Under-recognition of angina by physicians may result in undertreatment with revascularization or medications that could improve patients' quality of life. We sought to describe characteristics ...associated with under-recognition of patients' angina.
Patients with coronary disease from 25 US cardiology outpatient practices completed the Seattle Angina Questionnaire before their clinic visit, quantifying their frequency of angina during the previous month. Immediately after the clinic visit, physicians independently quantified their patients' angina. Angina frequency was categorized as none, monthly, and daily/weekly. Among 1257 patients, 411 reported angina in the previous month, of whom 173 (42%) were under-recognized by their physician, defined as the physician reporting a lower frequency category of angina than the patient. In a hierarchical logistic model, heart failure (odds ratio, 3.06, 95% confidence interval, 1.89-4.95) and less-frequent angina (odds ratio for monthly angina versus daily/weekly, 1.69; 95% confidence interval, 1.12-2.56) were associated with greater odds of under-recognition. No other patient or physician factors were associated with under-recognition. Significant variability across physicians (median odds ratio, 2.06) was observed.
Under-recognition of angina is common in routine clinical practice. Although patients with less-frequent angina and those with heart failure more often had their angina under-recognized, most variation was unrelated to patient and physician characteristics. The large variation across physicians suggests that some physicians are more accurate in assessing angina frequency than others. Standardized prospective use of a validated clinical tool, such as the Seattle Angina Questionnaire, should be tested as a means to improve recognition of angina and, potentially, improve appropriate treatment of angina.
The transactivator of transcription (Tat) is a HIV regulatory protein which promotes viral replication and chemotaxis. HIV-1 shows extensive genetic diversity, HIV-1 subtype C being the most dominant ...subtype in the world. Our hypothesis is the frequency of CSF CD3+CD56+ and CD3−CD56dim is reduced in HIV-1C compared to HIV-1B due to the Tat C30S31 substitution in HIV-1C. 34 CSF and paired blood samples (PWH, n = 20; PWoH, n = 14) were studied. In PWH, the percentage of CD3+CD56+ was higher in CSF than in blood (p < 0.001), comparable in both compartments in PWoH (p = 0.20). The proportion of CD3−CD56dim in CSF in PWH was higher than PWoH (p = 0.008). There was no subtype differences. These results showed CNS compartmentalization of NKT cell response in PWH.
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•The impact of HIV-1 Tat on the innate immune response, analyzed by flow cytometry, is not subtype-dependent.•There was elevated CD3+CD56+ cells in the CSF, but not peripheral blood of PWH compared to PWoH.•In PWH there was redistribution of CD3+CD56+ cells from PB to the CNS, and compartmentalization in CNS.•There was an increase in CD3−CD56dim in the CSF of PWH when compared to the PWoH group.
HIV-1 subtype C (HIV-1C) shows reduced Tat protein chemoattractant activity compared with HIV-1B. The impact of HIV-1C Tat on the chemotaxis of the main lymphocyte subpopulations in the cerebrospinal ...fluid (CSF) and the peripheral blood (PB) is unclear. We hypothesized that there would be a lower frequency of specific lymphocyte subpopulations CD3
+
or CD19
+
in CSF in HIV-1C than in HIV-1B. The objectives were to detect the differences in the proportions of main lymphocyte subpopulations in CSF and PB, between people with HIV (PWH) and HIV-1-uninfected volunteers (PWoH) and in HIV-1B and HIV-1C. Lymphocyte immunophenotyping was studied in CSF and paired PB samples of PWH (
n
= 22) and PWoH (
n
= 14). Lymphocytes were analyzed within the CD45
+
gated region. The proportions of CSF CD3
+
CD4
+
, CD3
+
CD8
+
, and CD3
−
CD19
+
lymphocytes in CSF were comparable in HIV-1B and C. There was an increase in the proportion of CD3
+
CD8
+
cells and a decrease in CD3
+
CD4
+
T cells (
p
s = 0.016) in the CSF samples of the PWH compared with the PWoH group. In the PWH group, both CD3
+
CD4
+
and CD3
+
CD8
+
lymphocytes were significantly higher in the CSF than in the PB (
p
= 0.047 and 0.005). The proportion of CD3
+
CD4
+
was lower and that of CD3
+
CD8
+
was higher in the CSF samples of the aviremic group than that of HIV-negative control (
p
= 0.0008 and < 0.0001, respectively). HIV-1C Tat substitution (C30S) did not interfere with the CNS migration of the main lymphocyte subpopulations. This is the first study to evaluate these lymphocytes in CSF and PB of HIV-1C compared with HIV-1B.
The preferential association of some chemokine receptors with human Th1 or Th2 cells has recently been reported. In this study, the expression of CCR3, CCR5, CXCR3, and CXCR4 were analyzed by flow ...cytometry in three distinct in vitro models of Th1/Th2 polarization, activated naive and memory T cells, and T‐cell clones, in which the intracellular synthesis of interferon‐γ (IFN‐γ) and interleukin‐4 (IL‐4) and the surface expression of CD30 and LAG‐3 were also assessed. Moreover, by using immunohistochemistry the in vivo expression of CCR3, CCR5, CXCR3, and CXCR4 was examined in the gut of patients suffering from Crohn's disease, a Th1‐dominated disorder, and in the skin of patients suffering from systemic sclerosis, a Th2‐dominated disorder. CCR5 and LAG‐3 exhibited the same pathway of Th1 association, whereas CXCR3 did not discriminate between Th1‐ and Th2‐dominated responses. On the other hand, CCR3 was found only occasionally in a small proportion of allergen‐specific memory T cells with Th2/Th0 profile of cytokine production in vitro. However, it was neither seen in Th2‐polarized activated naive T cells nor in established Th2 clones and could be detected in vivo only on non‐T cells. Finally, whereas CXCR4 expression was not limited to Th2 cells in vivo, it was markedly up‐regulated by IL‐4 and down‐regulated by IFN‐γ in vitro. Thus, the results of this study confirm the existence of flexible programs of chemokine receptor expression during the development of Th1 and Th2 cells. However, caution is advised in interpreting these receptors as surrogate markers of a given type of effector response. J. Leukoc. Biol. 65: 691–699; 1999.
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•Açaí seeds are a neglected source of bioactive phenolic compounds.•Açaí seed extract exhibits potent antioxidant activity.•Açaí seed extract prevents endothelial toxicity of ...H2O2.•Açaí seed extract activates antioxidant response through Nrf2-signaling.
The current study evaluated the content and profile of phenolic compounds, the in vitro antioxidant activity, and the role of the Nrf2-signaling pathway in the cellular antioxidant activity of açaí seed extract (ASE) in H2O2-induced oxidative stress in human endothelial cells (HUVEC). Seven phenolic compounds were quantified in ASE by HPLC-DAD-MS, among which (−)-epicatechin and (+)-catechin were the most abundant. ASE exhibited a potent in vitro antioxidant activity evaluated by different assays. In HUVEC, ASE decreased H2O2-induced cytotoxicity, prevented migratory capacity loss and oxidative stress. ASE promoted up-regulation of the master antioxidant transcription factor Nrf2 through activation of ERK, thus leading to an increased expression of antioxidant enzymes. Our results demonstrated that ASE, rich in phenolic compounds, reversed H2O2-induced oxidative stress and that this effect was partially attributed to positive modulation of Nrf2 signaling pathway in HUVEC.
Few studies have examined gender differences in health status and cardiovascular outcomes in patients with peripheral artery disease (PAD). This study assessed (1) self-reported health status at PAD ...diagnosis and 12-months later, and explored (2) whether outcomes in women with PAD differ with regard to long-term major adverse events.
A total of 816 patients (285 women) with PAD were enrolled from 2 vascular clinics in the Netherlands. Baseline clinical data and subsequent adverse events were recorded and patients completed the Short Form-12 (SF-12, Physical Component Score PCS and Mental Component Score MCS) upon PAD diagnosis and 12-months later. Women had similar ages and clinical characteristics, but poorer socio-economic status and more depressive symptoms at initial diagnosis, as compared with men. Women also had poorer physical (PCS: 37±10 versus 40±10, P=0.004) and mental (
47±12 versus 49±11, P=0.005) health status at the time of presentation. At 12-months, women still reported a poorer overall PCS score (41±12 versus 46±11, P=0.006) and MCS score (42±14 versus 49±12, P=0.002). Female gender was an independent determinant of a poorer baseline and 12-month PCS and MCS scores. However, there were no significant differences by gender on either mortality (unadjusted hazard ratio HR=0.93, 95% CI 0.60;1.44, P=0.74) or major adverse events (unadjusted HR=0.90, 95% CI 0.63;1.29, P=0.57), after a median follow-up of 3.2 years.
Women's physical and mental health status is compromised both at initial PAD diagnosis and at 12-month follow-up, despite experiencing a similar magnitude of change in their health scores throughout the first 12-months after diagnosis.
The detection of homologous recombination deficiency (HRD) can identify patients who are more responsive to platinum and poly ADP ribose polymerase inhibitors (PARPi). MyChoice CDx (Myriad) is the ...most used HRD test in ovarian cancer (OC). However, some limitations of commercial tests exist, because of the high rate of inconclusive results, costs, and the impossibility of evaluating functional resistance mechanisms.
Two academic genomic tests and a functional assay, the RAD51 foci, were evaluated to detect HRD. One hundred patients with high-grade OC enrolled in the MITO16A/MaNGO-OV2 trial and treated with first-line therapy with carboplatin, paclitaxel, and bevacizumab were analyzed.
The failure rate of the two genomic assays was 2%. The sensitivity in detecting HRD when compared with Myriad was 98.1% and 90.6%, respectively. The agreement rate with Myriad was 0.92 and 0.87, with a Cohen’s κ coefficient corresponding to 0.84 and 0.74, respectively. For the RAD51 foci assay, the failure rate was 30%. When the test was successful, discordant results for deficient and proficient tumors were observed, and additional HRD patients were identified compared to Myriad; sensitivity was 82.9%, agreement rate was 0.65, and Cohen’s κ coefficient was 0.18. The HRD detected by genomic assays and residual tumor at primary surgery and stage was correlated with progression-free survival at multivariate analysis.
Results suggest the feasibility of academic tests for assessing HRD status that show robust concordance with Myriad and correlation with clinical outcome. The contribution of the functional information related to the RAD51 foci test to the genomic data needs further investigation.
•Deficiency in homologous recombination repair of DNA generates genomic instability and permanent genomic changes.•HRD status is fundamental for identifying OC patients suitable for platinum and PARPi treatment.•HRD testing is considered a topic with urgent need for improvement, going beyond those available commercially.•Within this study, two academic genomic tests and a functional assay, the RAD51 foci, were evaluated to detect HRD.•Our tests compare favorably with the reference Myriad assay and correlate with the outcome of high-grade OC patients.
Background:
Early risk stratification is essential for in-hospital management of ST-segment–elevation myocardial infarction. Acute heart failure confers a worse prognosis, and although lung ...ultrasound (LUS) is recommended as a first-line test to assess pulmonary congestion, it has never been tested in this setting. Our aim was to evaluate the prognostic ability of admission LUS in patients with ST-segment–elevation myocardial infarction.
Methods:
LUS protocol consisted of 8 scanning zones and was performed before primary percutaneous coronary intervention by an operator blinded to Killip classification. A LUS combined with Killip (LUCK) classification was developed. Receiver operating characteristic and net reclassification improvement analyses were performed to compare LUCK and Killip classifications.
Results:
We prospectively investigated 215 patients admitted with ST-segment–elevation myocardial infarction between April 2018 and June 2019. Absence of pulmonary congestion detected by LUS implied a negative predictive value for in-hospital mortality of 98.1% (93.1–99.5%). The area under the receiver operating characteristic curve of the LUCK classification for in-hospital mortality was 0.89 (
P
=0.001), and of the Killip classification was 0.86 (
P
<0.001;
P
=0.05 for the difference between curves). LUCK classification improved Killip ability to predict in-hospital mortality with a net reclassification improvement of 0.18.
Conclusions:
In a cohort of patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention, admission LUS added to Killip classification was more sensitive than physical examination to identify patients at risk for in-hospital mortality. LUCK classification had a greater area under the receiver operating characteristic curve and reclassified Killip classification in 18% of cases. Moreover, absence of pulmonary congestion on LUS provided an excellent negative predictive value for in-hospital mortality.
Endoglin (CD105), a receptor of the transforming growth factor-β superfamily, has been reported to identify functional long-term repopulating hematopoietic stem cells, and has been detected in ...certain subtypes of acute leukemias. Whether this receptor plays a functional role in leukemogenesis remains unknown. We identified endoglin expression on the majority of blasts from patients with acute myeloid leukemia (AML) and acute B-lymphoblastic leukemia (B-ALL). Using a xenograft model, we find that CD105+ blasts are endowed with superior leukemogenic activity compared with the CD105− population. We test the effect of targeting this receptor using the monoclonal antibody TRC105, and find that in AML, TRC105 prevented the engraftment of primary AML blasts and inhibited leukemia progression following disease establishment, but in B-ALL, TRC105 alone was ineffective due to the shedding of soluble CD105. However, in both B-ALL and AML, TRC105 synergized with reduced intensity myeloablation to inhibit leukemogenesis, indicating that TRC105 may represent a novel therapeutic option for B-ALL and AML.
•Leukemia-forming activity is enriched in endoglin-expressing AML and B-ALL blasts using a mouse xenograft model.•Inhibition of endoglin function with TRC105 reduces leukemia development and progression.
Abstract Aims The coronary slow flow phenomenon CSFP is a coronary microvascular disorder, characterized by delayed distal vessel opacification despite the absence of obstructive coronary artery ...disease. Patients frequently present with an acute coronary syndrome ACS although the pathophysiological mechanisms responsible are unknown. The aim of this study was to identify potential mechanisms for the ACS presentation associated with the CSFP using a plasma proteomic profiling approach. Methods and results Plasma samples from nine CSFP subjects 56 ± 11 years were assayed for high sensitivity C-reactive protein hsCRP, troponin T TnT, creatine kinase CK, and proteomic analyses (n = 6), during an ACS presentation and one month later chronic phase. Proteomic analysis involved chromatographic depletion of abundant plasma proteins followed by two-dimensional differential gel electrophoresis 2-D DIGE. Protein spots demonstrating ± 1.5-fold change relative to the control were identified by mass spectrometry and two differentially expressed proteins were selected for validation via Western blotting. During the ACS presentation, hsCRP was elevated ACS = 14.9 ± 3.9 mg/L vs chronic = 4.23 ± 1.37 mg/L, p = 0.05 but TnT and CK levels were unchanged. Proteomic analysis identified six proteins that were significantly different in abundance between the acute and chronic samples. During the ACS presentation there was a 1.6 ± 0.13 fold increase in the anti-oxidant enzyme paraoxonase-1 and an increase in inflammatory proteins alpha-1-antichymotrypsin 1.65 ± 0.13 fold and alpha-1-antitrypsin 2.5 ± 0.34 fold. The latter was confirmed by Western blotting 1.33 ± 0.17 OD acute/chronic ratio, p = 0.05. Conclusion The findings from this novel detailed approach, implicate an inflammatory/oxidative stress process in the pathogenesis of the ACS presentation associated with the CSFP. Future studies should further elucidate these mechanisms.
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