The pathogenic role of T cells in hypertension has been documented well in recent animal studies. However, the existence of T-cell–driven inflammation in human hypertension has not been confirmed. ...Therefore, we undertook immunologic characterization of T cells from patients with hypertension and measured circulating levels of C-X-C chemokine receptor type 3 chemokines, which are well-known tissue-homing chemokines for T cells. We analyzed immunologic markers on T cells from patients with hypertension by multicolor flow cytometry. We then measured circulating levels of the C-X-C chemokine receptor type 3 chemokines, monokine induced by γ interferon (IFN), IFN γ–induced protein 10, and IFN-inducible T-cell α chemoattractant, in patients with hypertension and in age- and sex-matched control subjects by the cytometric bead array method. In addition, we examined histological features of IFN-inducible T-cell α chemoattractant expression from renal biopsy specimens of patients with hypertensive nephrosclerosis and control subjects. The total T-cell population from patients with hypertension showed an increased fraction of immunosenescent, proinflammatory, cytotoxic CD8 T cells. Circulating levels of C-X-C chemokine receptor type 3 chemokines were significantly higher in patients with hypertension than in control subjects. Furthermore, immunohistochemical staining revealed increased expression of the T-cell chemokine, IFN-inducible T-cell α chemoattractant, in the proximal and distal tubules of patients with hypertensive nephrosclerosis. Immunosenescent CD8 T cells and C-X-C chemokine receptor type 3 chemokines are increased in human hypertension, suggesting a role for T-cell–driven inflammation in hypertension. A more detailed characterization of CD8 T cells may offer new opportunities for the prevention and treatment of human hypertension.
Inflammatory responses play a critical role in left ventricular remodeling after myocardial infarction (MI). Tolerogenic dendritic cells (tDCs) can modulate immune responses, inducing regulatory T ...cells in a number of inflammatory diseases.
We generated tDCs by treating bone marrow-derived dendritic cells with tumor necrosis factor-α and cardiac lysate from MI mice. We injected MI mice, induced by a ligation of the left anterior descending coronary artery in C57BL/6 mice, twice with tDCs within 24 hours and at 7 days after the ligation.
In vivo cardiac magnetic resonance imaging and ex vivo histology confirmed the beneficial effect on postinfarct left ventricular remodeling in MI mice treated with tDCs. Subcutaneously administered infarct lysate-primed tDCs near the inguinal lymph node migrated to the regional lymph node and induced infarct tissue-specific regulatory T-cell populations in the inguinal and mediastinal lymph nodes, spleen, and infarcted myocardium, indicating that a local injection of tDCs induces a systemic activation of MI-specific regulatory T cells. These events elicited an inflammatory-to-reparative macrophage shift. The altered immune environment in the infarcted heart resulted in a better wound remodeling, preserved left ventricular systolic function after myocardial tissue damage, and improved survival.
This study showed that tDC therapy in a preclinical model of MI was potentially translatable into an antiremodeling therapy for ischemic tissue repair.
Norgalanthamine has been shown to possess hair-growth promoting effects, including increase in hair-fiber length in cultured rat vibrissa follicles and increase in dermal papilla cell (DPC) ...proliferation. However, the intracellular mechanisms that underlie the action of norgalanthamine in DPCs have not been investigated. In this study, we addressed the ability of norgalanthamine to trigger anagen-activating signaling pathways in DPCs. Norgalanthamine significantly increased extracellular signal-regulated kinase (ERK) 1/2 phosphorylation at 0.1 µM, a concentration at which DPC proliferation was also induced. Furthermore, the increases in norgalanthamine-induced ERK 1/2 activation and subsequent DPC proliferation were suppressed by the mitogen-activated protein kinase/ERK kinase (MEK) 1/2 inhibitor, U0126. A 0.1 µM dose of norgalanthamine also increased phosphorylation of AKT, which was followed by an increase in glycogen synthase kinase 3β phosphorylation and nuclear translocation of β-catenin. In addition, LY294002, a phosphatidylinositol 3 kinase (PI3K) inhibitor, blocked the effect of norgalanthamine on DPC proliferation. These results suggest that norgalanthamine can stimulate the anagen phase of the hair cycle in DPCs via activation of the ERK 1/2, PI3K/AKT, and Wnt/β-catenin pathways.
Background
Hypothyroidism has been known to be associated with hyperlipidemia, endothelial dysfunction and atherosclerosis. Elevation of thyroid‐stimulation hormone (TSH) is a gold standard to detect ...these conditions. However, no large studies have investigated the association between TSH elevation and long‐term clinical outcomes in patients with acute myocardial infarction (AMI).
Hypothesis
Hypothyroidism is associated with higher mortality in patients with AMI.
Methods
A total of 4748 AMI patients undergoing percutaneous coronary intervention (PCI) with drug‐eluting stents were consecutively enrolled. We analyzed 1977 patients whose thyroid function data available after the exclusion of hyperthyroidism and possible central hypothyroidism. Patients were divided into two groups; euthyroid group (n = 1846) with normal TSH and normal free thyroxine (FT4); hypothyroidism group (n = 131) with elevated TSH and normal or low FT4. The two groups were subsequently compared with their all‐cause and cardiac mortalities.
Results
Median follow‐up duration was 3.5 years. Hypothyroidism group were older, included in more females, and had higher incidences of atrial fibrillation, stroke, and renal dysfunction. Elevated TSH was associated with significantly higher all‐cause mortality (26.0% vs 11.7%, P < 0.0001) and cardiac mortality (9.2% vs 4.6%, P = 0.014). The multivariate Cox proportional hazards model identified that TSH elevation was a significant predictor of all‐cause mortality (adjusted hazard ratio 1.560, 95% confidence interval 1.017 to 2.392, P = 0.041).
Conclusions
Our data suggest that AMI patients with TSH elevation had worse clinical outcome. Moreover, TSH elevation was a predictor of all‐cause mortality in patients with AMI.
Invariant natural-killer T (iNKT) cells play pathogenic roles in allergic asthma in murine models and possibly also humans. While many studies show that the development and functions of innate and ...adaptive immune cells depend on their metabolic state, the evidence for this in iNKT cells is very limited. It is also not clear whether such metabolic regulation of iNKT cells could participate in their pathogenic activities in asthma. Here, we showed that acetyl-coA-carboxylase 1 (ACC1)-mediated de novo fatty-acid synthesis is required for the survival of iNKT cells and their deleterious functions in allergic asthma. ACC1, which is a key fatty-acid synthesis enzyme, was highly expressed by lung iNKT cells from WT mice that were developing asthma. Cd4-Cre::Acc1fl/fl mice failed to develop OVA-induced and HDM-induced asthma. Moreover, iNKT cell-deficient mice that were reconstituted with ACC1-deficient iNKT cells failed to develop asthma, unlike when WT iNKT cells were transferred. ACC1 deficiency in iNKT cells associated with reduced expression of fatty acid-binding proteins (FABPs) and peroxisome proliferator-activated receptor (PPAR)γ, but increased glycolytic capacity that promoted iNKT-cell death. Furthermore, circulating iNKT cells from allergic-asthma patients expressed higher ACC1 and PPARG levels than the corresponding cells from non-allergic-asthma patients and healthy individuals. Thus, de novo fatty-acid synthesis prevents iNKT-cell death via an ACC1-FABP-PPARγ axis, which contributes to their homeostasis and their pathogenic roles in allergic asthma.
Background:There are limited data comparing the outcomes of subintimal vs. intraluminal approach in the treatment of long femoropopliteal artery occlusions. The objective of this study was to ...investigate the efficacy and safety of the subintimal approach for long femoropopliteal artery occlusions.Methods and Results:From a multicenter retrospective registry cohort, we included a total of 461 patients with 487 femoropopliteal artery occlusions classified as Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC) II C/D for this analysis. We compared the immediate and mid-term outcomes of subintimal vs. intraluminal approaches. There were 228 patients with 243 limbs in the subintimal group, and 233 patients with 244 limbs in the intraluminal group. Baseline clinical and lesion characteristics were comparable between the 2 groups. The technical success rate was significantly higher in the subintimal group than in the intraluminal group (95.1% vs. 89.8%, P=0.041). The clinical primary patency (67.5% vs. 73.4% at 12 months, 54.0% vs. 61.3% at 24 months; P=0.086) and target lesion revascularization (TLR)-free survival (89.5% vs. 86.3% at 12 months, 77.6% vs. 76.0% at 24 months; P=0.710) did not differ significantly between the subintimal and the intraluminal groups.Conclusions:In long femoropopliteal occlusions, the subintimal approach achieved a higher technical success rate and similar mid-term primary patency and TLR-free survival compared with intraluminal approach.
Vascular calcification (VC) is often associated with cardiovascular and metabolic diseases. However, the molecular mechanisms linking VC to these diseases have yet to be elucidated. Here we report ...that MDM2-induced ubiquitination of histone deacetylase 1 (HDAC1) mediates VC. Loss of HDAC1 activity via either chemical inhibitor or genetic ablation enhances VC. HDAC1 protein, but not mRNA, is reduced in cell and animal calcification models and in human calcified coronary artery. Under calcification-inducing conditions, proteasomal degradation of HDAC1 precedes VC and it is mediated by MDM2 E3 ubiquitin ligase that initiates HDAC1 K74 ubiquitination. Overexpression of MDM2 enhances VC, whereas loss of MDM2 blunts it. Decoy peptide spanning HDAC1 K74 and RG 7112, an MDM2 inhibitor, prevent VC in vivo and in vitro. These results uncover a previously unappreciated ubiquitination pathway and suggest MDM2-mediated HDAC1 ubiquitination as a new therapeutic target in VC.
Stent thrombosis (ST) remains a catastrophic problem in patients undergoing percutaneous coronary intervention (PCI). However, a paucity of data exist regarding the incidence, implications, and ...predictors of ST in patients with acute myocardial infarction (AMI). We consecutively enrolled patients with AMI in the CardiOvascular Risk and idEntificAtion of potential high-risk population in AMI registry who underwent PCI from January 2004 to December 2009 and analyzed definite or probable ST according to Academic Research Consortium definitions. The median follow-up duration was 41.9 months. Definite or probable ST occurred in 136 patients (3.7%), including 44 with early ST (1.0%), 38 with late ST (0.9%), and 54 with very late ST (2.0%). The annual incidence of very late ST ranged from 0.5% to 0.6%. The all-cause mortality rate after ST was 29%, which was higher than that for patients without ST (17%; p <0.001). The independent predictors of ST were no-reflow phenomenon (hazard ratio HR 1.96, 95% confidence interval CI 1.28 to 3.03), decreased left ventricular ejection fraction (HR 1.70, 95% CI 1.21 to 2.40), anemia (HR 1.54, 95% CI 1.09 to 2.18), and a mean stent diameter <3.0 mm (HR 1.53, 95% CI 1.04 to 2.27). ST is not uncommon in patients with AMI and continues to occur beyond 1 year after PCI, irrespective of the stent type or clinical presentation. Patients with ST are associated with higher mortality than patients without ST. No reflow, decreased left ventricular ejection fraction, anemia, and a mean stent diameter <3.0 mm are independent predictors of ST.
Background: Limited data are available regarding the direct comparison of angiographic and clinical outcomes after percutaneous coronary intervention (PCI) with drug-eluting stents (DESs) for chronic ...total occlusion (CTO). Methods and Results: A prospective, randomized, multicenter trial was conducted to evaluate the non-inferiority of a zotarolimus-eluting stent (ZES; Endeavor Sprint®, n=80) to a sirolimus-eluting stent (SES; Cypher®, n=80) in patients with CTO lesion with a reference vessel diameter ≥2.5mm. The primary endpoint was in-segment binary restenosis rate at 9-month angiographic follow-up. Key secondary endpoints included target vessel failure (TVF; including cardiac death, myocardial infarction, and target vessel revascularization) and Academic Research Consortium-defined definite/probable stent thrombosis (ST) within 12 months. The ZES was non-inferior to the SES with respect to the primary endpoint, which occurred in 14.1% (95% confidence interval CI: 6.0-22.2) and in 13.7% (95%CI: 5.8-21.6) of patients, respectively (non-inferiority margin, 15.0%; P for non-inferiority <0.001). There were no significant between-group differences in the rate of TVF (10.0% vs. 17.5%; P=0.168) nor in the rate of ST (0.0% vs. 1.3%; P=0.316) during the 12-month clinical follow-up. Conclusions: The effectiveness and safety of ZES are similar to those of SES and therefore it is a good treatment option in patients undergoing PCI for CTO with DESs. (Circ J 2012; 76: 868-875)
Purpose
Few large-scale studies have focused on the prevalence of symptoms and signs during the last days of patients diagnosed with advanced cancer. Identifying the patterns of specific symptoms ...according to cancer type is helpful to provide end-of-life care for patients with advanced cancer. We investigated the prevalence and severity of symptoms and signs associated with impending death in patients with advanced cancer.
Methods
In this secondary analysis of an international multicenter cohort study conducted in three East Asian countries, we compared the severity of symptoms and signs among dying patients in the last 3 days of life according to the type of primary cancer using one-way analysis of variance (ANOVA). Post hoc analysis was conducted for multiple comparisons of each symptom according to the type of primary cancer.
Results
We analyzed 2131 patients from Japan, Korea, and Taiwan. The prevalence of most symptoms and signs were relatively stable from 1 week after admission to the last 3 days of life. According to cancer type, edema of the lower extremities was the most common symptom and fatigue/ ascites were the most severe symptoms in digestive tract cancer. For lung cancer, respiratory secretion was the most prevalent and dyspnea/respiratory secretion were the most severe symptoms.
Conclusion
We demonstrated the prevalence and severity of symptoms and signs associated with the impending death of patients with advanced cancer in East Asia. Our study can enable clinicians to recognize the specific symptoms and signs at the very end of life.
PDF
