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1.
J Am Geriatr Soc ; 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32010977

RESUMO

OBJECTIVES: Emergency department (ED) visits among older adults are frequently instigated by a fall at home. Some of these patients develop intracranial bleeding. The aim of this study was to identify the incidence of intracranial bleeding and the associated clinical features in older adults who present to the ED after falling. DESIGN: Prospective cohort study. SETTING: Three Canadian EDs. PARTICIPANTS: A total of 2 176 patients age 65 years or older who presented to the ED with a fall were assessed, and 1753 were included. Inclusion criteria were a fall on level ground, off a bed, chair, or toilet, or from one or two steps within 48 hours. MEASUREMENTS: Emergency physicians recorded predefined clinical findings on initial assessment. The primary outcome was intracranial bleeding, diagnosed either by computed tomography at the index visit or within 42 days. Associations between baseline clinical findings and the presence of intracranial bleeding were assessed with multivariable logistic regression. RESULTS: A total of 1753 patients (median age = 82 y) were enrolled, of whom 39% were male, 35% were on antiplatelet therapy, and 25% were on an anticoagulant. The incidence of intracranial bleeding was 5.0% (95% confidence interval [CI] = 4.1-6.1). Overall, 76 patients were diagnosed at the index ED visit, and 12 were diagnosed during follow-up. Multivariable regression identified four clinical variables that were independently associated with intracranial bleeding: new abnormalities on neurologic examination (odds ratio [OR] = 4.4; 95% CI = 2.4-8.1), bruise or laceration on the head (OR = 4.3; 95% CI = 2.7-7.0), chronic kidney disease (OR = 2.4; 95% CI = 1.3-4.6), and reduced Glasgow Coma Scale from normal (OR = 1.9; 95% CI = 1.0-3.4). CONCLUSION: The incidence of intracranial bleeding in our study was 5.0%. We found significant associations between intracranial bleeding and four simple clinical variables. We did not find significant associations between intracranial bleeding and antiplatelet or anticoagulant use.

2.
Toxicol Pathol ; 48(2): 317-322, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31801420

RESUMO

Reticulum cell hyperplasia (RCH) was a term used for many years by the National Toxicology Program (NTP) to describe a certain non-neoplastic bone marrow lesion of rats. Retrospective microscopic evaluation of RCH lesions and immunohistochemistry analyses were performed to reassess and further characterize these lesions. The NTP database was searched to identify femoral bone marrow specimens diagnosed with RCH from 1981 to 2014 (n = 254). The diagnosis last occurred in 2003, after which the term "cellular infiltration" was used. Eighty-three RCH slides, spanning 22 years, representing 34 different chemicals, were selected for microscopic review, and a subset (23) was chosen for ionized calcium binding adapter molecule 1 (Iba1) immunohistochemical staining; initial investigations revealed Iba1 worked as a macrophage marker on decalcified tissue. The following diagnoses were made upon reevaluation: 36 were consistent with cellularity increased, macrophage, 22 with histiocytic sarcoma, 8 with increased myeloid cells, 4 with autolysis, and 13 were normal appearance. All 23 RCH lesions stained positive for Iba1. Fifty-eight of 83 bone marrows previously diagnosed with RCH are consistent morphologically and immunohistochemically with cells of histiocytic origin. These results will help with interpretation of historical data and demonstrates that Iba1 can be used in decalcified bone marrow sections.

3.
Front Genet ; 9: 499, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30405704

RESUMO

Whilst cross-talk between stroma and epithelium is critical for tissue development and homeostasis, aberrant paracrine stimulation can result in neoplastic transformation. Chronic stimulation of epithelial cells with paracrine Fibroblast Growth Factor 10 (FGF10) has been implicated in multiple cancers, including breast, prostate and pancreatic ductal adenocarcinoma. Here, we examine the mechanisms underlying FGF10-induced tumourigenesis and explore novel approaches to target FGF10 signaling in cancer.

4.
Curr Obstet Gynecol Rep ; 7(2): 97-105, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30319927

RESUMO

Purpose of Review: Uterine fibroids are common benign tumors of women in the USA and worldwide, yet the biological nature and pathogenesis of these tumors remain largely unknown. This review presents our view of the stages in the life cycle of a subset of uterine fibroid myocytes, introduces hypothetical concepts and morphological data to explain these changes, and relates these changes in individual myocytes to the phases of fibroid tumor development. Recent Findings: The observations gained from light and electron microscopic, immunohistochemical, and morphometric studies in our laboratory have led to the hypothesis that fibroid changes over time may relate to the excessive production of collagen by phenotypically transformed myocytes. This accumulation of collagen results in decreased microvessel density, followed by myocyte injury and atrophy, with eventual senescence and involution through ischemic cellular degeneration and inanition. Summary: Uterine leiomyomas, or fibroids, are characterized by two histologic features-proliferation of myocytes and production of an extracellular collagenous matrix. In the larger tumors, the collagenous matrix is often abundant. Within those regions in which the accumulating collagen is excessive, the myocytes are progressively separated from their blood supply, resulting in myocyte atrophy and eventually cell death. It is within these hypocellular, hyalinized areas that the complete lifecycle of the fibroid myocyte is realized. It begins with the phenotypic transformation of a contractile cell to one characterized by proliferation and collagen synthesis, progresses through an intermediate stage of atrophy related to interstitial ischemia, and eventuates in cell death due to inanition. Lastly, resorption of inanotic cells appears to occur by a non-phagocytic, presumably enzymatic process of degradation and recycling that we refer to as reclamation.

5.
Toxicol Pathol ; 46(6): 653-659, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30089414

RESUMO

The use of three-dimensional (3-D) in vitro culture systems (spheroids, organoids) in biomolecular and drug discovery research has become increasingly popular. The popularity is due, in part, to a diminished reliance on animal bioassays and a desire to develop physiologically relevant cell culture systems that simulate the in vivo tissue microenvironment. Most evaluations of 3-D cultures are by confocal microscopy and high-content imaging; however, these technologies do not allow for detailed cellular morphologic assessments or permit basic hematoxylin and eosin histologic evaluations. There are few studies that have reported detailed processes for preparing 3-D cultures for paraffin embedding and subsequent use for histochemical or immunohistochemical staining. In an attempt to do so, we have developed a protocol to paraffin-embed human liver spheroids that can be sectioned with a microtome and mounted onto glass slides for routine histochemical and immunohistochemical staining and light microscopic evaluations.


Assuntos
Técnicas de Cultura de Células/métodos , Imuno-Histoquímica/métodos , Fígado/citologia , Microscopia , Esferoides Celulares/ultraestrutura , Técnicas de Cultura de Células/instrumentação , Linhagem Celular Tumoral , Humanos , Imuno-Histoquímica/instrumentação , Inclusão em Parafina , Coloração e Rotulagem
6.
CMAJ ; 190(33): E974-E984, 2018 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-30127037

RESUMO

BACKGROUND: Testing for high-sensitivity cardiac troponin (hs-cTn) may assist triage and clinical decision-making in patients presenting to the emergency department with symptoms of acute coronary syndrome; however, this could result in the misclassification of risk because of analytical variation or laboratory error. We sought to evaluate a new laboratory-based risk-stratification tool that incorporates tests for hs-cTn, glucose level and estimated glomerular filtration rate to identify patients at risk of myocardial infarction or death when presenting to the emergency department. METHODS: We constructed the clinical chemistry score (CCS) (range 0-5 points) and validated it as a predictor of 30-day myocardial infarction (MI) or death using data from 4 cohort studies involving patients who presented to the emergency department with symptoms suggestive of acute coronary syndrome. We calculated diagnostic parameters for the CCS score separately using high-sensitivity cardiac troponin I (hs-cTnI) and high-sensitivity cardiac troponin T (hs-cTnT). RESULTS: For the combined cohorts (n = 4245), 17.1% of participants had an MI or died within 30 days. A CCS score of 0 points best identified low-risk participants: the hs-cTnI CCS had a sensitivity of 100% (95% confidence interval [CI] 99.5%-100%), with 8.9% (95% CI 8.1%-9.8%) of the population classified as being at low risk of MI or death within 30 days; the hs-cTnT CCS had a sensitivity of 99.9% (95% CI 99.2%-100%), with 10.5% (95% CI 9.6%-11.4%) of the population classified as being at low risk. The CCS had better sensitivity than hs-cTn alone (hs-cTnI < 5 ng/L: 96.6%, 95% CI 95.0%-97.8%; hs-cTnT < 6 ng/L: 98.2%, 95% CI 97.0%-99.0%). A CCS score of 5 points best identified patients at high risk (hs-cTnI CCS: specificity 96.6%, 95% CI 96.0%-97.2%; 11.2% [95% CI 10.3%-12.2%] of the population classified as being at high risk; hs-cTnT CCS: specificity 94.0%, 95% CI 93.1%-94.7%; 13.1% [95% CI 12.1%-14.1%] of the population classified as being at high risk) compared with using the overall 99th percentiles for the hs-cTn assays (specificity of hs-cTnI 93.2%, 95% CI 92.3-94.0; specificity of hs-cTnT 73.8%, 95% CI 72.3-75.2). INTERPRETATION: The CCS score at the chosen cut-offs was more sensitive and specific than hs-cTn alone for risk stratification of patients presenting to the emergency department with suspected acute coronary syndrome. Study registration: ClinicalTrials.gov, nos. NCT01994577; NCT02355457.


Assuntos
Síndrome Coronariana Aguda/diagnóstico , Técnicas de Laboratório Clínico , Miocárdio/química , Troponina I/análise , Troponina T/análise , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Glicemia/análise , Morte , Serviço Hospitalar de Emergência , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Tempo
7.
Toxicol Pathol ; 46(5): 488-510, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29966501

RESUMO

Immunohistochemistry (IHC) is a valuable tool in pathology. This review provides a brief description of the technical aspects of IHC and a detailed discussion on the variables that affect the results, interpretation, and reproducibility of IHC results. Lists of antibodies that have and have not worked in IHC on various mouse and rat tissues in our laboratory are provided as a guidance for selection of antibodies. An approach to IHC method optimization is presented. Finally, the critical information that should be included as a part of peer-reviewed manuscript is also discussed.


Assuntos
Técnicas de Laboratório Clínico/métodos , Imuno-Histoquímica/métodos , Patologia/métodos , Toxicologia/métodos , Animais , Anticorpos/química , Humanos , Camundongos , Ratos , Reprodutibilidade dos Testes , Fixação de Tecidos
8.
Cell Rep ; 22(9): 2469-2481, 2018 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-29490281

RESUMO

Development of resistance causes failure of drugs targeting receptor tyrosine kinase (RTK) networks and represents a critical challenge for precision medicine. Here, we show that PHLDA1 downregulation is critical to acquisition and maintenance of drug resistance in RTK-driven cancer. Using fibroblast growth factor receptor (FGFR) inhibition in endometrial cancer cells, we identify an Akt-driven compensatory mechanism underpinned by downregulation of PHLDA1. We demonstrate broad clinical relevance of our findings, showing that PHLDA1 downregulation also occurs in response to RTK-targeted therapy in breast and renal cancer patients, as well as following trastuzumab treatment in HER2+ breast cancer cells. Crucially, knockdown of PHLDA1 alone was sufficient to confer de novo resistance to RTK inhibitors and induction of PHLDA1 expression re-sensitized drug-resistant cancer cells to targeted therapies, identifying PHLDA1 as a biomarker for drug response and highlighting the potential of PHLDA1 reactivation as a means of circumventing drug resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias do Endométrio/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Fatores de Transcrição/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias do Endométrio/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Lapatinib/farmacologia , Modelos Biológicos , Fosfoproteínas/metabolismo , Proteômica , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Transcrição/genética , Trastuzumab/farmacologia
9.
Clin Chim Acta ; 479: 166-170, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29366835

RESUMO

BACKGROUND: Clinicians regularly observe increased high-sensitivity cardiac troponin (hs-cTn) concentrations in patients with low estimated glomerular filtration rate (eGFR). The challenge is to differentiate acute coronary syndrome (ACS) from increased hs-cTn results across a range of eGFR. The objective of this study was to determined the optimal hs-cTn concentrations for acute myocardial infarction (MI) and a composite cardiovascular outcome across different eGFR ranges and to assess the utility of a low hs-cTn cutoff to rule-out events. METHODS: We undertook an observational study in the emergency department of patients (n = 1212) with symptoms suggestive of ACS who had an eGFR and at least one Roche hs-cTnT and one Abbott hs-cTnI result. The 7-day outcomes were MI or a composite of MI, unstable angina, congestive heart failure, serious ventricular cardiac arrhythmia, or death. The maximum hs-cTn concentration was assessed across different eGFR ranges (<30,30-59,60-89,≥90 ml/min/1.73m2) by spearman correlation, ROC-curve analyses, and sensitivity and negative predictive value (NPV) for the proposed rule-out hs-cTn cutoffs (hs-cTnI<5 ng/l and hs-cTnT<6 ng/l) for the outcomes. RESULTS: Both hs-cTnI and hs-cTnT concentrations were negatively correlated with eGFR. The lower the eGFR, the lower the AUC and the higher the optimal hs-cTn cutoffs for both MI and the composite outcome. The highest combined sensitivity (100%), NPV (100%) and proportion of low-risk for MI (45% of group) was observed for patients with hs-cTnT<6 ng/l with an eGFR≥90. CONCLUSION: The test performance for hs-cTn for diagnosing or ruling-out an acute cardiac event varies per the eGFR. Accurate risk stratification requires knowledge of the eGFR.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Serviço Hospitalar de Emergência , Taxa de Filtração Glomerular , Infarto do Miocárdio/sangue , Troponina I/sangue , Troponina T/sangue , Estudos de Coortes , Humanos , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/cirurgia
10.
Ann Clin Biochem ; 55(5): 604-607, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29169258

RESUMO

Background There is interest in utilizing different cut-offs per sex for high-sensitivity cardiac troponin I (hs-cTnI) but less so for high-sensitivity cardiac troponin T (hs-cTnT) for patient management in the acute setting. Our objective was to assess if differences in hs-cTn concentrations exist between males and females for an acute cardiac outcome following the presentation measurement in the emergency department. Methods An observational emergency department population with hs-cTn measurements (Roche Diagnostics and Abbott Diagnostics) at presentation with seven-day outcomes for a composite acute cardiac outcome (i.e. myocardial infarction, unstable angina, ventricular arrhythmia, heart failure or cardiovascular death) (ClinicalTrials.gov: NCT01994577). Receiver operating characteristic curve analyses were performed for each sex with both hs-cTn assays. Results In those patients who had a composite acute cardiac outcome ( n = 128 females; n = 145 males), there was no difference in hs-cTn concentrations between the sexes (median [IQR] female hs-cTnT = 35 ng/L [21-69] vs. male hs-cTnT = 38 ng/L [19-77], P = 0.95; and median [IQR] female hs-cTnI = 27 ng/L [12-75] vs. male hs-cTnI = 26 ng/L [12-85], P = 0.97]. There was also no difference in the area under the curve between the hs-cTn assays and between the sexes ( P > 0.10). Comparing hs-cTn concentrations in those patients with the composite outcome between the sexes <60 years and ≥60 years of age also did not yield significant differences ( P > 0.70). Conclusions The concentrations and area under the curves of hs-cTnT and hs-cTnI at patient presentation in the emergency department for an acute composite cardiac outcome were similar between the sexes in this exploratory study.


Assuntos
Cardiopatias/diagnóstico , Troponina I/sangue , Troponina T/sangue , Idoso , Idoso de 80 Anos ou mais , Serviço Hospitalar de Emergência , Feminino , Humanos , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Curva ROC , Fatores Sexuais
11.
JCI Insight ; 2(16)2017 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-28814662

RESUMO

The pathogenesis of primary Sjogren's syndrome (SS), an autoimmune disease that targets the mucosa of exocrine tissues, is poorly understood. Although several mouse models have been developed that display features of SS, most of these are within the larger context of a lupus-like presentation. Immunity-related GTPase family M protein 1 (Irgm1) is an interferon-inducible cytoplasmic GTPase that is reported to regulate autophagy and mitochondrial homeostasis. Here, we report that naive Irgm1-/- mice display lymphocytic infiltration of multiple mucosal tissues including the lung in a manner reminiscent of SS, together with IgA class-predominant autoantibodies including anti-Ro and anti-La. This phenotype persists in the germ-free state, but is abolished by deletion of Irgm3. Irgm1-/- mice have increased local production in the lung of TECP15-idiotype IgA, a natural antibody with dual reactivity against host and pneumococcal phosphorylcholine. Associated with this, Irgm1-/- mice display enhanced opsonization and clearance of Streptococcus pneumoniae from the lung and increased survival from pneumococcal pneumonia. Taken together, our results identify Irgm1 as a master regulator of mucosal immunity that dually modulates evolutionarily conserved self- and other-directed immune responses at the interface of host with environment.

12.
Can J Cardiol ; 33(7): 898-903, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28668141

RESUMO

The optimal high-sensitivity cardiac troponin (hs-cTn) cutoffs for determining risk in patients who present with acute coronary syndrome symptoms are unknown. In 1137 emergency department patients we calculated adjusted relative risks for a composite outcome (myocardial infarction, unstable angina, heart failure, ventricular arrhythmia, or cardiovascular death) within 7 days for the presentation of hs-cTnT (Roche) and hs-cTnI (Abbott) assay concentrations on the basis of literature cutoffs. Patients with hs-cTn concentrations ≥ 14 ng/L had an adjusted relative risk of 4.9 for the composite outcome, with different hs-cTnT/hs-cTnI concentration ranges yielding higher risks. A common low-risk cutoff of 14 ng/L may be used for hs-cTn with higher cutoffs identifying high-risk patients.


Assuntos
Serviço Hospitalar de Emergência , Cardiopatias/diagnóstico , Troponina I/sangue , Doença Aguda , Biomarcadores/sangue , Causas de Morte/tendências , Seguimentos , Cardiopatias/sangue , Cardiopatias/epidemiologia , Humanos , Incidência , Ontário/epidemiologia , Prevalência , Estudos Prospectivos , Curva ROC , Reprodutibilidade dos Testes , Fatores de Risco , Taxa de Sobrevida/tendências
13.
Clin Chim Acta ; 469: 69-74, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28342713

RESUMO

BACKGROUND: We evaluated whether a low high-sensitivity cardiac troponin (hs-cTn) cutoff combined with glucose, red cell distribution width (RDW), and the estimated glomerular filtration rate (eGFR) can be used to rule-out a serious cardiac outcome or death in patients presenting with symptoms suggestive of acute coronary syndrome (ACS). METHODS: This was a prospective observational emergency department (ED) study enrolling consecutive patients presenting with symptoms suggestive of ACS (ClinicalTrials.gov: NCT01994577). The primary outcome was a 7-day composite of myocardial infarction, unstable angina, decompensated congestive heart failure, serious ventricular cardiac arrhythmia, or death. A laboratory score combining glucose, RDW, eGFR with hs-cTnT (Roche) or hs-cTnI (Abbott) was compared to hs-cTn alone using the limit of detection (LoD; hs-cTnT<5ng/l/hs-cTnI<2ng/l) as the cutoff. A benchmark of >99% sensitivity was used to assess the laboratory panel with hs-cTn versus the LoD alone to identify low-risk patients suitable for discharge. RESULTS: A total of 1095 patients (n=267 composite-outcomes) had measurements of glucose, RDW, eGFR, hs-cTnT, and hs-cTnI at presentation. Applying the hs-cTn LoD alone as the cutoff missed 5 composite-outcomes (sensitivity=98.1%), however the addition of the laboratory panel to the hs-cTn LoD increased the sensitivity to >99% with approximately 10% of the population identified as low-risk. The percentage of low-risk patients was increased to 15% (1 composite-outcome missed) when employing a low measurable hs-cTnI cutoff with the laboratory panel (laboratory score<2 points). CONCLUSION: A laboratory score with hs-cTn may identify low-risk patients suitable for ED discharge at presentation.


Assuntos
Síndrome Coronariana Aguda/diagnóstico , Técnicas de Laboratório Clínico , Miocárdio/metabolismo , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/metabolismo , Síndrome Coronariana Aguda/fisiopatologia , Adulto , Glicemia/metabolismo , Morte , Serviço Hospitalar de Emergência , Contagem de Eritrócitos , Taxa de Filtração Glomerular , Humanos , Prognóstico , Troponina/metabolismo
14.
Clin Chem ; 63(1): 403-414, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28062631

RESUMO

BACKGROUND: Early rule-in/rule-out of myocardial infarction (MI) in patients presenting to the emergency department (ED) is important for patient care and resource allocation. Given that dysglycemia is a strong risk factor for MI, we sought to explore and compare different combinations of cardiac troponin (cTn) cutoffs with glycemic markers for the early rule-in/rule-out of MI. METHODS: We included ED patients (n = 1137) with symptoms suggestive of acute coronary syndrome (ACS) who had cTnI, high-sensitivity cTnI (hs-cTnI), hs-cTnT, glucose, and hemoglobin A1c (Hb A1c) measurements. We derived rule-in/rule-out algorithms using different combinations of ROC-derived and literature cutoffs for rule-in and rule-out of MI within 7 days after presentation. These algorithms were then tested for MI/cardiovascular death and ACS/cardiovascular death at 7 days. ROC curves, sensitivity, specificity, likelihood ratios, positive and negative predictive values (PPV and NPV), and CIs were determined for various biomarker combinations. RESULTS: MI was diagnosed in 133 patients (11.7%; 95% CI, 9.8-13.8). The algorithms that included cTn and glucose produced the greatest number of patients ruled out/ruled in for MI and yielded sensitivity ≥99%, NPV ≥99.5%, specificity ≥99%, and PPV ≥80%. This diagnostic performance was maintained for MI/cardiovascular death but not for ACS/cardiovascular death. The addition of hemoglobin A1c (Hb A1c) (≥6.5%) to these algorithms did not change these estimates; however, 50 patients with previously unknown diabetes may have been identified if Hb A1c was measured. CONCLUSIONS: Algorithms incorporating glucose with cTn may lead to an earlier MI diagnosis and rule-out for MI/cardiovascular death. Addition of Hb A1c into these algorithms allows for identification of diabetes. Future studies extending these findings are needed for ACS/cardiovascular death. ClinicalTrials.gov identifier: NCT01994577.


Assuntos
Síndrome Coronariana Aguda/diagnóstico , Glicemia/análise , Infarto do Miocárdio/diagnóstico , Troponina I/sangue , Troponina T/sangue , Síndrome Coronariana Aguda/sangue , Idoso , Algoritmos , Biomarcadores/sangue , Estudos de Coortes , Feminino , Humanos , Masculino , Infarto do Miocárdio/sangue , Curva ROC
15.
Clin Chem ; 63(2): 593-602, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27811206

RESUMO

BACKGROUND: We have previously demonstrated the utility of a rule-in/rule-out strategy for myocardial infarction (MI) using glycemic biomarkers in combination with cardiac troponin in the emergency department (ED). Given that the cost of assessing patients with possible MI in the ED is increasing, we sought to compare the health services cost of our previously identified early rule-in/rule-out approaches for MI among patients who present to the ED with symptoms suggestive of acute coronary syndrome (ACS). METHODS: We compared the cost differences between different rule-in/rule-out strategies for MI using presentation cardiac troponin I (cTnI), high-sensitivity cTnI (hs-cTnI), high-sensitivity cardiac troponin T (hs-cTnT), glucose, and/or hemoglobin A1c (Hb A1c) in 1137 ED patients (7-day MI n = 133) as per our previously defined algorithms and compared them with the European Society of Cardiology (ESC) 0-h algorithm-cutoffs. Costs associated with each decision model were obtained from site-specific sources (length of stay) and provincial sources (Ontario Case Costing Initiative). RESULTS: Algorithms incorporating cardiac troponin and glucose for early rule-in/rule-out were the most cost effective and clinically safest methods (i.e., ≤1 MI missed) for early decision making, with hs-cTnI and glucose yielding lower costs compared to cTnI and glucose, despite the higher price for the hs-cTnI test. The addition of Hb A1c to the algorithms increased the cost of these algorithms but did not miss any additional patients with MI. Applying the ESC 0-h algorithm-cutoffs for hs-cTnI and hs-cTnT were the most costly. CONCLUSIONS: Rule-in/rule-out algorithms incorporating presentation glucose with high-sensitivity cardiac troponin are the safest and most cost-effective options as compared to the ESC 0-h algorithm-cutoffs.


Assuntos
Algoritmos , Glicemia/análise , Serviço Hospitalar de Emergência/economia , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/economia , Troponina I/sangue , Troponina T/sangue , Biomarcadores/análise , Estudos de Coortes , Humanos , Infarto do Miocárdio/sangue , Troponina I/economia , Troponina T/economia
16.
J Biol Chem ; 291(35): 18310-25, 2016 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-27334922

RESUMO

Aberrant Ras signaling drives numerous cancers, and drugs to inhibit this are urgently required. This compelling clinical need combined with recent innovations in drug discovery including the advent of biologic therapeutic agents, has propelled Ras back to the forefront of targeting efforts. Activated Ras has proved extremely difficult to target directly, and the focus has moved to the main downstream Ras-signaling pathways. In particular, the Ras-Raf and Ras-PI3K pathways have provided conspicuous enzyme therapeutic targets that were more accessible to conventional drug-discovery strategies. The Ras-RalGEF-Ral pathway is a more difficult challenge for traditional medicinal development, and there have, therefore, been few inhibitors reported that disrupt this axis. We have used our structure of a Ral-effector complex as a basis for the design and characterization of α-helical-stapled peptides that bind selectively to active, GTP-bound Ral proteins and that compete with downstream effector proteins. The peptides have been thoroughly characterized biophysically. Crucially, the lead peptide enters cells and is biologically active, inhibiting isoform-specific RalB-driven cellular processes. This, therefore, provides a starting point for therapeutic inhibition of the Ras-RalGEF-Ral pathway.


Assuntos
Isoenzimas/antagonistas & inibidores , Peptídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas ral de Ligação ao GTP/antagonistas & inibidores , Linhagem Celular , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/genética , Peptídeos/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas ral de Ligação ao GTP/genética , Proteínas ral de Ligação ao GTP/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismo
17.
Toxicol Pathol ; 44(1): 71-87, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26682919

RESUMO

Vinylidene chloride (VDC) has been widely used in the production of plastics and flame retardants. Exposure of B6C3F1 mice to VDC in the 2-year National Toxicology Program carcinogenicity bioassay resulted in a dose-dependent increases in renal cell hyperplasia, renal cell adenoma, and renal cell carcinomas (RCCs). Among those differentially expressed genes from controls and RCC of VDC-exposed mice, there was an overrepresentation of genes from pathways associated with chronic xenobiotic and oxidative stress as well as c-Myc overexpression and dysregulation of TP53 cell cycle checkpoint and DNA damage repair pathways in RCC. Trend analysis comparing RCC, VDC-exposed kidney, and chamber control kidney showed a conservation of pathway dysregulation in terms of overrepresentation of xenobiotic and oxidative stress, and DNA damage and cell cycle checkpoint pathways in both VDC-exposed kidney and RCC, suggesting that these mechanisms play a role in the pathogenesis of RCC in VDC-exposed mice.


Assuntos
Carcinoma de Células Renais , Dicloroetilenos/toxicidade , Neoplasias Renais , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Animais , Carcinoma de Células Renais/induzido quimicamente , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/fisiopatologia , Relação Dose-Resposta a Droga , Feminino , Perfilação da Expressão Gênica , Rim/efeitos dos fármacos , Rim/patologia , Neoplasias Renais/induzido quimicamente , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Neoplasias Renais/fisiopatologia , Masculino , Camundongos , Mutação , Testes de Toxicidade Crônica , Proteína Supressora de Tumor p53/metabolismo
18.
Toxicol Pathol ; 43(5): 681-93, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25452433

RESUMO

Methyl eugenol induces neuroendocrine (NE) cell hyperplasia and tumors in F344/N rat stomach. Detailed histopathological and immunohistochemical (IHC) characterization of these tumors has not been previously reported. The objective of this study was to fill that data gap. Archived slides and paraffin blocks were retrieved from the National Toxicology Program Archives. NE hyperplasias and tumors were stained with chromogranin A, synaptophysin, amylase, gastrin, H(+)/K(+) adenosine triphosphatase (ATPase), pepsinogen, somatostatin, and cytokeratin 18 (CK18) antibodies. Many of the rats had gastric mucosal atrophy, due to loss of chief and parietal cells. The hyperplasias and tumors were confined to fundic stomach, and females were more affected than the males. Hyperplasia of NE cells was not observed in the pyloric region. Approximately one-third of the females with malignant NE tumors had areas of pancreatic acinar differentiation. The rate of metastasis was 21%, with liver being the most common site of metastasis. Immunohistochemically, the hyperplasias and tumors stained consistently with chromogranin A and synaptophysin. Neoplastic cells were also positive for amylase and CK18 and negative for gastrin, somatostatin, H(+)/K(+) ATPase, and pepsinogen. Metastatic neoplasms histologically similar to the primary neoplasm stained positively for chromogranin A and synaptophysin. Based on the histopathological and IHC features, the neoplasms appear to arise from enterochromaffin-like cells.


Assuntos
Eugenol/análogos & derivados , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Animais , Eugenol/toxicidade , Feminino , Imuno-Histoquímica , Masculino , Células Neuroendócrinas/efeitos dos fármacos , Células Neuroendócrinas/metabolismo , Células Neuroendócrinas/patologia , Tumores Neuroendócrinos/induzido quimicamente , Ratos , Ratos Endogâmicos F344 , Neoplasias Gástricas/induzido quimicamente
19.
Dementia (London) ; 14(1): 63-79, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24339090

RESUMO

We studied caregivers' willingness-to-pay for Alzheimer's disease drug therapy. We recruited 216 caregivers of persons with mild or moderate Alzheimer's disease and presented them with four scenarios describing a hypothetical Alzheimer's disease medication. The scenarios described the medication as capable of either treating the symptoms of disease or modifying the course of disease. The scenarios also presented two different probabilities of adverse effects occurrence, i.e., 0% or 30%. Most caregivers said they would pay out-of-pocket for the medication, with support for such payment ranging from 68% to 93%, depending on the specific scenario. The highest level of support was for the 'disease modifying and no adverse effects' scenario, while the lowest level was for the 'symptom treatment and 30% chance of adverse effects' scenario. On average, caregivers' monthly willingness-to-pay out-of-pocket for the medication ranged from $214 to $277 (Canadian dollars). Dollar amounts were highest for the 'disease modifying and no adverse effects' scenario and lowest for the 'symptom treatment and 30% chance of adverse effects' scenario. Support for out-of-pocket payment and specific dollar amounts were highest when the medication did not involve adverse effects. Caregivers placed more value on the absence of adverse effects than on drug efficacy.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/economia , Cuidadores , Financiamento Pessoal , Idoso , Canadá , Análise Custo-Benefício , Tratamento Farmacológico/economia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários
20.
Toxicol Pathol ; 43(2): 171-85, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24958746

RESUMO

A majority (∼80%) of human malignant mesotheliomas are asbestos-related. However, non-asbestos risk factors (radiation, chemicals, and genetic factors) account for up to 30% of cases. A recent 2-year National Toxicology Program carcinogenicity bioassay showed that male F344/N rats exposed to the industrial toxicant vinylidene chloride (VDC) resulted in a marked increase in malignant mesothelioma. Global gene expression profiles of these tumors were compared to spontaneous mesotheliomas and the F344/N rat mesothelial cell line (Fred-PE) in order to characterize the molecular features and chemical-specific profiles of mesothelioma in VDC-exposed rats. As expected, mesotheliomas from control and VDC-exposed rats shared pathways associated with tumorigenesis, including cellular and tissue development, organismal injury, embryonic development, inflammatory response, cell cycle regulation, and cellular growth and proliferation, while mesotheliomas from VDC-exposed rats alone showed overrepresentation of pathways associated with pro-inflammatory pathways and immune dysfunction such as the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway, interleukin (IL)-8 and IL-12 signaling, interleukin responses, Fc receptor signaling, and natural killer and dendritic cells signaling, as well as overrepresentation of DNA damage and repair. These data suggest that a chronic, pro-inflammatory environment associated with VDC exposure may exacerbate disturbances in oncogene, growth factor, and cell cycle regulation, resulting in an increased incidence of mesothelioma.


Assuntos
Dicloroetilenos/toxicidade , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Doenças do Sistema Imunitário/induzido quimicamente , Inflamação/induzido quimicamente , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/genética , Mesotelioma/induzido quimicamente , Mesotelioma/genética , Animais , Linhagem Celular Tumoral , Dano ao DNA , Feminino , Genes cdc/efeitos dos fármacos , Doenças do Sistema Imunitário/imunologia , Inflamação/fisiopatologia , Masculino , Análise em Microsséries , Neoplasias Peritoneais/induzido quimicamente , Neoplasias Peritoneais/patologia , RNA Neoplásico/biossíntese , Ratos , Ratos Endogâmicos F344 , Transdução de Sinais/efeitos dos fármacos , Neoplasias Testiculares/induzido quimicamente , Neoplasias Testiculares/patologia
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