Low heart-type fatty acid binding protein level during aging may protect down syndrome people against atherosclerosis.

BACKGROUND: Aging is considered an important independent risk factor for atherosclerosis. Down syndrome people (DS) display an accelerated aging process compared to healthy subjects, anyway they are relatively resistant to developing atherosclerosis. The mechanisms involved in such protective effect are not well known. Since heart-type fatty acid binding protein (H-FABP) is a protein involved in the transport of fatty acids and it has been recently correlated with the presence of atherosclerosis, we aimed to measure H-FABP level both in DS and in healthy subjects during aging to evaluate the association between this molecule, aging and atherosclerosis. FINDINGS: We quantified plasmatic H-FABP level in three groups of male DS and age-matched healthy subjects (children, age 2-14 years; adults, age 20-50 years; elderly, > 60 years) using a biochip array analyzer. We observed that aging is associated with increased H-FABP level in healthy subjects but not in DS which display both the same protein level in the different ages of life and have also lower level compared to their age-matched healthy subjects. CONCLUSION: Reduced H-FABP level during aging in DS may play a protective role against atherosclerosis. The potential involvement of H-FABP in the relationship between aging, atherosclerosis and development of coronary artery disease needs further investigations.

Adipokines, hormonal parameters, and cardiovascular risk factors: similarities and differences between patients with erectile dysfunction of arteriogenic and nonarteriogenic origin.

INTRODUCTION: Erectile dysfunction (ED) is often associated with metabolic disorders. Leptin and adiponectin are adipose tissue-derived hormones involved in the regulation of metabolic homeostasis and considered important players in the relationship among obesity and cardiovascular diseases. AIM: Leptin, adiponectin, leptin to adiponectin ratio (L/A), and their correlation with hormonal and metabolic parameters were examined in male with arteriogenic- (A-ED) and nonarteriogenic-ED (NA-ED). MAIN OUTCOME MEASURES: Biochemical, metabolic, and hormonal parameters of men with A-ED were compared with those of male with NA-ED. METHODS: Diagnosis of ED was based on the International Index of Erectile Function Score. Its etiology was classified with penile echo-color Doppler at baseline and after intracavernous injection of prostaglandin E1. Leptin and adiponectin were measured by enzyme-linked immunosorbent assay. RESULTS: In A-ED subjects, increased levels of insulin, glycated hemoglobin, homeostasis model assessment of insulin resistance (HOMA-IR) index, body mass index (BMI), leptin, and L/A and decreased levels of total, free, and bioavailable testosterone were observed compared with NA-ED subjects. A trend toward lower estradiol level was also present in A-ED patients, even if not statistically significant. Reduced levels of adiponectin have been observed in both groups compared with patients without ED. Leptin and L/A correlated similarly with several parameters (negatively with testosterone/estradiol ratio and positively with BMI, insulin, HOMA-IR, and 17-beta estradiol). L/A resulted further correlated negatively with high-density lipoprotein and positively with triglycerides. CONCLUSIONS: Not all ED cases are similar. In fact, A-ED patients display a more complicated metabolic status characterized by overweight and obesity and associated to sexual hormone alteration. Whether changes in body composition and modulation of adipokine levels can improve local endothelial function need further investigation.

Reduced plasma levels of P-selectin and L-selectin in a pilot study from Alzheimer disease: relationship with neuro-degeneration.

Neurodegenerative processes associated with Alzheimer's disease (AD) are accompanied by reactive astrogliosis and microglia activation and a role for chronic inflammation in the brain degeneration of these patients has been suggested. Moreover impaired immune functions in AD brains might also influence the disease's progression. Therefore, it is of interest to further characterized inflammatory molecules in the peripheral blood of patients with AD and its relationship with cognitive decline. A complex picture emerged in this pilot study and IL-8, IFN-gamma, MCP-1 and VEGF levels were increased in AD. Levels of P-selectin and L-selectin were decreased in AD and lowest in AD patients with highest cognitive decline. Our findings suggest that these molecules may induce alterations of endothelial regulation and influence neurodegenerative processes of AD.

Plasma concentrations of angiogenetic factors and angiogenetic inhibitors in patients with ductal pancreatic neoplasms. A pilot study.

BACKGROUND: The aim of the study was to evaluate the circulating concentrations of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGFR-2), vascular endothelial growth factor-D (VEGF-D) and endostatin in patients with intraductal papillary mucinous neoplasm (IPMN), and in those with ductal adenocarcinomas. METHODS: Sixty patients (32 males, 28 females, mean age 69.3±11.3 years) were enrolled: 31 (51.7%) had IPMNs and 29 (48.3%) had histologically confirmed pancreatic adenocarcinomas. Thirty blood donors were also studied as controls. In all study subjects, the concentrations of VEGF, VEGF-D, VEGFR-2, and endostatin were determined using enzyme-linked immunosorbent assays. RESULTS: Serum concentrations of VEGF, VEGF-D, and VEGFR-2 were significantly higher in patients with pancreatic ductal adenocarcinoma and those with IPMNs compared with healthy subjects, while endostatin was significantly higher only in patients with pancreatic ductal adenocarcinoma compared with healthy subjects. Within the group of patients, VEGFR-2 was significantly higher in patients with ductal adenocarcinoma compared to those with IPMNs. The sensitivity and the specificity of VEGFR-2 in differentiating patients with ductal adenocarcinomas from those with IPMN at a cut-off range of 4003-4034 pg/mL was 86.2% and 54.8%, respectively. CONCLUSIONS: IPMNs have serum VEGFR-2 concentrations different from those in patients with ductal adenocarcinomas. However, serum VEGFR-2 cannot be routinely utilized to differentiate IPMNs from pancreatic ductal adenocarcinomas.

Plasma and drainage fluid levels of soluble receptor activator of nuclear factor-kB (sRANK), soluble receptor activator of nuclear factor-kB ligand (sRANKL) and osteoprotegerin (OPG) during proximal humerus fracture healing.

Fracture healing is an ordered process that restores the structural integrity of the bone. Soluble receptor activator of nuclear factor-kB (sRANK), its ligand (sRANKL) and osteoprotegerin (OPG) are involved in bone remodelling, thus they may play a role in fracture repair. OPG, soluble RANK and RANKL levels were measured in plasma and in drainage fluid, collected from pre-surgery phase to healing in ten patients of both genders (age range 26-65 years) with proximal humerus fracture needing osteosynthesis. All patients showed fracture healing. No significant modifications in the concentrations of sRANKL and OPG were observed, while sRANK showed a significant increase in drainage fluid 24 hours post-surgery compared with intra-surgery time. OPG levels were higher in plasma and drainage fluid than sRANK and sRANKL at each time point. Since there are no published data about sRANK involvement in fracture healing, our study represents the first preliminary indication about a local increase of this marker concentration immediately after surgery.

Molecular basis of anti-inflammatory action of platelet-rich plasma on human chondrocytes: mechanisms of NF-κB inhibition via HGF.

Loss of articular cartilage through injury or disease presents major clinical challenges also because cartilage has very poor regenerative capacity, giving rise to the development of biological approaches. As autologous blood product, platelet-rich plasma (PRP) provides a promising alternative to surgery by promoting safe and natural healing. Here we tested the possibility that PRP might be effective as an anti-inflammatory agent, providing an attractive basis for regeneration of articular cartilage, and two principal observations were done. First, activated PRP in chondrocytes reduced the transactivating activity of NF-κB, critical regulator of the inflammatory process, and decreased the expression of COX-2 and CXCR4 target genes. By analyzing a panel of cytokines with different biological significance, in activated PRP we observed increases in hepatocyte growth factor (HGF), interleukin-4 and tumor necrosis factor-α (TNF-α). HGF and TNF-α, by disrupting NF-κB-transactivating activity, were important for the anti-inflammatory function of activated PRP. The key molecular mechanisms involved in PRP-inhibitory effects on NF-κB activity were for HGF the enhanced cellular IkBα expression, that contributed to NF-κB-p65 subunit retention in the cytosol and nucleo-cytoplasmic shuttling, and for TNF-α the p50/50 DNA-binding causing inhibition of target-gene expression. Second, activated PRP in U937-monocytic cells reduced chemotaxis by inhibiting chemokine transactivation and CXCR4-receptor expression, thus possibly controlling local inflammation in cartilage. In conclusion, activated PRP is a promising biological therapeutic agent, as a scaffold in micro-invasive articular cartilage regeneration, not only for its content of proliferative/differentiative growth factors, but also for the presence of anti-inflammatory agents including HGF.

O-beta-N-acetyl-D-glucosaminidase in erythrocytes of Italian air force acrobatic pilots.

BACKGROUND: Italian air force acrobatic pilots are occupationally susceptible to oxidative stress damage that can lead to overt signs and symptoms of hypoxia. We propose erythrocyte glycohydrolases as new, sensitive markers to assess oxidative stress. METHODS: We measured erythrocyte concentrations of beta-D-glucuronidase (GCR), hexosaminidase, O-beta-N-acetyl-D-glucosaminidase (O-GlcNAcase), plasma membrane fluidity and plasma hydroperoxides from 19 pilots and compared these to 40 matched healthy subjects. RESULTS: Plasma hydroperoxide concentrations and the erythrocyte ghosts' fluorescence anisotropy were significantly lower in the pilots. Concentrations of GCR, O-GlcNAcase and hexosaminidase in pilots were significantly different from controls, being lower, higher and higher, respectively. CONCLUSIONS: Pilots, in spite of their oxidative stress, are better protected than controls, probably as a result of their physical training and proper diet. Our results confirm that erythrocytes, with their 120-day life span, are a useful model for investigating physiopathological conditions, and glycohydrolases are good markers for monitoring oxidative stress, even in healthy people.

Age-related changes in plasma levels of BDNF in Down syndrome patients.

BACKGROUND: The prevalence of coronary artery diseases is low among Down Syndrome (DS) patients and they rarely die of atherosclerotic complications. Histopathological investigations showed no increase in atherosclerosis, or even a total lack of atherosclerotic changes, in DS AIM: The aim of our study is to investigate the relationship between age and brain-derived neurotrophic factor (BDNF) levels in Down Syndrome (DS). SUBJECTS AND METHODS: Three groups of DS patients were studied: the first consisted of 23 children (age 2-14 years); the second of 14 adults (age 20-50 years), the third group of 13 elderly persons (>60 years) and a controls group of 20 healthy patients (age 15-60 years).The analytes of interest were quantified using a biochip array analyzer (Evidence, Randox Ltd., Crumlin, UK). RESULTS: Plasma BDNF was higher in DS patients than in controls and there was a significant age-related increase. Serum levels of IL-6 and MCP-1 were also higher in DS children and adults, but not in older patients, than in healthy control. High levels of circulating BDNF may protect DS patients from the clinical complications of atherosclerosis. However, the striking drop in peripheral BDNF levels with age might predispose these patients to clinical manifestations of dementia in later life.

Serum neutrophil gelatinase-B associated lipocalin (NGAL) levels in Down's syndrome patients.

Neutrophil gelatinase-associated lipocalin (NGAL) is a group of proteins with different functions.NGAL is released by different cell types such as epithelial cell, hepatocytes and renal tubular cells during inflammation and after cell injury. Expression of NGAL is induced under various pathophysiological conditions such as infection, cancer, inflammation, kidney injury, cardiovascular disease, burn injury, and intoxication, which has an important anti-apoptotic and anti-inflammatory role.Subjects with Down's syndrome (DS) are affected by many pathological age related conditions such as mental retardation, Alzheimer's disease, immune defects and increased susceptibility to infections. The aim of this study is to evaluate possible use of NGAL as a marker of inflammatory status for allow an early diagnosis of inflammatory disease such as autoimmune disease in DS patients, that are more susceptible to these pathologies, especially in elderly subjects.In this study were recruited 3 groups of DS subjects (children, adults and elderly) and compared them to healthy control group.The molecules of interest was determinated by immuno-enzymatic assay (ELISA).Our results show that NGAL plasmatic level was significantly higher in DS patients compared to healthy controls. Moreover NGAL levels increase in correlation with the age, and showed a significantly correlation between the increase with the severity of disease.DS is characterized by an enhancement of gene production such as GART, SOD-1 and CBS that encode specific protein and enzyme involved in hydrogen peroxide and superoxide production, species highly cytotoxic implicated in inflammation and ageing.NGAL may have the potential application to ameliorate the toxicity induced by oxidative stress conditions such as Alzheimer's disease, thalassemia, cardiovascular disease, burn injury, transplantation, diabetes, and aging.

NT-proBNP concentrations in mountain marathoners.

The 76 amino acid N-terminal proB-type natriuretic peptide (NT-proBNP) is proposed for evaluating and monitoring heart pathologies characterized by myocardial wall stress. Strenuous exercise might generate transitory ischemia, myocardial stress, and diastolic left ventricular dysfunction, possibly inducing an increase of some biochemical parameter concentrations. An alert has been claimed owing to biochemical and instrumental signs of heart dysfunction in recreational athletes during marathon races. We studied the behaviour of NT-proBNP in 15 mountain marathoners before and after a race. The concentrations of the parameter were lower than that observed in controls at rest and were similar to that observed in professional soccer and rugby players. The concentrations significantly increased after the race. NT-proBNP is low at rest in professional athletes, and the increase after physical exercise is physiological. The marathoners, even when performing races in a high-altitude environment, show NT-proBNP concentrations similar to those of athletes from other sports disciplines, characterized by low levels of effort and by a mix of aerobic and anaerobic metabolism. The increase of NT-proBNP is linked to strenuous physical exercise and to heavy heart effort, testified also by an increase of troponin I. However, the role of the NT-proBNP could be important to screen recreational and professional marathoners to avoid possible heart problems and sudden cardiac death in subjects with occult heart disease. The results of the present study are relevant to the design and evaluation of training programs for improving strength and function of professional marathoners.

Oxidative stress and antioxidant status in patients with erectile dysfunction.

INTRODUCTION: Erectile dysfunction (ED) is increasingly recognized as a public health problem. The interaction between nitric oxide and reactive oxygen species is one of the important mechanisms implicated in the pathophysiological process of ED. Plasma contains various antioxidant components to prevent free-radical injury. AIM: The aim of this study was to determine and compare the oxidative and antioxidant status of peripheral venous blood in patients with ED of arteriogenic and non-arteriogenic origin. METHODS: Oxidative stress and antioxidant status were assessed in 40 patients with ED and 20 healthy controls. MAIN OUTCOME MEASURES: Plasma reactive oxygen metabolite (ROM) concentrations were measured as an indicator of oxidative stress, and plasma total antioxidant status (TAS) to indicate antioxidant defense. RESULTS: Plasma ROM concentrations were higher (349.75 +/- 53.35 standard deviation [SD] U.Carr vs. 285.43 +/- 25.58 U.Carr, P < 0.001) and plasma TAS lower (0.54 +/- 0.16 SD mmol/L vs. 0.94 +/- 0.28 SD mmol/L, P < 0.0001) in patients with arteriogenic ED in comparison to those in patients with non-arteriogenic ED. Plasma ROM and TAS in controls were not significantly different from those in non-arteriogenic ED. Conclusions. This observation may be useful to better understand and distinguish arteriogenic from non-arteriogenic ED using laboratory tests. In addition, our findings provide important support for an antioxidant therapy to try to correct oxidative stress in arteriogenic ED patients.

Release of growth factors after arthroscopic acromioplasty.

It has recently been postulated that a variety of growth factors may be released from cancellous bone after an acromioplasty. The aim of this study was to demonstrate the presence of growth factors in the subacromial space after acromioplasty. Between October 2006 and March 2007, 23 patients underwent arthroscopic acromioplasty. A sample of at least 3 ml of fluid from the shoulder was obtained 15 min after the end of the procedure. At the same time another sample of 3 ml of the patient's venous blood was obtained as a control. The concentrations of growth factors in the fluids collected were determined using enzyme-linked immunosorbent assay (ELISA). The growth factors assayed were platelet-derived growth factor-AB (PDGF-AB), basic fibroblast growth factor basic (bFGF) and transforming growth factor beta 1 (TGF-beta1). The concentrations of TGF-beta1 (p = 0.0001), PDGF-AB (p = 0.02), and bFGF (p < 0.0001) were significantly higher in the fluid from the subacromial space than in the blood sample. There are high concentrations of several growth factors in the subacromial space after acromioplasty.

Membrane-binding and activation of LKB1 by phosphatidic acid is essential for development and tumour suppression.

The serine/threonine kinase LKB1 regulates various cellular processes such as cell proliferation, energy homeostasis and cell polarity and is frequently downregulated in various tumours. Many downstream pathways controlled by LKB1 have been described but little is known about the upstream regulatory mechanisms. Here we show that targeting of the kinase to the membrane by a direct binding of LKB1 to phosphatidic acid is essential to fully activate its kinase activity. Consequently, LKB1 mutants that are deficient for membrane binding fail to activate the downstream target AMPK to control mTOR signalling. Furthermore, the in vivo function of LKB1 during development of Drosophila depends on its capacity to associate with membranes. Strikingly, we find LKB1 to be downregulated in malignant melanoma, which exhibit aberrant activation of Akt and overexpress phosphatidic acid generating Phospholipase D. These results provide evidence for a fundamental mechanism of LKB1 activation and its implication in vivo and during carcinogenesis.

Does Down's syndrome support the homocysteine theory of atherogenesis? Experience in elderly subjects with trisomy 21.

Down syndrome (DS) is generally considered as an "atheroma-free model". In this preliminary study, we investigated homocysteine, folate and Vitamin B(12) levels in 13 DS patients (male, average age 60 years) and 20 age-matched individuals. We also studied lipid fractions, and polymorphisms for Cystothionine beta-synthase (CBS), 5,10-methyl-tetrahydro-folate reductase (MTHFR) and apolipoprotein E (Apo-E) genes. However, DS patients with the MTHFR TT genotype showed an increased of plasma homocysteine (tHcy). Our results indicate that this group of "healthy old" Down syndrome patients, although showing some classical biochemical risk factors for atherosclerosis, did not suffer clinical cardiovascular alterations.

Plasma nerve growth factor (NGF) and inflammatory cytokines (IL-6 and MCP-1) in young and adult subjects with Down syndrome: an interesting pathway.

OBJECTIVES: Down's syndrome (DS) is the most frequent chromosomal aberration in men and it is invariably associated with mental retardation. MATERIAL AND METHODS: Plasma levels of nerve growth factor (NGF), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) from non demented DS subjects of three different age-cohorts (2-14 years; 20-50 yrs; >60 yrs) and healthy controls were measured. No clinical and sub-clinical inflammation was apparent in DS patients. RESULTS: Plasma levels of NGF were higher in children, adult and old DS subjects than in controls. However, a significant age-related decrease of NGF levels was present in DS subjects. Serum levels of IL-6 and MCP-1 were also increased in DS children and adults, but not in older DS patients. CONCLUSIONS: High levels of circulating NGF might protect DS from clinical complications of atherosclerosis. However, the striking decrement of peripheral NGF levels with advancing age may predispose DS to clinical manifestation of dementia after adulthood.

Inactivation of the LKB1-AMPK signaling pathway does not contribute to salivary gland tumor development - a short report.

PURPOSE: Activation of AMPK by the tumor suppressor LKB1 represents an essential gatekeeping step for cells under energetic stress to prevent their growth and proliferation by inhibiting mTOR activation, until the energy supply normalizes. The LKB1/AMPK pathway is frequently downregulated in various types of cancer, thereby uncoupling tumor cell growth and proliferation from energy supply. As yet, little information is available on the role of the LKB1/AMPK pathway in tumors derived from salivary gland tissues. METHODS: We performed LKB1 protein expression and AMPK and mTOR activation analyses in several salivary gland tumor types and their respective healthy control tissues using immunohistochemistry. RESULTS: No significant downregulation of LKB1 expression or decreased activation of AMPK or mTOR were observed in any of the salivary gland tumors tested. In contrast, we found that the salivary gland tumors exhibited an increased rather than a decreased AMPK activation. Although the PI3K/Akt pathway was found to be activated in most of the analyzed tumor samples, the unchanged robust activity of LKB1/AMPK likely prevents (over)activation of mTOR. CONCLUSION: In contrast to many other types of cancer, inactivation or downregulation of the LKB1/AMPK pathway does not substantially contribute to the pathogenesis of salivary gland tumors.

Interleukin-15 and soluble interleukin-15 receptor α in coronary artery disease patients: association with epicardial fat and indices of adipose tissue distribution.

Interleukin-15 (IL-15) is a pro-inflammatory cytokine which signals via a specific alpha receptor subunit (IL-15Rα). Increased IL-15 level has been observed in cardiovascular patients and IL-15 immunoreactivity has been detected at vulnerable atherosclerotic plaques. Due to the association between adipose tissue distribution, inflammation and coronary artery disease (CAD), we quantified IL-15 and IL-15Rα in CAD patients with different adiposity and adipose tissue distribution and we evaluated whether epicardial adipose tissue (EAT), a visceral fat depot surrounding and infiltrating myocardium, may be a source of both molecules. IL-15 and IL-15Rα proteins were quantified by enzyme-linked immunosorbent assays. Gene expression of IL-15 and IL-15Rα in EAT depots was evaluated by one colour microarray platform. EAT thickness was measured by echocardiography. Plasmatic IL-15 and IL-15Rα levels were higher in CAD than non-CAD patients. After classification according to adipose tissue distribution, IL-15 was higher in CAD patients with increased abdominal adiposity. Increased level of IL-15Rα was observed both in CAD and non-CAD patients with increased abdominal fat. EAT was a source of IL-15 and IL-15Rα and their expression was higher in CAD patients with increased EAT thickness. In conclusion, our data suggest that circulating levels of IL-15 and IL-15Rα seem to reflect visceral distribution of adipose tissue and that EAT may be a potential source of both IL-15 and IL-15Rα. Future studies on the relationship between IL-15, visceral fat and characteristics of atherosclerotic plaques could help to better understand the complex biology of this cytokine.

Bone remodelling biomarkers after whole body cryotherapy (WBC) in elite rugby players.

Whole body cryotherapy (WBC) consists of a brief exposure to extreme cold air (-110°C) in a controlled chamber and it is applied in sports medicine to improve recovery from musculoskeletal trauma. The aim of this study is to better define the beneficial effect of WCB on the musculoskeletal system of athletes, in particular on bone remodelling. Remodelling osteoimmunological biomarkers OPG, RANKL and RANK were measured after WBC treatment in 10 male rugby players randomly selected from the Italian National team. OPG levels were increased significantly, supporting the view that WBC induces an osteogenic effect. Further studies evaluating the effect of WBC on bone metabolism are desirable.