A tryptophan metabolite prevents depletion of circulating endothelial progenitor cells in systemic low-grade inflammation.

Background: Chronic systemic inflammation reduces the bioavailability of circulating endothelial progenitor cells (EPCs). Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme of immune tolerance catalyzing the initial step of tryptophan degradation along the so-called l-kynurenine (l-kyn) pathway, that is induced by inflammatory stimuli and exerts anti-inflammatory effects. A specific relationship between IDO1 activity and circulating EPC numbers has not yet been investigated. Methods: In this study, circulating EPCs were examined in mice treated with low doses of lipopolysaccharide (LPS) to mimic low-grade inflammation. Moreover, the association between IDO1 activity and circulating EPCs was studied in a cohort of 277 patients with variable systemic low-grade inflammation. Results: Repeated low doses of LPS caused a decrease in circulating EPCs and l-kyn supplementation, mimicking IDO1 activation, significantly increased EPC numbers under homeostatic conditions preventing EPC decline in low-grade endotoxemia. Accordingly, in patients with variable systemic low-grade inflammation, there was a significant interaction between IDO1 activity and high-sensitivity C-reactive protein (hs-CRP) in predicting circulating EPCs, with high hs-CRP associated with significantly lower EPCs at low IDO1 activity but not at high IDO1 activity. Interpretation: Overall, these findings demonstrate that systemic low-grade inflammation reduces circulating EPCs. However, high IDO1 activity and l-kyn supplementation limit circulating EPC loss in low-grade inflammation.

Effects of structured home-based exercise training on circulating endothelial progenitor cells and endothelial function in patients with intermittent claudication.

INTRODUCTION: Exercise training improves walking capacity in patients with intermittent claudication (IC). Endothelial progenitor cells (EPCs), endothelial microparticles (EMPs), and endothelial dysfunction could play a role in this process. METHODS: We measured EPCs and EMPs in a group of 60 patients with IC, and in a control group of 20 individuals without IC, before a treadmill test and 2, 24, and 48 hours after the test. Thirty patients with IC were randomly assigned to perform a 12-week home-based exercise training program. The EPC count, flow-mediated dilation (FMD) of the brachial artery, pain-free walking time (PFWT), and maximum walking time (MWT) were measured at the baseline and after the exercise training program. RESULTS: In patients with IC, EMPs significantly increased 2 hours after the treadmill test, whereas EPCs significantly increased after 24 hours. Among the subjects assigned to complete the training program, we observed a significant increase in the number of EPCs after 12 weeks, as well as an improvement in FMD, PFWT, and MWT. A significant correlation between the variation of EPCs, FMD, and MWT was found. The increase of EPCs and FMD were independent determinants of the walking capacity improvement, without significant interaction. CONCLUSION: Our results suggest that EPCs mobilization contributes to the improvement of walking capacity in patients with IC undergoing structured physical training. A number of different, partly independent, mechanisms are involved in this process, and our results highlight the potential role of EMPs release and endothelial function improvement. ClinicalTrials.gov Identifier: NCT04302571.

Hematological and Biochemical Reference Intervals for 5 Adult Hunting Dog Breeds Using a Blood Donor Database.

Numerous studies have shown the importance of breed-related differences between hematological and biochemical results in veterinary medicine. The aim of this study is to determine hematologic and biochemical Reference Intervals (RIs) for 5 hunting dog breeds from a blood donor database, adopting an indirect sampling method, and to compare them with laboratory established and published RIs to identify possible breed and attitude-related differences. The study analyzed the blood parameters of 445 adults (222 females and 223 male, with age ranging from 2 to 8 years, mean age 5.3 years), client-owned, clinically healthy blood donor dogs of 5 breeds: 156 Ariégeois, 52 Bleu de Gascogne, 64 Bracco italiano, 123 Segugio italiano, and 50 Briquet Griffon Vandeen. Statistical analysis was performed as recommended by the American Society of Veterinary Clinical Pathology (ASVCP) guidelines. RIs for red blood cells (RBC), hematocrit (HCT), hemoglobin (HB), main corpuscular volume (MCV), main corpuscular hemoglobin (MCH), main corpuscular hemoglobin concentration (MCHC), red distribution widht (RDW), white blood cells (WBC), and differential leukocytes count, PLT, Albumin, Total Protein, Urea, Creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) for each of the 5 breeds were performed, and significant differences with the established RIs were detected. We found significant differences in 12 hematologic and serum biochemical analytes for which a breed-specific variation appears to be the most plausible explanation. New RIs for HCT, MCH, MCHC, RDW, PLT, Monocytes, Eosinophils, Albumin, Urea, Creatinine, AST, and ALT are provided for at least 1 breed. Breed-specific RIs for adult hunting dogs will help avoid misinterpretation of laboratory results in these breeds.

Maraviroc Intensification Modulates Atherosclerotic Progression in HIV-Suppressed Patients at High Cardiovascular Risk. A Randomized, Crossover Pilot Study.

BACKGROUND: Experimental CCR5 antagonism with maraviroc in atherosclerosis-prone mice and preliminary data in humans suggest an anti-atherosclerotic effect of the drug. We assessed the impact of maraviroc treatment in persons living with HIV on subclinical indicators of atherosclerosis. METHODS: Persons living with HIV on effective antiretroviral therapy (ART) including only protease inhibitors were recruited if they had a Framingham risk score >20% and brachial flow-mediated dilation (bFMD) <4%, as indices of high cardiovascular risk. Maraviroc (300 mg per os for 24 weeks) was administered, in addition to ongoing ART, to all patients using a crossover design. Brachial FMD, carotid-femoral pulse wave velocity (cfPWV), and carotid intima-media thickness (cIMT) were measured as markers of atherosclerosis. Vascular competence-as expressed by the ratio of circulating endothelial microparticles (EMPs) to endothelial progenitor cells (EPCs)-and markers of systemic inflammation and monocyte and platelet activation were assessed. RESULTS: Maraviroc treatment significantly improved bFMD, cfPWV, and cIMT by 66%, 11%, and 13%, respectively (P = .002, P = .022, P = .038, respectively). We also found a beneficial effect of maraviroc on the EMP/EPC ratio (P < .001) and platelet/leucocyte aggregates (P = .013). No significant changes in markers of systemic inflammation, monocyte activation, and microbial translocation were observed. CONCLUSIONS: Maraviroc led to significant improvements in several markers for cardiovascular risk, endothelial dysfunction, arterial stiffness, and early carotid atherosclerosis, which was accompanied by an increase of vascular competence, without seeming to affect systemic inflammation. Our data support the need for larger studies to test for any effects of maraviroc on preventing atherosclerosis-driven pathologies.

NUtraceutical TReatment for hYpercholesterolemia in HIV-infected patients: The NU-TRY(HIV) randomized cross-over trial.

BACKGROUND AND AIMS: Despite hypercholesterolemia has been recognized to increase cardiovascular risk in human immunodeficiency virus (HIV)-infected patients, cholesterol-lowering therapy is underused in this population, due to fear of drug-drug interactions with antiretroviral therapy (ART). We investigated the effects of a nutraceutical combination (NC) on lipid profile, proprotein convertase subtilisin/kexin type 9 (PCSK9), subclinical inflammation and arterial stiffness in ART-treated HIV-infected patients. METHODS: This was a prospective randomized open-label trial with a cross-over design including 30 stable HIV-infected patients on ART with low-density lipoprotein cholesterol (LDL-C) >115 mg/dL, not taking lipid-lowering treatment. After a 3-week lipid stabilization period, the effects associated with 3 months of an oral NC containing red yeast rice and berberine vs. no active treatment (noNC) were assessed for plasma total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), lipoprotein(a), PCSK9, high-sensitivity C-reactive protein (hs-CRP) levels and aortic pulse wave velocity (aPWV). RESULTS: At baseline, significant correlations between PCSK9 levels, age (rho = -0.51, p=0.004), waist circumference (rho = 0.36, p=0.005) and CD4+ cell count (rho = -0.40, p=0.027) were observed. NC treatment effects corrected for noNC were significant for TC (-14%, p<0.001), LDL-C (-19%, p<0.001), PCSK9 (-12%, p=0.02), hs-CRP (-14%, p=0.03) and aPWV (-6%, p=0.005). No significant effects were observed for HDL-C, TG and lipoprotein(a). NC treatment was safe and no significant alterations in muscle, liver and immunovirological parameters were observed. No carry over effect was recorded. CONCLUSIONS: The tested NC significantly reduced plasma cholesterol and PCSK9 levels, attenuated subclinical inflammation and improved arterial stiffness in stable HIV-infected patients on ART.

S1P promotes migration, differentiation and immune regulatory activity in amniotic-fluid-derived stem cells.

Stem cells have high potential for cell therapy in regenerative medicine. We previously isolated stem cell types from human amniotic fluid, derived from prenatal amniocentesis. One type, characterized by a fast doubling time, was designated as fast human amniotic stem cells (fHASCs). These cells exhibited high differentiation potential and immunoregulatory properties. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that influences stem-cell pluripotency, differentiation, mobility, and regulates immune functions. In this study, we investigated the influence of S1P on fHASC migration, proliferation, differentiation and immune regulatory functions. We found that fHASC stimulation with S1P potentiated their migratory and proliferative activity in vitro. Notably, short fHASC exposure to S1P enhanced their differentiation towards multiple lineages, including adipocytes, osteocytes and endothelial cells, an effect that was associated with downregulation of the main transcription factors involved in the maintenance of a stem-cell undifferentiated state. A specific crosstalk between S1P and tumor growth factor ß1 (TGF-ß1) has recently been demonstrated. We found that fHASC exposure to S1P in combination with TGF-ß1 promoted the expression of the immune regulatory pathway of indoleamine 2,3-dioxygenase 1 (IDO1). In addition, human peripheral blood mononuclear cells, co-cultured with fHASCs treated with S1P and TGF-ß1, expanded regulatory T-cells, via a mechanism requiring IDO1. Overall, this study demonstrates that S1P potentiates several properties in fHASCs, an effect that may be critical for exploiting the therapeutic potential of fHASCs and might explain the specific effects of S1P on stem cells during pregnancy.

Elevated serum uric acid levels are associated with endothelial dysfunction in HIV patients receiving highly-active antiretroviral therapy.

BACKGROUND AND AIMS: Elevated serum uric acid (SUA) levels may be associated with endothelial dysfunction. Increased rates of metabolic syndrome (MS) and elevated SUA levels were described in human immunodeficiency virus (HIV) infected patients. We investigated whether SUA levels are associated with endothelial dysfunction in HIV positive patients receiving highly-active antiretroviral therapy (HAART) irrespective of MS. METHODS: In this cross-sectional study of 250 HIV positive patients receiving stable HAART, we evaluated the relationship between MS, SUA levels and endothelial function. SUA levels and brachial artery flow-mediated dilation (bFMD) were measured. The relationship between logarithmic (LG)-transformed SUA levels and bFMD was evaluated after correction for MS. RESULTS: MS was detected in 28.4% of patients and elevated SUA levels (≥6 mg/dL) in 25.2%. MS was associated with higher LG-SUA levels (age-, gender- and glomerular filtration rate-adjusted beta = 0.204, p = 0.001). The crude linear association between LG-SUA levels and LG-bFMD (beta = -0.166, p = 0.008) was abolished after correction for MS (beta = -0.089, p = 0.172). When SUA levels were used as a categorical variable (≥6 mg/dL or <6 mg/dL and SUA quartiles, respectively), the association between LG-SUA levels and LG-bFMD remained significant after adjustment for MS (beta = -0.142, p = 0.022 and beta = -0.163, p = 0.010, respectively). CONCLUSIONS: MS significantly affects SUA levels in HAART-treated HIV infected patients. The negative association between SUA and bFMD is independent of MS only for elevated SUA levels.

Endothelial and cardiac progenitor cells for cardiovascular repair: A controversial paradigm in cell therapy.

Stem cells have the potential to differentiate into cardiovascular cell lineages and to stimulate tissue regeneration in a paracrine/autocrine manner; thus, they have been extensively studied as candidate cell sources for cardiovascular regeneration. Several preclinical and clinical studies addressing the therapeutic potential of endothelial progenitor cells (EPCs) and cardiac progenitor cells (CPCs) in cardiovascular diseases have been performed. For instance, autologous EPC transplantation and EPC mobilization through pharmacological agents contributed to vascular repair and neovascularization in different animal models of limb ischemia and myocardial infarction. Also, CPC administration and in situ stimulation of resident CPCs have been shown to improve myocardial survival and function in experimental models of ischemic heart disease. However, clinical studies using EPC- and CPC-based therapeutic approaches have produced mixed results. In this regard, intracoronary, intra-myocardial or intramuscular injection of either bone marrow-derived or peripheral blood progenitor cells has improved pathological features of tissue ischemia in humans, despite modest or no clinical benefit has been observed in most cases. Also, the intriguing scientific background surrounding the potential clinical applications of EPC capture stenting is still waiting for a confirmatory proof. Moreover, clinical findings on the efficacy of CPC-based cell therapy in heart diseases are still very preliminary and based on small-size studies. Despite promising evidence, widespread clinical application of both EPCs and CPCs remains delayed due to several unresolved issues. The present review provides a summary of the different applications of EPCs and CPCs for cardiovascular cell therapy and underlies their advantages and limitations.

Autologous Cell Therapy for Vascular Regeneration: The Role of Proangiogenic Cells.

BACKGROUND: Autologous cell therapy represents a novel treatment option for vascular regeneration in different disease conditions, with experimental and clinical studies indicating a therapeutic potential for proangiogenic cells (PCs), including endothelial progenitor cells, in the treatment of coronary and peripheral artery disease. OBJECTIVE: To provide a summary of the therapeutic potential of PCs administration or mobilization in peripheral artery disease, ischemic heart and cerebrovascular diseases, diabetic microvascular complications and inflammatory rheumatic diseases. METHODS: We undertook a search of bibliographic databases for peer-reviewed research literature on the role of PCs in vascular regeneration in preclinical and clinical models. RESULTS: Improvement of ischemic symptoms has been reported in different trials evaluating PCs for the treatment of critical limb ischemia. However, in this setting, contrasting results from meta-analyses question the long-term clinical efficacy of PC-based approaches. Preclinical studies and clinical trials support the safety and feasibility of PC therapy in the treatment of ischemic heart and cerebrovascular diseases, while evidence indicating a benefit on hard clinical outcomes is uncertain. Despite accumulating experimental results support a therapeutic role for PCs in diabetic retinopathy, results from randomized clinical trials are lacking. Whether PC therapy may limit premature atherosclerosis and reduce cardiovascular risk in inflammatory rheumatic diseases needs to be investigated. CONCLUSION: Although the potential clinical applications of PCs are accumulating, there is also evidence of multiple limitations for autologous PC therapy. Thus, novel strategies aimed at improving PC viability and angiogenic function are warranted in order to improve the efficacy of cell therapy applications.

Hepatitis C virus and proprotein convertase subtilisin/kexin type 9: a detrimental interaction to increase viral infectivity and disrupt lipid metabolism.

From viral binding to the hepatocyte surface to extracellular virion release, the replication cycle of the hepatitis C virus (HCV) intersects at various levels with lipid metabolism; this leads to a derangement of the lipid profile and to increased viral infectivity. Accumulating evidence supports the crucial regulatory role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipoprotein metabolism. Notably, a complex interaction between HCV and PCSK9 has been documented. Indeed, either increased or reduced circulating PCSK9 levels have been observed in HCV patients; this discrepancy might be related to several confounders, including HCV genotype, human immunodeficiency virus (HIV) coinfection and the ambiguous HCV-mediated influence on PCSK9 transcription factors. On the other hand, PCSK9 may itself influence HCV infectivity, inasmuch as the expression of different hepatocyte surface entry proteins and receptors is regulated by PCSK9. The aim of this review is to summarize the current evidence about the complex interaction between HCV and liver lipoprotein metabolism, with a specific focus on PCSK9. The underlying assumption of this review is that the interconnections between HCV and PCSK9 may be central to explain viral infectivity.

Lipoprotein(a) and inflammation: A dangerous duet leading to endothelial loss of integrity.

Lipoprotein(a) [Lp(a)] is an enigmatic lipoprotein whose ancestral useful properties have been gradually obscured by its adverse pro-atherogenic and pro-thrombotic effects, that culminate into an increased risk of ischemic cardiovascular events. Although plasma Lp(a) levels are largely determined on a genetic basis, multiple factors have been reported to interfere with its plasma levels. Inflammation is one of these factors and it is believed to promote pro-atherogenic and pro-thrombotic changes leading to increased cardiovascular disease risk. The influence of inflammation on plasma Lp(a) levels is variable, with studies reporting either increased, reduced or unchanged Lp(a) expression and plasma concentrations following exposure to pro-inflammatory stimuli. The complex association between inflammation and Lp(a) is further amplified by additional findings showing that Lp(a) may promote the expression of a plethora of pro-inflammatory cytokines and induces the endothelium to switch into an activated status which results in adhesion molecules expression and inflammatory cells invasion into the arterial wall. In this picture, it emerges that increased plasma Lp(a) levels and inflammation may coexist and their coexistence may exert a deleterious impact on endothelial integrity both at a functional and structural level. Also, the detrimental duet of inflammation and Lp(a) may interfere with the physiological endothelial repair response, thus further amplifying endothelial loss of integrity and protective functions. A fundamental understanding of the interaction between Lp(a) and inflammation is critical for our comprehension of the mechanisms leading to the derangement of endothelial homeostasis and vascular dysfunction.

Urinary albumin-to-creatinine ratio is associated with endothelial dysfunction in HIV-infected patients receiving antiretroviral therapy.

Endothelial dysfunction, a marker of cardiovascular (CV) risk, is common in human immunodeficiency virus (HIV)-infected patients. Microalbuminuria is frequent in HIV-infected patients, and is a predictor of renal impairment and CV risk. We investigated the association between microalbuminuria and endothelial dysfunction among HIV-infected patients receiving highly-active antiretroviral therapy (HAART). Endothelial function, measured by brachial artery flow-mediated dilatation (bFMD), and urine albumin-to-creatinine ratio (UACR), were measured in 170 HAART-treated HIV-infected adults. The relationship between UACR and bFMD was evaluated. The prevalence of increased UACR, defined by two cut-off levels (20 mg/g and 30 mg/g), was 29% and 17%. UACR was significantly higher while bFMD was lower among patients with metabolic syndrome (MS). UACR was associated with bFMD (r = -0.31; p < 0.001). This association was stronger in MS-patients (r = -0.44; p = 0.003). UACR above 20 mg/g was associated with an increased risk (OR 2.37, 95% CI 1.15-4.89, p = 0.020) of severely impaired bFMD (bFMD ≤ 2.1%). Patients with MS and increased UACR had the lowest bFMD compared with those with none or one of the two conditions. Microalbuminuria and endothelial dysfunction are positively associated in HIV-infected patients regardless of known confounders. The coexistence of microalbuminuria and MS amplifies their deleterious influence on endothelial function.

Reduced survival in patients with early-stage non-small-cell lung cancer is associated with high pleural endothelial progenitor cell levels.

OBJECTIVES: Endothelial progenitor cells are capable of contributing to neovascularization in tumours. In patients with either malignant or transudative pleural effusion, we tested the presence of pleural endothelial progenitor cells. We also measured the number of endothelial progenitor cells in post-surgery pleural drainage of either patients with early non-small-cell lung cancer or control patients with benign lung disease undergoing pulmonary resection. The prospective influence of post-surgery pleural-drainage endothelial progenitor cells on cancer recurrence/survival was investigated. METHODS: Pleural endothelial progenitor cell levels were quantified by fluorescence-activated cell sorting analysis in pleural effusion of 15 patients with late-stage non-small-cell lung cancer with pleural involvement and in 15 control patients with congestive heart failure. Also, pleural-drainage endothelial progenitor cells were measured in pleural-drainage fluid 48 h after surgery in 64 patients with early-stage non-small-cell lung cancer and 20 benign lung disease patients undergoing pulmonary resection. Cancer recurrence and survival was evaluated in patients with high pleural-drainage endothelial progenitor cell levels. RESULTS: The number of pleural endothelial progenitor cells was higher in non-small-cell lung cancer pleural effusion than in transudative pleural effusion. Also, pleural-drainage endothelial progenitor cell levels were higher in patients with non-small-cell lung cancer than in patients with benign lung disease undergoing pulmonary resection (P < 0.05). Non-small-cell lung cancer patients with high pleural-drainage endothelial progenitor cell levels had a significantly 4.9 higher rate of cancer recurrence/death than patients with lower pleural-drainage endothelial progenitor cell levels, irrespective of confounders. CONCLUSIONS: Endothelial progenitor cells are present in the pleural effusion and are higher in patients with late-stage non-small-cell lung cancer with pleural involvement than in congestive heart failure patients. Endothelial progenitor cell levels are higher in the post-surgery pleural drainage of patients with non-small-cell lung cancer than in non-neoplastic pleural-drainage fluid. High pleural-drainage endothelial progenitor cell levels in patients undergoing pulmonary resection for early non-small-cell lung cancer predict an increased risk of cancer recurrence and death.

The effects of a nutraceutical combination on plasma lipids and glucose: A systematic review and meta-analysis of randomized controlled trials.

Dyslipidemia and hyperglycemia are associated with an increased risk of ischemic cardiovascular disease. Positive effects of a nutraceutical combination comprising red yeast rice, berberine, policosanol, astaxanthin, coenzyme Q10 and folic acid (NComb) on plasma lipid and glucose levels have been reported in some but not all clinical trials. To address this inconsistency, we tried to estimate the size of lipid- and glucose-lowering effects of NComb through a systematic review and meta-analysis of randomized controlled trials. A systematic literature search in PubMed-Medline, SCOPUS and Google Scholar databases was conducted to identify randomized controlled trials investigating the effects of NComb on plasma lipids and glucose levels. Inverse variance-weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated for net changes in lipid and glucose levels using a random-effects model. Random-effects meta-regression was performed to assess the effect of putative confounders on plasma lipid and glucose levels. Fourteen trials (1670 subjects in the NComb arm and 1489 subjects in the control arm) met the eligibility criteria for lipid analysis and 10 trials (1014 subjects in the NComb arm and 962 subjects in the control arm) for glucose analysis. Overall, WMDs were significant for the impact of NComb supplementation on plasma levels of total cholesterol (-26.15mg/dL, p<0.001), LDL-cholesterol (-23.85mg/dL, p<0.001), HDL-cholesterol (2.53mg/dL, p<0.001), triglycerides (-13.83mg/dL, p<0.001) and glucose (-2.59mg/dL, p=0.010). NComb-induced amelioration of lipid profile was not affected by duration of supplementation nor by baseline lipid levels; conversely, a greater glucose-lowering effect of NComb was found with higher baseline glucose levels and longer durations of supplementation. In conclusion, the present results suggest that NComb supplementation is associated with improvement of lipid and glucose profile. Short-term beneficial effects of NComb supplementation appear to be maintained in the long term.

Effects of a nutraceutical combination on lipids, inflammation and endothelial integrity in patients with subclinical inflammation: a randomized clinical trial.

Cholesterol elevations are associated with systemic inflammation and endothelial fragmentation into microparticles. The cholesterol-lowering efficacy of nutraceutical combinations (NC) has not been investigated in patients with low-grade systemic inflammation and normal-borderline cholesterol levels. This is a 3-month prospective randomized open-label interventional study in patients with elevated plasma high sensitivity C-reactive protein (hsCRP) levels (>2 mg/L) and low-density lipoprotein (LDL) cholesterol of 100-160 mg/dL. The effect of either an oral cholesterol-lowering nutraceutical combination (NC) or no active treatment (noNC) was tested on LDL cholesterol, hsCRP and endothelial microparticle (EMPs) levels. Patients taking the NC had a significant reduction of total (-12%) and LDL cholesterol (-23%) compared to those who received noNC (p < 0.001 for both). Also, hsCRP and EMPs were significantly reduced by the NC (-41% and -16%, respectively). LDL cholesterol change was positively associated with hsCRP (rho = 0.21, p = 0.04) and EMP changes (rho = 0.56, p < 0.001), hsCRP and EMP changes being associated with each other (rho = 0.28, p = 0.005). Patients experiencing both LDL cholesterol and hsCRP reduction were those having the greatest EMP decrease. In conclusion, among patients with low-grade systemic inflammation, an oral NC significantly improved cholesterol profile and attenuated the degree of systemic inflammation and endothelial injury.

Systemic inflammation and imbalance between endothelial injury and repair in patients with psoriasis are associated with preclinical atherosclerosis.

BACKGROUND: Systemic inflammation and imbalance between endothelial injury and repair, the latter referred to as vascular incompetence, are associated with atherosclerosis and cardiovascular risk. Psoriasis, an inflammatory disease of the skin, has been associated with atherosclerosis. We investigated whether, in psoriasis, inflammation and vascular incompetence are associated with carotid intima-media thickness (cIMT) irrespective of metabolic syndrome and other established cardiovascular risk factors. METHODS: High sensitivity C-reactive protein (hsCRP), the ratio between endothelial microparticles (EMPs) and progenitors (EPCs), a marker of vascular incompetence, and cIMT were measured in 84 patients with psoriasis and 90 healthy controls, balanced for age, gender and the prevalence of metabolic syndrome. RESULTS: Patients with psoriasis had higher hsCRP, EMP/EPC ratio and cIMT than controls. Patients with both psoriasis and metabolic syndrome had the highest hsCRP levels, psoriasis and metabolic syndrome being associated with a 3.1- and 2.6-fold increased risk of having high hsCRP levels, respectively. Logarithm transformed hsCRP and EMP/EPC ratio were predictors of high cIMT (odds ratio 3.8; 95% confidence interval 1.3-11.4; p = 0.02 and odds ratio 8.7; 95% confidence interval 2.7-27.5; p < 0.001, respectively) regardless of confounders. Patients with high hsCRP and EMP/EPC ratio had higher cIMT than those with none or at least one of risk variable. CONCLUSIONS: Patients with psoriasis have an increased burden of cardiovascular risk, including inflammation, vascular incompetence and early atherosclerosis. Increased hsCRP levels, possibly sustained by the inflammatory nature of psoriasis and metabolic syndrome, and vascular incompetence are associated with early carotid atherosclerosis, regardless of metabolic syndrome and other established cardiovascular risk factors.

miR128 up-regulation correlates with impaired amyloid ß(1-42) degradation in monocytes from patients with sporadic Alzheimer's disease.

Alzheimer's disease (AD), the most common form of dementia in elderly individuals, is characterized by neurofibrillary tangles, extracellular amyloid-ß (Aß) plaques and neuroinflammation. New evidence has shown that the lysosomal system might be a crossroad in which etiological factors in AD pathogenesis converge. This study shows that several lysosomal enzymes, including Cathepsin B, D, S, ß-Galactosidase, α-Mannosidase, and ß-Hexosaminidase, were less expressed in monocytes and lymphocytes from patients with a clinical diagnosis of AD dementia compared with cells from healthy controls. In vitro experiments of gain and loss of function suggest that down-regulation is a direct consequence of miR-128 up-regulation found in AD-related cells. The present study also demonstrates that miR-128 inhibition in monocytes from AD patients improves Aß(1-42) degradation. These results could contribute to clarify the molecular mechanisms that affect the imbalanced Aß production/clearance involved in the pathogenesis of AD.

Baseline and post-surgery endothelial progenitor cell levels in patients with early-stage non-small-cell lung carcinoma: impact on cancer recurrence and survival.

OBJECTIVES: Endothelial progenitor cells (EPCs) are believed to play a role in promoting abnormal vascularization in neoplastic sites. We measured the number of circulating EPCs in treatment-naïve patients with early non-small-cell lung cancer (NSCLC) and healthy controls. The prospective influence of baseline and post-surgery EPC levels on cancer recurrence and survival was investigated. METHODS: Circulating EPCs were quantified by FACS analysis in 34 patients with Stage I-II NSCLC and 68 healthy age- and sex-matched controls. Measurement of EPCs was repeated 48 h after thoracic surgery and at the hospital discharge. Cancer recurrence and survival was evaluated after 446 ± 106 days of follow-up (range 182-580 days). RESULTS: The base 10 logarithmic [log] number of circulating EPCs was comparable between patients with NSCLC and controls [mean ± standard deviation (SD): 2.3 ± 0.32 vs 2.3 ± 0.26 n/ml, P = 0.776]. In regression analysis, smoking status [standardized coefficient beta (ß) = -0.26, 95% confidence interval (CI) for B -0.29/-0.03, P = 0.014] and systolic blood pressure [ß = -0.23, 95% CI for B -0.011/-0.001, P = 0.018] were independent predictors of the number of EPCs, irrespective of the NSCLC status. The mean number of EPCs did not change after surgical treatment. However, a post-surgery EPC increase was observed in 44% patients. Patients with a 48 h post-surgery EPC increase had a higher rate of cancer recurrence/death than patients with either stable or decreased post-surgery EPC levels [hazard ratio (HR) 4.4, 95% CI 1.1-17.3; P = 0.032], irrespective of confounders. CONCLUSIONS: Circulating EPC levels are comparable between patients with early-stage NSCLC and healthy controls. Overall, surgical cancer resection was not associated with a significant early EPC change. However, an early post-surgery EPC increase is able to predict an increased risk of cancer recurrence and death.

On-treatment C-reactive protein and HDL cholesterol levels in patients at intermediate cardiovascular risk: impact on carotid intima-media thickness.

AIMS: Statin therapy is followed by reductions in carotid intima-media thickness (CIMT) and C-reactive protein (CRP) levels, but a significant number of treated patients still have increased CIMT. We investigated whether on-treatment levels of CRP are associated with CIMT in hypercholesterolemic patients receiving statin therapy. The influence of blood pressure and anti-hypertensive therapy on the association between CRP and CIMT was evaluated. MAIN METHODS: The assessment of cardiovascular risk factors, CRP and CIMT, was performed in a cross-sectional study of 240 hypercholesterolemic patients at intermediate cardiovascular risk under statin therapy; 125 patients received only a statin (statin group) and 115 also anti-hypertensive therapy (combined therapy group). KEY FINDINGS: Logarithmically transformed CRP (ß=0.17, p=0.01) and HDL cholesterol levels (ß=-0.27, p<0.001) were correlates of CIMT, irrespective of confounders. High CRP levels (>3mg/L) were associated with a 2.7-fold increased risk of having high CIMT (>1.25mm). High CIMT was present in a high percentage of patients not at target for cholesterol and blood pressure levels (61%). Patients in the statin group had lower Framingham risk and CIMT than those in the combined therapy group. In the statin group, logarithmically transformed CRP (ß=0.28, p=0.004) and HDL cholesterol (ß=-0.21, p=0.03) were associated with CIMT. In the combined therapy group, HDL cholesterol was the only significant CIMT correlate (ß=-0.33, p=0.001). SIGNIFICANCE: On-treatment CRP and HDL cholesterol levels are associated with CIMT among hypercholesterolemic patients under statin therapy. In patients receiving both statin and anti-hypertensive therapy, HDL cholesterol remains the main covariate of CIMT.

Association of parathyroid hormone and 25-OH-vitamin D levels with arterial stiffness in postmenopausal women with vitamin D insufficiency.

AIM: Vitamin D insufficiency and increased parathyroid hormone (PTH) levels have been suggested as prognostic indices for cardiovascular disease. Arterial stiffness, a surrogate marker for cardiovascular disease, is often increased in patients with primary hyperparathyroidism. PTH levels increase in patients with low 25-OH-vitamin D levels, but the influence of such an increase on arterial stiffness has not been investigated in postmenopausal women with reduced 25-OH-vitamin D levels. We therefore investigated the association between PTH and aortic stiffness in postmenopausal women with reduced 25-OH-vitamin D levels. METHODS: One hundred fifty postmenopausal women with 25-OH-vitamin D insufficiency (<30 ng/mL) were recruited. Aortic pulse wave velocity (aPWV), a measure of arterial stiffness, PTH and 25-OH-vitamin D levels were measured. Cardiovascular risk factors and markers of bone formation were evaluated. RESULTS: The 25-OH-vitamin D levels were associated with aPWV (rho=-0.23, p=0.006), but the association was not significant when controlling for PTH. Significant correlates of aPWV included age, body mass index, mean arterial pressure and PTH (rho=0.39, p<0.001). Arterial stiffness was predicted by logarithmically transformed PTH levels (ß=0.23, p=0.007), independent of traditional cardiovascular risk factors and factors involved in bone formation. Increased PTH levels (>62 pg/mL) were associated with a 3.0-5.4-fold increased probability of having a mild-severe increase in aortic stiffness, irrespective of confounders. CONCLUSION: Among postmenopausal women with reduced 25-OH-vitamin D levels, elevated PTH levels were a significant predictor of aortic stiffness, irrespective of cardiovascular risk factors and of factors involved in bone formation. PTH accounted for the association between 25-OH-vitamin D levels and aortic stiffness.