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Aim: This study aimed to explore how varying inspiratory muscle training workloads affect exercise capacity, health-related quality of life (HrQoL), depression, peripheral and respiratory muscle strength, pulmonary function, dyspnea, fatigue, and physical activity levels in hypertension (HT) patients. Methods: A randomized, controlled three-arm study. Forty-five patients (58.37 ± 8.53 y, 7F/38M) with HT received IMT (7 days/8 weeks) by POWERbreathe® Classic LR device and were randomized to control group (CG, 10% maximal inspiratory pressure (MIP), n: 15), low-load group (LLG, 30% MIP), and high-load group (HLG, %50 MIP). Exercise capacity, HrQoL, depression, peripheral and respiratory muscle strength, pulmonary function, fatigue, physical activity level, dyspnea, and sleep quality were evaluated before and after the training. Results: Exercise capacity, physical functioning, peripheral muscle strength, and resting dyspnea were statistically significantly improved in HLG and LLG after the training compared to CG (p < 0.05). Similar improvements in perception of depression, fatigue, and sleep quality were seen within and between the groups (p > 0.05). Statistically significant differences were found within all the groups in terms of MIP and PEF values of respiratory functions (p < 0.05). The superior improvement in the physical activity level was found in the HLG (p < 0.05). Discussion. High-load IMT was particularly effective in increasing physical activity level, peripheral muscle strength, exercise capacity, and improved HrQoL. Low-load IMT was effective in reducing dyspnea and improving respiratory function. Device-guided breathing exercises decreased blood pressure, improved sleep quality, and strengthened respiratory muscles. IMT, an efficient method, is suggested for inclusion in rehabilitation programs due to its capacity to increase physical activity, exercise capacity, and peripheral muscle strength, enhance HrQoL and respiratory function, and alleviate dyspnea. Also, the efficacy of IMT should be investigated with different training protocols such as endurance IMT or functional IMT in HT patients.
Subject(s)
Exercise Tolerance , Quality of Life , Humans , Exercise Tolerance/physiology , Inhalation/physiology , Respiratory Muscles/physiology , Dyspnea , Muscle Strength , Fatigue , Randomized Controlled Trials as TopicABSTRACT
Background: Chronic coronary syndrome (CCS) is one of the most life-restricting coronary artery diseases, and symptom relief is the main goal in CCS patients who suffer from angina. Objectives: To assess the potential benefits of device-guided breathing in CCS patients with angina in this randomized, controlled, single-blinded study. Methods: Fifty-one patients with CCS received device-guided breathing for 7 days/8 weeks. Exercise capacity [exercise stress test], cardiac function [transthoracic echocardiography], and angina severity [Canadian Cardiovascular Society Classification] were evaluated initially and after the training. Device-guided breathing was performed at the lowest resistance of the device (POWERbreathe® Classic LR) for the control group (n = 17). The low load training group (LLTG; n = 18) and high load training group (HLTG; n = 16) were trained at 30% and 50% of maximal inspiratory pressure. Baseline characteristics were compared using one-way ANOVA and Kruskal-Wallis test. Categorical data were compared using the chi-square test. ANCOVA was performed to compare changes between three groups. A p value < 0.05 was considered statistically significant. Results: Metabolic equivalent values were significantly improved in both HLTG and LLTG groups (p < 0.001, p = 0.003). The Duke treadmill score significantly improved and shifted to low-risk both in the HLTG (p < 0.001) and LLTG (p < 0.001) groups. Angina severity significantly alleviated after the training in both HLTG and LLTG groups (p < 0.001, p = 0.002). Conclusions: An 8-week long program of short-term respiratory muscle training provided positive gains in exercise capacity and angina severity in CCS patients with angina. The effects of long-term training programs on CCS patients should be investigated clinically because of the possibility of helping to decrease the need for invasive treatments.
ABSTRACT
In murine experimental glioma models, TLR3 or TLR9 activation of microglial/macrophages has been shown to impair glioma growth, which could, however, not been verified in recent clinical trials. We therefore tested whether combined TLR3 and TLR9 activation of microglia/macrophages would have a synergistic effect. Indeed, combined TLR3/TLR9 activation augmented the suppression of glioma growth in organotypic brain slices from male mice in a microglia-dependent fashion, and this synergistic suppression depended on interferon ß release and phagocytic tumor clearance. Combined TLR3/TLR9 stimulation also augmented several functional features of microglia, such as the release of proinflammatory factors, motility, and phagocytosis activity. TLR3/TLR9 stimulation combined with CD47 blockade further augmented glioma clearance. Finally, we confirmed that the coactivation of TLR3/TLR9 also augments the impairment of glioma growth in vivo Our results show that combined activation of TLR3/TLR9 in microglia/macrophages results in a more efficient glioma suppression, which may provide a potential strategy for glioma treatment.SIGNIFICANCE STATEMENT Glioma-associated microglia/macrophages (GAMs) are the predominant immune cells in glioma growth and are recently considered as antitumor targets. TLRs are involved in glioma growth, but the TLR3 or TLR9 ligands were not successful in clinical trials in treating glioma. We therefore combined TLR3 and TLR9 activation of GAMs, resulting in a strong synergistic effect of tumor clearance in vitro, ex vivo, and in vivo Mechanisms of this GAM-glioma interaction involve IFNß signaling and increased tumor clearance by GAMs. Interfering with CD47 signaling had an additional impact on tumor clearance. We propose that these signaling pathways could be exploited as anti-glioma targets.
Subject(s)
Brain Neoplasms/metabolism , Microglia/metabolism , Toll-Like Receptor 3/metabolism , Toll-Like Receptor 9/metabolism , Animals , Apoptosis , Female , Inflammation Mediators/metabolism , Macrophages/metabolism , Male , Mice, Inbred C57BL , Mice, Transgenic , Organ Culture Techniques , Signal TransductionABSTRACT
BACKGROUND: Vasodilator-induced transient left ventricular cavity dilation (LVCD) by positron emission tomography (PET) is associated with microvascular dysfunction in hypertrophic cardiomyopathy (HCM). Here we assessed whether HCM patients who develop LVCD by PET during vasodilator stress also develop LV cavity dilation by echocardiography (ECHO-LVCD) following exercise stress. METHODS: A retrospective analysis of cardiac function and myocardial blood flow (MBF) was conducted in 108 HCM patients who underwent perfusion-PET and exercise-ECHO as part of their clinical evaluation. We performed a head-to-head comparison of LV volumes and ejection fraction (LVEF) at rest and stress (during vasodilator stress, post-exercise), in 108 HCM patients. A ratio > 1.13 of stress to rest LV volumes was used to define PET-LVCD, and a ratio > 1.17 of stress to rest LVESV was used to define ECHO-LVCD. Patients were divided into 2 groups based on the presence/absence of PET-LVCD. MBF and myocardial flow reserve were quantified by PET, and global longitudinal strain (GLS) was assessed by ECHO at rest/stress in the two groups. RESULTS: PET-LVCD was observed in 51% (n = 55) of HCM patients, but only one patient had evidence of ECHO-LVCD (ratio = 1.36)-this patient also had evidence of PET-LVCD (ratio = 1.20). The PET-LVCD group had lower PET-LVEF during vasodilator stress, but ECHO-LVEF increased in both groups post-exercise. The PET-LVCD group demonstrated higher LV mass, worse GLS at rest/stress, and lower myocardial flow reserve. Incidence of ischemic ST-T changes was higher in the PET-LVCD group during vasodilator stress (42 vs 17%), but similar (30%) in the two groups during exercise. CONCLUSION: PET-LVCD reflects greater degree of myopathy and microvascular dysfunction in HCM. Differences in the cardiac effects of exercise and vasodilators and timing of stress-image acquisition could underlie discordance in ischemic EKG changes and LVCD by ECHO and PET, in HCM.
Subject(s)
Cardiomyopathy, Hypertrophic/diagnostic imaging , Echocardiography/methods , Exercise Test/methods , Positron Emission Tomography Computed Tomography/methods , Positron-Emission Tomography/methods , Vasodilator Agents/adverse effects , Adult , Aged , Cardiomyopathy, Hypertrophic/epidemiology , Exercise , Female , Genotype , Heart Ventricles , Humans , Hypertrophy, Left Ventricular/complications , Incidence , Male , Microcirculation , Middle Aged , Muscular Diseases , Myocardial Ischemia , Registries , Retrospective StudiesABSTRACT
First identified in the 1980s, tenascin-C (TNC) is a multi-domain extracellular matrix glycoprotein abundantly expressed during the development of multicellular organisms. TNC level is undetectable in most adult tissues but rapidly and transiently induced by a handful of pro-inflammatory cytokines in a variety of pathological conditions including infection, inflammation, fibrosis, and wound healing. Persistent TNC expression is associated with chronic inflammation and many malignancies, including glioma. By interacting with its receptor integrin and a myriad of other binding partners, TNC elicits context- and cell type-dependent function to regulate cell adhesion, migration, proliferation, and angiogenesis. TNC operates as an endogenous activator of toll-like receptor 4 and promotes inflammatory response by inducing the expression of multiple pro-inflammatory factors in innate immune cells such as microglia and macrophages. In addition, TNC drives macrophage differentiation and polarization predominantly towards an M1-like phenotype. In contrast, TNC shows immunosuppressive function in T cells. In glioma, TNC is expressed by tumor cells and stromal cells; high expression of TNC is correlated with tumor progression and poor prognosis. Besides promoting glioma invasion and angiogenesis, TNC has been found to affect the morphology and function of tumor-associated microglia/macrophages in glioma. Clinically, TNC can serve as a biomarker for tumor progression; and TNC antibodies have been utilized as an adjuvant agent to deliver anti-tumor drugs to target glioma. A better mechanistic understanding of how TNC impacts innate and adaptive immunity during tumorigenesis and tumor progression will open new therapeutic avenues to treat brain tumors and other malignancies.
Subject(s)
Brain Neoplasms/immunology , Brain Neoplasms/metabolism , Glioma/immunology , Glioma/metabolism , Immunomodulation , Tenascin/immunology , Tenascin/metabolism , Extracellular Matrix , HumansABSTRACT
BACKGORUND: Quantification of myocardial blood flow (MBF) by positron emission tomography (PET) is important for investigation of angina in hypertrophic cardiomyopathy (HCM). Several software programs exist for MBF quantification, but they have been mostly evaluated in patients (with normal cardiac geometry), referred for evaluation of coronary artery disease (CAD). Software performance has not been evaluated in HCM patients who frequently have hyperdynamic LV function, LV outflow tract (LVOT) obstruction, small LV cavity size, and variation in the degree/location of LV hypertrophy. AIM: We compared results of MBF obtained using PMod, which permits manual segmentation, to those obtained by FDA-approved QPET software which has an automated segmentation algorithm. METHODS: 13N-ammonia PET perfusion data were acquired in list mode at rest and during pharmacologic vasodilation, in 76 HCM patients and 10 non-HCM patients referred for evaluation of CAD (CAD group.) Data were resampled to create static, ECG-gated and 36-frame-dynamic images. Myocardial flow reserve (MFR) and MBF (in ml/min/g) were calculated using QPET and PMod softwares. RESULTS: All HCM patients had asymmetric septal hypertrophy, and 50% had evidence of LVOT obstruction, whereas non-HCM patients (CAD group) had normal wall thickness and ejection fraction. PMod yielded significantly higher values for global and regional stress-MBF and MFR than for QPET in HCM. Reasonably fair correlation was observed for global rest-MBF, stress-MBF, and MFR using these two softwares (rest-MBF: r = 0.78; stress-MBF: r = 0.66.; MFR: r = 0.7) in HCM patients. Agreement between global MBF and MFR values improved when HCM patients with high spillover fractions (> 0.65) were excluded from the analysis (rest-MBF: r = 0.84; stress-MBF: r = 0.72; MFR: r = 0.8.) Regionally, the highest agreement between PMod and QPET was observed in the LAD territory (rest-MBF: r = 0.82, Stress-MBF: r = 0.68) where spillover fraction was the lowest. Unlike HCM patients, the non-HCM patients (CAD group) demonstrated excellent agreement in MBF/MFR values, obtained by the two softwares, when patients with high spillover fractions were excluded (rest-MBF: r = 0.95; stress-MBF: r = 0.92; MFR: r = 0.95). CONCLUSIONS: Anatomic characteristics specific to HCM hearts contribute to lower correlations between MBF/MFR values obtained by PMod and QPET, compared with non-HCM patients. These differences indicate that PMod and QPET cannot be used interchangeably for MBF/MFR analyses in HCM patients.
Subject(s)
Cardiomyopathy, Hypertrophic/diagnostic imaging , Cardiomyopathy, Hypertrophic/physiopathology , Coronary Artery Disease/diagnostic imaging , Coronary Circulation/physiology , Positron-Emission Tomography , Software , Adult , Aged , Algorithms , Cardiomyopathy, Hypertrophic/complications , Cohort Studies , Coronary Artery Disease/etiology , Coronary Artery Disease/physiopathology , Echocardiography , Female , Humans , Image Processing, Computer-Assisted , Male , Middle AgedABSTRACT
The following information is missing from the Funding footnote on the first page of the published article: "This study was partly funded by NIH RO1 HL092985." The last/corresponding author is incorrectly listed on the first page of the published article: The correct name is Abraham MR.
ABSTRACT
Myocardial remodeling is developed by increased stress in acute or chronic pathophysiologies. Stressed heart morphology (SHM) is a new description representing basal septal hypertrophy (BSH) caused by emotional stress and chronic stress due to increased afterload in hypertension. Acute stress cardiomyopathy (ASC) and hypertension could be together in clinical practice. Therefore, there are some geometric and functional aspects regarding this specific location, septal base under acute and chronic stress stimuli. The findings by our and the other research groups support that hypertension-mediated myocardial involvement could be pre-existed in ASC cases. Beyond a frequently seen predominant base, hyperkinetic tissue response is detected in both hypertension and ASC. Furthermore, hypertension is the responsible factor in recurrent ASC. The most supportive prospective finding is BSH in which a hypercontractile base takes a longer time to exist morphologically than an acutely developed syndrome under both physiologic exercise and pressure overload by transaortic binding in small animals using microimaging. However, cardiac decompensation with apical ballooning could mask the possible underlying hypertensive disease. In fact, enough time for the assessment of previous hypertension history or segmental analysis could not be provided in an emergency unit, since ASC is accepted as an acute coronary syndrome during an acute episode. Additional supportive findings for SHM are increased stress scores in hypertensive BSH and the existence of similar tissue aspects in excessive sympathetic overdrive like pheochromocytoma which could result in both hypertensive disease and ASC. Exercise hypertension as the typical form of blood pressure variability is the sum of physiologic exercise and pathologic increased blood pressure and results in increased mortality. Hypertension is not rare in patients with a high stress score and leads to repetitive attacks in ASC supporting the important role of an emotional component as well as the potential danger due to multiple stressors at the same time. In the current review, the impact of multiple stressors on segmental or global myocardial remodeling and the hazardous potential of multiple stressors at the same time are discussed. As a result, incidentally determined segmental remodeling could be recalled in patients with multiple stressors and contribute to the early and combined management of both hypertension and chronic stress in the prevention of global remodeling and heart failure.
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Tumor-associated microglia and blood-derived macrophages (TAMs) play a central role in modulating the immune suppressive microenvironment in glioma. Here, we show that GPNMB is predominantly expressed by TAMs in human glioblastoma multiforme and the murine RCAS-PDGFb high grade glioma model. Loss of GPNMB in the in vivo tumor microenvironment results in significantly smaller tumor volumes and generates a pro-inflammatory innate and adaptive immune cell microenvironment. The impact of host-derived GPNMB on tumor growth was confirmed in two distinct murine glioma cell lines in organotypic brain slices from GPNMB-KO and control mice. Using published data bases of human glioma, the elevated levels in TAMs could be confirmed and the GPNMB expression correlated with a poorer survival.
Subject(s)
Brain Neoplasms , Glioblastoma , Glioma , Animals , Humans , Mice , Brain Neoplasms/pathology , Cell Line, Tumor , Glioblastoma/pathology , Glioma/pathology , Macrophages/metabolism , Membrane Glycoproteins/metabolism , Microglia/metabolism , Tumor MicroenvironmentABSTRACT
Hodgkin-Reed-Sternberg cells (HRSCs) in classic Hodgkin Lymphoma (HL) frequently lack expression of human leukocyte antigen class I (HLA-I), considered to hamper activation of cytotoxic T cells in the tumor microenvironment (TME). Here, we demonstrate HLA-I expression on HRSCs to be a strong determinant of TME composition whereas expression of HLA-II was associated with only minor differential gene expression in the TME. In HLA-I-positive HL the HRSC content and expression of CCL17/TARC in HRSCs are low, independent of the presence of Epstein-Barr virus in HRSCs. Additionally, HLA-I-positive HL shows a high content of CD8+ cytotoxic T cells. However, an increased expression of the inhibitory immune checkpoint LAG3 on CD8+ T cells in close proximity to HRSCs is observed. Suggesting interference with cytotoxic activity, we observed an absence of clonally expanded T cells in the TME. While HLA-I-positive HL is not associated with an unfavorable clinical course in our cohorts, they share features with the recently described H2 subtype of HL. Given the major differences in TME composition, immune checkpoint inhibitors may differ in their mechanism of action in HLA-I-positive compared to HLA-I-negative HL.
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Background: Coronary microvascular dysfunction (CMD) and hypertension (HTN) occur frequently in hypertrophic cardiomyopathy (HCM), but whether blood pressure (BP) influences CMD and outcomes is unknown. Objective: The purpose of this study was to test the hypothesis that HTN is associated with worse CMD and outcomes. Methods: This retrospective study included 690 HCM patients. All patients underwent cardiac magnetic resonance imaging, echocardiography, and rhythm monitoring; 127 patients also underwent rest/vasodilator stress 13NH3 positron emission tomography myocardial perfusion imaging. Patients were divided into 3 groups based on their rest systolic blood pressure (SBP) (group 1 ≤110 mm Hg; group 2 111-140; group 3 >140 mm Hg) and were followed for development of ventricular tachycardia (VT)/ventricular fibrillation (VF), heart failure (HF), death, and composite outcome. Results: Group 1 patients had the lowest age and left ventricular (LV) mass but the highest prevalence of nonobstructive hemodynamics and restrictive diastolic filling. LV scar was similar in the 3 groups. Group 1 had the lowest rest and stress myocardial blood flow (MBF) and highest SDS (summed difference score). Rest SBP was positively correlated with stress MBF and negatively correlated with SDS. Group 1 had the highest incidence of VT/VF, whereas the incidences of HF, death, and composite outcome were similar among the 3 groups. In multivariate analysis, rest SBP ≤110 mm Hg was independently associated with VT/VF (hazard ratio 2.6; 95% confidence interval 1.0-6.7; P = .04). Conclusion: SBP ≤110 mm Hg is associated with greater severity of CMD and coronary microvascular ischemia and higher incidence of ventricular arrhythmias in HCM.
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BACKGROUND: Primary lymphoma of the central nervous system (PCNSL) encompasses a variety of lymphoma subtypes, with the majority being diffuse large B-cell lymphomas, which require aggressive systemic treatment. In contrast, low-grade lymphomas are reported infrequently and are mostly limited to dural manifestations. Very rarely, parenchymal low-grade PCNSL is diagnosed, and the cases documented in the literature show a wide variety of treatment approaches. METHODS: We screened all cases of PCNSL treated at our department (a tertiary hematooncology and neurooncology center) in the last 15 years and conducted a comprehensive literature research in the PubMed database. RESULTS: Overall, two cases of low-grade primary parenchymal PCNSL treated with irradiation were identified. The dose prescriptions ranged from 30.6 to 36 Gy for the involved site, with sparing of the hippocampal structures. Both patients had an excellent response to the treatment with a mean follow-up of 20 months. No clinical or radiological signs of treatment toxicity were detected. CONCLUSIONS: Our analysis corroborates the results from the literature and demonstrates that parenchymal low-grade PCNSL shows a good response to localized radiation treatment, enabling a favorable outcome while avoiding long-term treatment toxicity.
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PURPOSE: The most important complication encountered in patients with b-thalassaemia major is degenerative fibrosis developing as a result of iron accumulation in myocardial tissue. Dysfunction pursues this accumulation. Recently, presence of fragmented QRS (fQRS) in ECG has been regarded as a predictor of myocardial fibrosis. We aimed in our study to investigate the frequency with which fQRS develops in patients with b-thalassaemia major and to disclose the correlation between fQRS frequency and Doppler-derived indices. METHODS: The patients with b-thalassaemia major (n=66; mean age: 23±6 years) and healthy controls (n=30; mean age: 23±4 years) were included. fQRS pattern was described as presence of RSR' manifested as existence of additional R wave and notching in either R or S waves in ECG recordings. 2D, M-mode, conventional Doppler, tissue Doppler echocardiography parameters were assessed. Mean serum ferritin levels over past 5 years were also calculated. RESULTS: When compared to those in control group, fQRS was more frequent in b-thalassaemia major group, indicating statistical significance (p = 0.001). While E/Em and ferritin level exhibited statistically significant increase in thalassaemia patients with fQRS (p < 0.05), the mean Em and Sm values were found to be significantly low (p < 0.05). CONCLUSIONS: fQRS was frequently observed in the patients with b-thalassaemia major, which was of statistical significance. Tissue Doppler-derived diastolic and systolic indices in thalassaemia cases with fQRS showed statistically significant impairment compared to those without fQRS. In conclusion, fQRS may represent a novel noninvasive marker for cardiac involvement in patients with b-thalassaemia major.
Subject(s)
Myocardium/pathology , beta-Thalassemia/complications , Case-Control Studies , Echocardiography, Doppler , Electrocardiography , Female , Fibrosis , Heart/physiopathology , Humans , Male , Young Adult , beta-Thalassemia/pathology , beta-Thalassemia/physiopathologyABSTRACT
A 24-year-old male patient was admitted to the coronary intensive care unit with atrial fibrillation with rapid ventricular response. He was given amiodarone (Cordarone 150 mg i.v., Sanofi-Aventis) intravenous loading dose of 300 mg in 100 mL dextrose 5% in water (D5W) over 1 hour, followed by a maintenance dose of 900 mg in 500 mL D5W for infusion up to 24 hours. At the emergency department, the patient was conscious and cooperative; his pretreatment arterial blood pressure was 120/80 mm Hg, and the arrhythmic tachycardia was 145 per minute. After intravenous amiodarone loading and half an hour into maintenance infusion, extreme perspiration, hypotension (blood pressure immeasurable), and mild cyanosis developed. The patient was conscious; his auscultation and pulse were normal. He was given physiologic serum and dopamine support. Approximately an hour later, the blood pressure was measurable. Infusion was terminated because of suspicion of an allergic reaction to acetylsalicylic acid or amiodarone. The allergic reaction observed was attributed to acetylsalicylic acid and amiodarone; infusion was resumed when the clinical situation worsened during the maintenance infusion. Once again, the patient was given physiologic serum (2000 mL), dopamine (20 mg/kg per minute), and, additionally, 250 mg of methyprednisolone sodium succinate intravenous, whereby the clinical condition improved within 20 minutes. Anaphylactic shock cases due to amiodarone are rare; it is important to take a history of drug-mediated anaphylaxis before prescribing amiodarone. An addition to a review of the literature regarding treatment of amiodarone-related anaphylactic shock cases had not been reported before.
Subject(s)
Amiodarone/adverse effects , Anaphylaxis/chemically induced , Anti-Arrhythmia Agents/adverse effects , Amiodarone/administration & dosage , Anti-Arrhythmia Agents/administration & dosage , Atrial Fibrillation/drug therapy , Humans , Infusions, Intravenous , Male , Young AdultABSTRACT
In cardiovascular medicine, hemodynamic stress with hypertension is a major risk [...].
ABSTRACT
Glioblastoma (GBM, WHO grade IV glioma) is the most common and lethal malignant brain tumor in adults with a dismal prognosis. The extracellular matrix (ECM) supports GBM progression by promoting tumor cell proliferation, migration, and immune escape. Uridine diphosphate (UDP)-glucose 6-dehydrogenase (UGDH) is the rate-limiting enzyme that catalyzes the biosynthesis of glycosaminoglycans that are the principal component of the CNS ECM. We investigated how targeting UGDH in GBM influences the GBM immune microenvironment, including tumor-associated microglia/macrophages (TAMs) and T cells. TAMs are the main immune effector cells in GBM and can directly target tumor cells if properly activated. In co-cultures of GBM cells and human primary macrophages, UGDH knockdown in GBM cells promoted macrophage phagocytosis and M1-like polarization. In orthotropic human GBM xenografts and syngeneic mouse glioma models, targeting UGDH decreased ECM deposition, increased TAM phagocytosis marker expression, reduced M2-like TAMs and inhibited tumor growth. UGDH knockdown in GBM cells also promoted cytotoxic T cell infiltration and activation in orthotopic syngeneic mouse glioma models. The potent and in-human-use small molecule GAG synthesis inhibitor 4-methylumbelliferone (4-MU) was found to inhibit GBM cell proliferation and migration in vitro, mimic the macrophage and T-cell responses to UGDH knockdown in vitro and in vivo and inhibit growth of orthotopic murine GBM. Our study shows that UGDH supports GBM growth through multiple mechanisms and supports the development of ECM-based therapeutic strategies to simultaneously target tumor cells and their microenvironment.
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Various diagnostic methods have been used to evaluate hypertensive patients under physical and pharmacological stress. Several studies have shown that exercise hypertension has an independent, adverse impact on outcome; however, other prognostic studies have shown that exercise hypertension is a favorable prognostic indicator and associated with good outcome. Exercise hypertension may be encountered as a warning signal of hypertension at rest and future hypertensive left ventricular hypertrophy. The results of diagnostic stress tests support that hypertensive response to exercise is frequently associated with high rate-pressure product in hypertensives. In addition to the observations on high rate-pressure product and enhanced ventricular contractility in patients with hypertension, evaluation of myocardial contractility by Doppler tissue imaging has shown hyperdynamic myocardial function under pharmacological stress. These recent quantitative data in hypertensives suggest that hyperdynamic myocardial function and high rate-pressure product response to stress may be related to exaggerated hypertension, which may have more importance than that it has been already given in clinical practice.
Subject(s)
Echocardiography/standards , Exercise Test/standards , Hypertension/diagnostic imaging , Hypertension/physiopathology , Stress, Physiological/physiology , Cardiotonic Agents , Dobutamine , Echocardiography/methods , Exercise/physiology , Exercise Test/methods , HumansABSTRACT
AIMS: Diabetic retinopathy (DR) is a serious complication of type 2 diabetes mellitus (T2DM) and is the most common cause of impaired vision for adults. DR is related to a number of risk factors. The aim of this study was to investigate the relationship between burden of coronary artery disease assessed by Syntax Score (SS) and DR in T2DM. METHODS: A total of 96 T2DM patients undergoing coronary angiography were prospectively included in the study. Presence and severity of DR were assessed by ocular fundus examination. DR was graded as no apparent retinopathy (NDR), non-proliferative (NPDR), and proliferative DR (PDR). The SS for each patient was calculated. RESULTS: The mean age was 58.0 ± 8.2 years. SS gradually increased from NDR group to PDR group. The median (IQR) value of SS was 10 (5-16) in patients with NDR, 22.8 (17-35.8) in those with NPDR, and 35.5 (28-37) in those with PDR (p < 0.001). On multivariate analysis SS [odds ratio (OR) 1.145, p = 0.001] and duration of diabetes (OR 1.753, p = 0.031) were independent factors for DR. CONCLUSIONS: The SS is independently associated with the occurrence of DR in T2DM. Ophthalmologists and cardiologists must cooperate when evaluating patients with DM because of possible complications.
Subject(s)
Coronary Artery Disease , Diabetes Mellitus, Type 2 , Diabetic Retinopathy , Aged , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/epidemiology , Coronary Artery Disease/etiology , Diabetes Mellitus, Type 2/complications , Diabetic Retinopathy/diagnostic imaging , Diabetic Retinopathy/epidemiology , Humans , Middle Aged , Odds Ratio , Risk FactorsABSTRACT
Early recognition of hypertensive heart disease is needed to prevent macrovascular and microvascular damage. Hypertension (HTN) is a risk factor for coronary artery disease, and plays a prominent role in the development of adverse left ventricular (LV) remodeling and heart failure. Here, we review new knowledge on effects of HTN on cardiac geometry and function, obtained from multimodality cardiac imaging, including echocardiography, positron emission tomography and magnetic resonance imaging. Early recognition of changes in LV geometry and function induced by HTN could identify patients at risk for end-organ damage, who could be targeted for close monitoring and intensive therapy. Basal septal hypertrophy as the early imaging biomarker at the adaptive phase may be a specific aspect not only in hypertensive heart but stress-related conditions and called stressed heart morphology.
ABSTRACT
BACKGROUD: Heart responds to physiologic and pathologic conditions and sympathetic drive plays an important role. It has been documented that LV base is more dominantly affected by sympathetic drive compared to the other regions. LV base is more dominantly exposed to wall stress in the initial period of remodeling due to pressure-overload, since LV cavity is the largest at base. Basal septal hypertrophy (BSH) in cross-sectional data is associated with the early phase of hypertensive heart disease. BSH was confirmed by 3rd generation microscopic ultrasound in small animals. BSH as the closest location to increased afterload could be detected in variety of stress stimuli and result in a huge septal hypertrophy in advance cases possibly related to earlier exposure of hemodynamic stress to septal wall. CONCLUSION: Effective geometric and functional evaluation of initial remodeling due to hemodynamic stress is important according to both human and animal data. These findings possibly contribute to early recognition of adaptive phase of hypertensive remodeling and more effective management in a timely fashion.