antioxidant properties. The present study investigated whether andrographolide could restore steroid sensitivity to block LPS/IFN-γ-induced IL-27 production and AHR via its antioxidative property. The mouse macrophage cell line Raw 264.7, mouse primary lung monocytes/macrophages, and BALB/c mice were treated with LPS/IFN-γ, in the presence and absence of dexamethasone and/or andrographolide. Levels of IL-27 in vitro and in vivo were examined and mouse AHR was assessed. Dexamethasone alone failed to inhibit LPS/IFN-γ-induced IL-27 production and AHR in mice. Andrographolide significantly restored the suppressive effect of dexamethasone on LPS/IFN-γ-induced IL-27 mRNA and protein levels in the macrophage cell line and primary lung monocytes/macrophages, mouse bronchoalveolar lavage fluid and lung tissues, and AHR in mice. LPS/IFN-γ markedly reduced the nuclear level of histone deacetylase (HDAC)2, an essential epigenetic enzyme that mediates steroid anti-inflammatory action. LPS/IFN-γ also decreased total HDAC activity but increased the total histone acetyltransferase/HDAC activity ratio in mouse lungs. Andrographolide significantly restored nuclear HDAC2 protein levels and total HDAC activity, and it diminished the total histone acetyltransferase/HDAC activity ratio in mouse lungs exposed to LPS/IFN-γ, possibly via suppression of PI3K/Akt/HDAC2 phosphorylation, and upregulation of the antioxidant transcription factor NF erythroid-2-related factor 2 level and DNA binding activity. Our data suggest that andrographolide may have therapeutic value in resensitizing steroid action in respiratory disorders such as asthma.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Diterpenos/farmacologia , Interferon gama/imunologia , Interleucina-27/imunologia , Lipopolissacarídeos/imunologia , Hipersensibilidade Respiratória/tratamento farmacológico , Esteroides/farmacologia , Animais , Relação Dose-Resposta a Droga , Feminino , Interferon gama/administração & dosagem , Lipopolissacarídeos/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Células RAW 264.7 , Hipersensibilidade Respiratória/imunologia , Relação Estrutura-Atividade
9.
BMC Palliat Care ; 17(1): 11, 2018 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-29298714

RESUMO

BACKGROUND: Around the world, different models of paediatric palliative care have responded to the unique needs of children with life shortening conditions. However, research confirming their utility and impact is still lacking. This study compared patient-related outcomes and healthcare expenditures between those who received home-based paediatric palliative care and standard care. The quality of life and caregiver burden for patients receiving home-based paediatric palliative care were also tracked over the first year of enrolment to evaluate the service's longitudinal impact. METHOD: A structured impact and cost evaluation of Singapore-based HCA Hospice Care's Star PALS (Paediatric Advance Life Support) programme was conducted over a three-year period, employing both retrospective and prospective designs with two patient groups. RESULTS: Compared to the control group (n = 67), patients receiving home-based paediatric palliative care (n = 71) spent more time at home than in hospital in the last year of life by 52 days (OR = 52.30, 95% CI: 25.44-79.17) with at least two fewer hospital admissions (OR = 2.46, 95% CI: 0.43-4.48); and were five times more likely to have an advance care plan formulated (OR = 5.51, 95% CI: 1.55-19.67). Medical costs incurred by this group were also considerably lower (by up to 87%). Moreover, both patients' quality of life (in terms of pain and emotion), and caregiver burden showed improvement within the first year of enrolment into the programme. DISCUSSION: Our findings suggest that home-based paediatric palliative care brings improved resource utilization and cost-savings for both patients and healthcare providers. More importantly, the lives of patients and their caregivers have improved, with terminally ill children and their caregivers being able to spend more quality time at home at the final stretch of the disease. CONCLUSIONS: The benefits of a community paediatric palliative care programme have been validated. Study findings can become key drivers when engaging service commissioners or even policy makers in appropriate settings.


Assuntos
Custos de Cuidados de Saúde/estatística & dados numéricos , Cuidados Paliativos/normas , Avaliação de Resultados da Assistência ao Paciente , Pediatria/normas , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Serviços de Assistência Domiciliar/organização & administração , Humanos , Lactente , Masculino , Estudos Prospectivos , Qualidade de Vida/psicologia , Estudos Retrospectivos , Singapura
11.
J Allergy Clin Immunol ; 138(1): 84-96.e1, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27157131

RESUMO

BACKGROUND: Asthma is related to airway inflammation and oxidative stress. High levels of reactive oxygen and nitrogen species can induce cytotoxic DNA damage. Nevertheless, little is known about the possible role of allergen-induced DNA damage and DNA repair as modulators of asthma-associated pathology. OBJECTIVE: We sought to study DNA damage and DNA damage responses induced by house dust mite (HDM) in vivo and in vitro. METHODS: We measured DNA double-strand breaks (DSBs), DNA repair proteins, and apoptosis in an HDM-induced allergic asthma model and in lung samples from asthmatic patients. To study DNA repair, we treated mice with the DSB repair inhibitor NU7441. To study the direct DNA-damaging effect of HDM on human bronchial epithelial cells, we exposed BEAS-2B cells to HDM and measured DNA damage and reactive oxygen species levels. RESULTS: HDM challenge increased lung levels of oxidative damage to proteins (3-nitrotyrosine), lipids (8-isoprostane), and nucleic acid (8-oxoguanine). Immunohistochemical evidence for HDM-induced DNA DSBs was revealed by increased levels of the DSB marker γ Histone 2AX (H2AX) foci in bronchial epithelium. BEAS-2B cells exposed to HDM showed enhanced DNA damage, as measured by using the comet assay and γH2AX staining. In lung tissue from human patients with asthma, we observed increased levels of DNA repair proteins and apoptosis, as shown by caspase-3 cleavage, caspase-activated DNase levels, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining. Notably, NU7441 augmented DNA damage and cytokine production in the bronchial epithelium and apoptosis in the allergic airway, implicating DSBs as an underlying driver of asthma pathophysiology. CONCLUSION: This work calls attention to reactive oxygen and nitrogen species and HDM-induced cytotoxicity and to a potential role for DNA repair as a modulator of asthma-associated pathophysiology.


Assuntos
Alérgenos/imunologia , Antígenos de Dermatophagoides/imunologia , Asma/etiologia , Asma/metabolismo , Quebras de DNA de Cadeia Dupla , Pulmão/imunologia , Pulmão/metabolismo , Estresse Oxidativo , Pyroglyphidae/imunologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Caspase 3/metabolismo , Morte Celular/genética , Morte Celular/imunologia , Citocinas/metabolismo , Reparo do DNA , Modelos Animais de Doenças , Eosinófilos/imunologia , Eosinófilos/metabolismo , Eosinófilos/patologia , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Pulmão/patologia , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia
12.
Int J Colorectal Dis ; 31(2): 235-45, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26490055

RESUMO

BACKGROUND: Stage IV colorectal cancer patients with unresectable metastasis who undergo elective primary tumour resection experience heterogeneous post-operative survival. We aimed to develop a scoring model for predicting post-operative survival using pre-operative variables to identify patients who are least likely to experience extended survival following the procedure. METHODS: Survival data were collected from stage IV colorectal cancer patients who had undergone elective primary tumour resection between January 1999 and December 2007. Coefficients of significant covariates from the multivariate Cox regression model were used to compute individual survival scores to classify patients into three prognostic groups. A survival function was derived for each group via Kaplan-Meier estimation. Internal validation was performed. RESULTS: Advanced age (hazard ratio, HR 1.43 (1.16-1.78)); poorly differentiated tumour (HR 2.72 (1.49-5.04)); metastasis to liver (HR 1.76 (1.33-2.33)), lung (HR 1.37 (1.10-1.71)) and bone (HR 2.08 ((1.16-3.71)); carcinomatosis (HR 1.68 (1.30-2.16)); hypoalbuminaemia (HR 1.30 (1.04-1.61) and elevated carcinoembryonic antigen levels (HR 1.89 (1.49-2.39)) significantly shorten post-operative survival. The scoring model separated patients into three prognostic groups with distinct median survival lengths of 4.8, 12.4 and 18.6 months (p < 0.0001). Internal validation revealed a concordance probability estimate of 0.65 and a time-dependent area under receiver operating curve of 0.75 at 6 months. Temporal split-sample validation implied good local generalizability to future patient populations (p < 0.0001). CONCLUSION: Predicting survival following elective primary tumour resection using pre-operative variables has been demonstrated with the scoring model developed. Model-based survival prognostication can support clinical decisions on elective primary tumour resection eligibility.


Assuntos
Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Modelos de Riscos Proporcionais , Idoso , Algoritmos , Antígeno Carcinoembrionário/sangue , Neoplasias Colorretais/sangue , Estudos de Viabilidade , Feminino , Hemoglobinas/metabolismo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Albumina Sérica/metabolismo
13.
J Nat Prod ; 79(5): 1308-15, 2016 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-27104764

RESUMO

Cigarette smoke (CS) is associated with many maladies, one of which is chronic obstructive pulmonary disease (COPD). As the disease progresses, patients are more prone to develop COPD exacerbation episodes by bacterial infection, particularly to nontypeable Haemophilus influenza (NTHi) infection. The present study aimed to develop a CS-exposed mouse model that increases inflammation induced by NTHi challenge and investigate the protective effects of andrographolide, a bioactive molecule with anti-inflammatory and antioxidant properties isolated from the plant Andrographis paniculata. Female BALB/c mice exposed to 2 weeks of CS followed by a single intratracheal instillation of NTHi developed increased macrophage and neutrophil pulmonary infiltration, augmented cytokine levels, and heightened oxidative damage. Andrographolide effectively reduced lung cellular infiltrates and decreased lung levels of TNF-α, IL-1ß, CXCL1/KC, 8-OHdG, matrix metalloproteinase-8 (MMP-8), and MMP-9. The protective actions of andrographolide on CS-predisposed NTHi inflammation might be attributable to increased nuclear factor erythroid-2-related factor 2 (Nrf2) activation and decreased Kelch-like ECH-associated protein 1 (Keap1) repressor function, resulting in enhanced gene expression of antioxidant enzymes including heme oxygenase-1 (HO-1), glutathione reductase (GR), glutathione peroxidase-2 (GPx-2), glutamate-cysteine ligase modifier (GCLM), and NAD(P)H quinone oxidoreductase 1 (NQO1). Taken together, these findings strongly support a therapeutic potential for andrographolide in preventing lung inflammation caused by NTHi in cigarette smokers.


Assuntos
Andrographis/química , Diterpenos/farmacologia , Haemophilus influenzae/efeitos dos fármacos , Nicotiana/efeitos adversos , Plantas Medicinais/química , Fumar/efeitos adversos , Animais , Diterpenos/química , Feminino , Glutamato-Cisteína Ligase/metabolismo , Infecções por Haemophilus/tratamento farmacológico , Heme Oxigenase-1/metabolismo , Humanos , Metaloproteinase 8 da Matriz/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Estrutura Molecular , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Pneumonia/prevenção & controle , Doença Pulmonar Obstrutiva Crônica/patologia , Fator de Necrose Tumoral alfa/metabolismo
14.
Tech Coloproctol ; 18(11): 1023-7, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24925354

RESUMO

BACKGROUND: The aim of this study was to review a consecutive series of patients who had undergone excision of recurrent retrorectal tumours and propose surgical strategies to tackle such recurrences. METHODS: Patients were identified from a prospectively maintained database. Demographic details, preoperative imaging and pathology, intra- and post-operative problems and follow-up details were noted. RESULTS: Fifteen patients (11 females) with a median age of 38 years (range 19-75 years) underwent excision of recurrent retrorectal tumours (13 benign) between 2002 and 2012. The median interval between the first and second surgical procedure was 3.5 years (range 1-19 years). Three patients had surgery performed via the transperineal approach, while 12 patients had resection via the abdominal approach. En bloc resection of adjacent organs was needed in three patients. Major pelvic bleeding occurred in two patients. R0 resection was achieved in all 15 patients, and there have been no subsequent recurrences [median follow-up 73 months (range 12-148 months)]. CONCLUSIONS: Benign recurrent retrorectal tumours can be safely excised usually without sacrifice of adjacent organs, while en bloc resection is needed for malignant tumours.


Assuntos
Procedimentos Cirúrgicos do Sistema Digestório/normas , Recidiva Local de Neoplasia/cirurgia , Guias de Prática Clínica como Assunto , Neoplasias Retais/cirurgia , Adulto , Idoso , Biópsia , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Estudos Prospectivos , Neoplasias Retais/diagnóstico , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto Jovem
15.
Radiography (Lond) ; 29(4): 786-791, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37267841

RESUMO

INTRODUCTION: This study aimed to provide clinically-relevant insights into establishing CT DRLs based on indication-based protocols in Ireland, focusing on CT head examinations performed at a neurology centre of excellence hospital. METHODS: Dose data were collected retrospectively. Typical values for six CT head indication-based protocols were established using a sample size of 50 patients for each protocol. Typical values for each protocol were set as the median of the distribution curve. Dose distributions for each protocol were calculated and compared using non-parametric median test (k-samples) to ascertain significant dose differences between the typical values. RESULTS: Most typical values pairings showed significant differences (p < 0.001) except between stroke/non-vascular brain, stroke/acute brain, and acute brain/non-vascular brain pairings. This was expected due to similar scan parameters. The typical value for stroke (3-phases angiogram) was 52% lower than the typical value for stroke. Dose levels of the male populations recorded were higher than female populations for all protocols. Statistical comparison showed significant differences for dose quantities and/or scan length between both genders in five protocols. CONCLUSION: Proposed values for DLP were up to 63% and 69% lower than the EU and Irish national DRLs respectively. Establishment of CT stroke DRLs should be based on the scan performed instead of number of scan acquisitions. Lastly, gender-based CT DRLs for specific protocols within the head region require further investigation. IMPLICATIONS FOR PRACTICE: With increasing CT examinations worldwide, radiation dose optimisation is key. The value of indication based DRLs is to enhance the required patient protection so image quality can be maintained, however with relevant DRLs for varying protocols. Establishment of CT typical values and site specific DRLs for procedures beyond the national DRLs can drive dose optimisation locally.


Assuntos
Níveis de Referência de Diagnóstico , Acidente Vascular Cerebral , Humanos , Masculino , Feminino , Estudos Retrospectivos , Doses de Radiação , Valores de Referência , Tomografia Computadorizada por Raios X/métodos , Acidente Vascular Cerebral/diagnóstico por imagem
16.
Acta Biomater ; 167: 69-82, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37331613

RESUMO

The role of poroelasticity on the functional performance of articular cartilage has been established in the scientific literature since the 1960s. Despite the extensive knowledge on this topic there remain few attempts to design for poroelasticity and to our knowledge no demonstration of an engineered poroelastic material that approaches the physiological performance. In this paper, we report on the development of an engineered material that begins to approach physiological poroelasticity. We quantify poroelasticity using the fluid load fraction, apply mixture theory to model the material system, and determine cytocompatibility using primary human mesenchymal stem cells. The design approach is based on a fiber reinforced hydrated network and uses routine fabrication methods (electrohydrodynamic deposition) and materials (poly[ɛ-caprolactone] and gelatin) to develop the engineered poroelastic material. This composite material achieved a mean peak fluid load fraction of 68%, displayed consistency with mixture theory, and demonstrated cytocompatibility. This work creates a foundation for designing poroelastic cartilage implants and developing scaffold systems to study chondrocyte mechanobiology and tissue engineering. STATEMENT OF SIGNIFICANCE: Poroelasticity drives the functional mechanics of articular cartilage (load bearing and lubrication). In this work we develop the design rationale and approach to produce a poroelastic material, known as a fiber reinforced hydrated network (FiHy™), that begins to approach the native performance of articular cartilage. This is the first engineered material system capable of exceeding isotropic linear poroelastic theory. The framework developed here enables fundamental studies of poroelasticity and the development of translational materials for cartilage repair.


Assuntos
Cartilagem Articular , Humanos , Condrócitos , Engenharia Tecidual
17.
J Appl Microbiol ; 112(1): 119-31, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21992228

RESUMO

AIMS: To display a liver-specific ligand on the hepatitis B virus core particles for cell-targeting delivery. METHODS AND RESULTS: A liver cell-binding ligand (preS1) was fused at the N-terminal end of the hepatitis B core antigen (HBcAg), but the fusion protein (preS1His(6) HBcAg) was insoluble in Escherichia coli and did not form virus-like particles (VLPs). A method to display the preS1 on the HBcAg particle was established by incorporating an appropriate molar ratio of the truncated HBcAg (tHBcAg) to the preS1His(6) HBcAg. Gold immunomicroscopy showed that the subunit mixture reassembled into icosahedral particles, displaying the preS1 ligand on the surface of VLPs. Fluorescence microscopy revealed that the preS1 ligand delivered the fluorescein-labelled VLPs into the HepG2 cells efficiently. CONCLUSIONS: Chimeric VLPs containing the insoluble preS1His(6) HBcAg and highly soluble tHBcAg were produced by a novel incorporation method. The preS1 ligand was exposed on the surface of the VLPs and was shown to deliver fluorescein molecules into liver cells. SIGNIFICANCE AND IMPACT OF STUDY: The newly established incorporation method can be used in the development of chimeric VLPs that could serve as potential nanovehicles to target various cells specifically by substituting the preS1 ligand with different cell-specific ligands.


Assuntos
Técnicas Genéticas , Antígenos do Núcleo do Vírus da Hepatite B/genética , Antígenos do Núcleo do Vírus da Hepatite B/metabolismo , Hepatócitos/metabolismo , Ligantes , Proteínas Recombinantes de Fusão/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Células HeLa , Células Hep G2 , Humanos , Transporte Proteico , Proteínas Recombinantes de Fusão/genética
18.
J Dairy Sci ; 95(4): 1680-9, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22459816

RESUMO

Flavor development in ripening Cheddar cheese depends on complex microbial and biochemical processes that are difficult to study in natural cheese. Thus, our group has developed Cheddar cheese extract (CCE) as a model system to study these processes. In previous work, we found that CCE supported growth of Lactobacillus casei, one of the most prominent nonstarter lactic acid bacteria (NSLAB) species found in ripening Cheddar cheese, to a final cell density of 10(8) cfu/mL at 37°C. However, when similar growth experiments were performed at 8°C in CCE derived from 4-mo-old cheese (4mCCE), the final cell densities obtained were only about 10(6) cfu/mL, which is at the lower end of the range of the NSLAB population expected in ripening Cheddar cheese. Here, we report that addition of Tween 80 to CCE resulted in a significant increase in the final cell density of L. casei during growth at 8°C and produced concomitant changes in cytoplasmic membrane fatty acid (CMFA) composition. Although the effect was not as dramatic, addition of milk fat or a monoacylglycerol (MAG) mixture based on the MAG profile of milk fat to 4mCCE also led to an increased final cell density of L. casei in CCE at 8°C and changes in CMFA composition. These observations suggest that optimal growth of L. casei in CCE at low temperature requires supplementation with a source of fatty acids (FA). We hypothesize that L. casei incorporates environmental FA into its CMFA, thereby reducing its energy requirement for growth. The exogenous FA may then be modified or supplemented with FA from de novo synthesis to arrive at a CMFA composition that yields the functionality (i.e., viscosity) required for growth in specific conditions. Additional studies utilizing the CCE model to investigate microbial contributions to cheese ripening should be conducted in CCE supplemented with 1% milk fat.


Assuntos
Membrana Celular/química , Queijo/microbiologia , Ácidos Graxos/administração & dosagem , Lacticaseibacillus casei/crescimento & desenvolvimento , Leite/química , Animais , Ácidos Graxos/análise , Manipulação de Alimentos/métodos , Tecnologia de Alimentos/métodos , Lacticaseibacillus casei/ultraestrutura , Modelos Biológicos , Paladar , Temperatura
19.
Poult Sci ; 89(12): 2589-96, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21076096

RESUMO

The efficacy of bacteriophage EC1, a lytic bacteriophage, against Escherichia coli O78:K80, which causes colibacillosis in poultry, was determined in the present study. A total of 480 one-day-old birds were randomly assigned to 4 treatments groups, each with 4 pens of 30 birds. Birds from the control groups (groups I and II) received PBS (pH 7.4) or 10(10) pfu of bacteriophage EC1, respectively. Group III consisted of birds challenged with 10(8) cfu of E. coli O78:K80 and treated with 10(10) pfu of bacteriophage EC1 at 2 h postinfection, whereas birds from group IV were challenged with 10(8) cfu of E. coli O78:K80 only. All the materials were introduced into the birds by intratracheal inoculation. Based on the results of the present study, the infection was found to be less severe in the treated E. coli-challenged group. Mean total viable cell counts of E. coli identified on eosin methylene blue agar (designated EMB + E. coli) in the lungs were significantly lower in treated, E. coli-challenged birds than in untreated, E. coli-challenged birds on d 1 and 2 postinfection. The EMB + E. coli isolation frequency was also lower in treated birds; no E. coli was detectable in blood samples on any sampling day, and E. coli were isolated only in the liver, heart, and spleen of treated chickens at a ratio of 2/6, 1/6, and 3/6, respectively, at d 1 postinfection. The BW of birds from the E. coli-challenged group treated with bacteriophage EC1 were not significantly different from those of birds from both control groups but were 15.4% higher than those of the untreated, E. coli-challenged group on d 21 postinfection. The total mortality rate of birds during the 3-wk experimental period decreased from 83.3% in the untreated, E. coli-challenged birds (group IV) to 13.3% in birds treated with bacteriophage EC1 (group III). These results suggest that bacteriophage EC1 is effective in vivo and could be used to treat colibacillosis in chickens.


Assuntos
Bacteriófagos/isolamento & purificação , Galinhas/microbiologia , Infecções por Escherichia coli/veterinária , Doenças das Aves Domésticas/microbiologia , Animais , Bacteriófagos/genética , Bacteriófagos/patogenicidade , Sangue/microbiologia , Galinhas/virologia , Escherichia coli/isolamento & purificação , Escherichia coli/virologia , Infecções por Escherichia coli/patologia , Infecções por Escherichia coli/terapia , Infecções por Escherichia coli/transmissão , Amplificação de Genes , Coração/microbiologia , Fígado/microbiologia , Fígado/patologia , Pulmão/microbiologia , Pulmão/patologia , Miocárdio/patologia , Doenças das Aves Domésticas/mortalidade , Doenças das Aves Domésticas/terapia , Doenças das Aves Domésticas/virologia , Baço/microbiologia , Baço/patologia
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