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Biomedical subjects

Roberto Pola

Publications and source records attributed to Roberto Pola.

At least 19 recordsLinked to original sources
PubMed2026

Global prevalence of hereditary hemorrhagic telangiectasia-associated variants estimated by analysis of large-scale genomic databases.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder with an overwhelming hemorrhagic phenotype. It is mainly caused by variants in the ENG and ACVRL1 genes. HHT prevalence is currently estimated to be 1 in 5000 individuals, but the disease is likely underdiagnosed due to variable clinical presentation, misdiagnosis, and delayed recognition. OBJECTIVES: To estimate the global genetic prevalence of HHT-associated variants in ENG and ACVRL1. METHODS: We analyzed 3 large population-scale genomic databases: gnomAD, All of Us, and Regeneron Genetics Center-Million Exome. We considered known pathogenic and likely pathogenic variants of ENG and ACVRL1 and extended the analysis to potentially pathogenic variants passing the pathogenic criteria established by the guidelines for HHT of the American College of Medical Genetics and Genomics/Association for Molecular Pathology. RESULTS: The genetic prevalence of HHT ranged from 1.753 to 2.555 in 5000 individuals, when considering only pathogenic and likely pathogenic variants, and from 2.874 to 4.327 in 5000 individuals, when also potentially pathogenic variants were considered. CONCLUSION: This study assesses the prevalence of HHT-associated variants in the general population. Our unbiased approach demonstrates that the genetic prevalence of the disease is substantially higher than currently estimated.

Humans↗
PubMed2006

Angiogenesis as a novel component of inflammatory bowel disease pathogenesis.

BACKGROUND & AIMS: Angiogenesis is a critical component of neoplastic and chronic inflammatory disorders, but whether angiogenesis also occurs in inflammatory bowel disease (IBD) has yet to be established. We assessed mucosal vascularization, expression of endothelial alphaVbeta3 integrin, angiogenic factors, and their bioactivity in Crohn's disease (CD) and ulcerative colitis (UC) mucosa. METHODS: Mucosal endothelium was immunostained for CD31 and factor VIII and quantified by digital morphometry. alphaVbeta3 expression was studied in vivo by confocal microscopy and in vitro by flow cytometric analysis of human intestinal microvascular endothelial cells (HIMECs). Vascular endothelial growth factor (VEGF), interleukin (IL)-8, and bFGF levels were measured in mucosal extracts and cells and angiogenic bioactivity shown by induction of HIMEC migration and the corneal and chorioallantoic membrane angiogenesis assays. RESULTS: Microvessel density was increased in IBD mucosa. Endothelial alphaVbeta3 was strongly expressed in IBD but only sporadically in normal mucosa and was up-regulated in HIMECs by VEGF, tumor necrosis factor alpha, and bFGF. IBD mucosal extracts induced a significantly higher degree of HIMEC migration than control mucosa, and this response was mostly dependent on IL-8 and less on basic fibroblast growth factor or vascular endothelial growth factor. Compared with normal mucosa, IBD mucosal extracts induced a potent angiogenic response in both the corneal and chorioallantoic membrane assays. CONCLUSIONS: These results provide morphological, phenotypic and functional evidence of potent angiogenic activity in both CD and UC mucosa, indicating that the local microvasculature undergoes an intense process of inflammation-dependent angiogenesis. Thus, angiogenesis appears to be an integral component of IBD pathogenesis, providing the practical and conceptual framework for anti-angiogenic therapies in IBD.

Biopsy, Needle↗
PubMed2006

Analysis of functional polymorphisms of metalloproteinase genes in persons with vascular dementia and Alzheimer's disease.

BACKGROUND: Vascular dementia (VAD) and Alzheimer's disease (AD) may share common neuropathological mechanisms. Matrix metalloproteinases (MMPs) may induce destruction of the extracellular matrix, neuronal dysfunction, and death. Increased expression of these molecules has been found in a number of neurological diseases, including cerebral ischemia and AD. Expression and activity of MMPs may be genetically influenced by common polymorphisms in the promoter regions of the corresponding genes. The purpose of this study was to evaluate whether functional polymorphisms of MMP genes are associated with dementia. METHODS: This is a cross-sectional study including a total of 599 individuals: 193 with VAD, 183 with AD, and 223 controls. Polymorphisms of the MMP-1, MMP-3, and MMP-9 genes were studied. RESULTS: MMP-1 2G2G, MMP-1 1G2G, MMP-3 5A5A, and MMP-9 TT genotypes were significantly and independently associated with VAD (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.4-4.4, OR = 1.7, 95% CI, 1.0-2.7, OR = 2.9, 95% CI, 1.5-5.9, and OR = 6.8, 95% CI, 1.3-35.1, respectively). MMP-1 2G2G and MMP-3 5A5A genotypes were associated with increased risk of AD only in persons who carry the apolipoprotein E (APOE) epsilon4 allele (OR = 6.0, 95% CI, 2.3-15.5, and OR = 14.3, 95% CI, 3.2-63.0, respectively). Interestingly, the odds of VAD and AD was further increased in persons concomitantly carrying more than one MMP gene variation, compared to individuals that only had one high-risk genotype. CONCLUSIONS: Our study suggests that MMP gene polymorphisms are associated with VAD and AD, although these results need to be treated with caution until replicated. MMP genotypes may influence the risk of dementia and merit further investigation as potential genetic markers of disease.

Aged↗
PubMed2005

Sonic hedgehog myocardial gene therapy: tissue repair through transient reconstitution of embryonic signaling.

Sonic hedgehog (Shh) is a crucial regulator of organ development during embryogenesis. We investigated whether intramyocardial gene transfer of naked DNA encoding human Shh (phShh) could promote a favorable effect on recovery from acute and chronic myocardial ischemia in adult animals, not only by promoting neovascularization, but by broader effects, consistent with the role of this morphogen in embryogenesis. After Shh gene transfer, the hedgehog pathway was upregulated in mammalian fibroblasts and cardiomyocytes. This resulted in preservation of left ventricular function in both acute and chronic myocardial ischemia by enhanced neovascularization, and reduced fibrosis and cardiac apoptosis. Shh gene transfer also enhanced the contribution of bone marrow-derived endothelial progenitor cells to myocardial neovascularization. These data suggest that Shh gene therapy may have considerable therapeutic potential in individuals with acute and chronic myocardial ischemia by triggering expression of multiple trophic factors and engendering tissue repair in the adult heart.

Acute Disease↗
PubMed2005

Responsiveness to cholinesterase inhibitors in Alzheimer's disease: a possible role for the 192 Q/R polymorphism of the PON-1 gene.

Cholinesterase inhibitors (ChEIs) are the most established treatment strategy in Alzheimer's disease (AD). However, the responsiveness to these drugs is widely heterogeneous and the majority of AD subjects do not respond to treatment. Paraoxonase-1 (PON-1) is a potent endogenous ChEI and has been widely studied for its ability to hydrolyze environmental neurotoxins. Serum levels and biological activity of PON-1 display wide inter-individual variability and are strongly influenced by a common polymorphism at position 192 of the PON-1 gene. Here, we evaluated whether this gene variation is associated with differences in the ability of AD subjects to respond to therapy with ChEIs. We found that individuals that respond to ChEIs had a significantly higher frequency of the R allele, compared to non-responders (P<0.05). This study indicates that the 192 Q/R polymorphism of the PON-1 gene might influence responsiveness to ChEIs, with potentially important implications for the treatment of AD. Mutations of genes encoding for endogenous modulators of the cholinergic system should merit further investigation as prognostic indicators of individual response to treatment in AD subjects.

Aged↗
PubMed2005

Homocysteine triggers mucosal microvascular activation in inflammatory bowel disease.

OBJECTIVES: Increased homocysteine contributes to the pathophysiology of several chronic inflammatory diseases. Whether homocysteine could participate in mucosal inflammation in inflammatory bowel disease (IBD) has not been explored yet. Our aims were to study the levels of plasma and mucosal homocysteine in IBD patients and to assess whether homocysteine can trigger an inflammatory reaction on human intestinal microvascular endothelial cells (HIMECs). METHODS: Homocysteine was measured in the plasma, mucosal biopsy, and lamina propria mononuclear cell (LPMC) supernatants from normal and IBD subjects. HIMEC were cultured in presence of homocysteine, TNF-alpha, or folic acid, alone or in combination. Expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular cell adhesion molecule 1 was measured by flow cytometry and monocyte chemoattractant protein-1 (MCP-1) production by ELISA. Phosphorylation of p38 and p42/44 was assessed by immunoblot in HIMEC extracts. T-cell- and monocyte-HIMEC adhesion assays were used to evaluate the impact of homocysteine on leukocyte adhesion to intestinal endothelial cells. RESULTS: Patients with IBD displayed significantly higher homocysteine plasma and mucosal levels than control subjects. IBD-derived LPMC released higher homocysteine than control-derived LPMC. Treatment of HIMEC with homocysteine, and synergistically with the combination of TNF-alpha and homocysteine, triggered HIMEC inflammation, resulting in VCAM-1 up-regulation, MCP-1 production, and p38 phosphorylation. These events lead to an increased capacity of HIMEC to adhere T- and monocyte cells and were blocked by folic acid treatment. CONCLUSIONS: Homocysteine is increased in both the mucosa and plasma of patients with Crohn's disease and ulcerative colitis and contributes to the inflammatory state of the mucosal IBD endothelium. Therefore, homocysteine could play a proinflammatory role in IBD, which can be efficiently targeted by folic acid supplementation.

Adolescent↗
PubMed2005

Hyperhomocyst(e)inemia impairs angiogenesis in a murine model of limb ischemia.

Hyperhomocyst(e)inemia (HH) is an established independent risk factor for coronary, cerebral and peripheral vascular diseases. Recent studies have indicated that certain cardiovascular risk factors, including diabetes and hypercholesterolemia, impair expression of vascular endothelial growth factor (VEGF) and endogenous angiogenesis. In this study, we investigate the impact of moderate HH on angiogenesis and VEGF pathway in a mouse model of hindlimb ischemia. Upon induction of unilateral hindlimb ischemia, endogenous angiogenesis, expression of VEGF, and phosphorylation of the VEGF receptor Flk-1 were evaluated in mice heterozygous for a deletion of the cystathionine beta-synthase gene (CBS) and compared with those observed in CBS+/+ mice. CBS+/- mice exhibit moderate HH, as demonstrated by measuring plasma total homocyst(e)ine (tHcy) levels, which were significantly higher in these animals compared with CBS+/+ mice (4.77 +/- 0.82 vs 2.10 +/- 0.28, p < 0.01). Twenty-eight days after induction of ischemia, hindlimb blood flow was significantly reduced in CBS+/- mice compared with CBS+/+ animals (0.49 +/- 0.03, n = 12 vs 0.71 +/- 0.09, n = 10; p < 0.05). In addition, there was a significant negative correlation between plasma homocyst(e)ine levels and the laser Doppler perfusion ratio in CBS+/- mice (p = 0.0087, r = -0.7171). While VEGF expression and Flk-1 phosphorylation were not impaired in the ischemic muscles of CBS+/- mice, phosphorylation of the endothelial cell survival factor Akt was significantly inhibited by homocyst(e)ine in a dose-dependent manner in human umbilical vein endothelial cell (HUVECs) in vitro. In conclusion, our findings demonstrate that endogenous angiogenesis is inversely related to plasma levels of homocyst(e)ine in genetically engineered, heterozygous mice with moderate HH. This impairment, however, is not dependent on reduced expression of VEGF or impaired phosphorylation of its receptor Flk-1. In contrast, our data suggest that impaired Akt phosphorylation mediates the impairment of angiogenesis associated with HH.

Animals↗
PubMed2004

Sonic hedgehog induces arteriogenesis in diabetic vasa nervorum and restores function in diabetic neuropathy.

OBJECTIVE: The embryonic morphogen sonic hedgehog (SHh) has been shown to induce neovascularization of ischemic tissue but has not been shown to play a role in regulating vascular nerve supply. Accordingly, we investigated the hypothesis that systemic injection of SHh protein could improve nerve blood flow and function in diabetic neuropathy (DN). METHODS AND RESULTS: Twelve weeks after induction of diabetes with streptozotocin, motor and sensory nerve conduction velocities (MCV and SCV) of the sciatic nerves were significantly reduced in diabetic rats. SHh-treated diabetic rats demonstrated marked improvement of both MCV and SCV (P<0.05). Laser Doppler perfusion imaging showed that nerve blood flow was significantly reduced in the diabetic rats but was restored in SHh-treated diabetic rats (P<0.05 versus diabetic saline-treated rats) to levels similar to those achieved with vascular endothelial growth factor-2 (VEGF-2) gene therapy. In vivo perfusion of Bandeuraea simplicifolia (BS)-1 lectin showed marked reduction in the vasa nervora in diabetic sciatic nerves but restoration of nerve vasculature to nondiabetic levels in the SHh-treated and plasmid DNA encoding human VEGF-2 (phVEGF-2)-treated diabetic nerves. Interestingly, the SHh-induced vasculature was characterized by larger diameter and more smooth muscle cell-containing vessels, compared with VEGF-2 gene-treated diabetic rats. CONCLUSIONS: These data indicate that Shh induces arteriogenesis and restores nerve function in DN.

Animals↗
PubMed2004

Proinflammatory genetic profiles in subjects with history of ischemic stroke.

BACKGROUND AND PURPOSE: Proinflammatory genetic profiles, resulting from the combination of single nucleotide polymorphisms in genes encoding inflammatory molecules, may contribute to the development and progression of cardiovascular diseases. We evaluated the association between history of ischemic stroke and genetic profiles determined by the synergistic effects of polymorphisms in genes encoding prototypical inflammatory proteins. METHODS: The study included 237 individuals with history of ischemic stroke and 223 age-matched and gender-matched controls. The polymorphisms of the C-reactive protein (CRP), interleukin-6 (IL-6), macrophage migration inhibitory factor (MIF), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin (E-sel), and matrix metalloproteinase-3 (MMP-3) genes were studied. RESULTS: IL-6 GG, IL-6 GC, MCP-1 GG, ICAM-1 EE, E-sel AA, and MMP-3 5A5A genotypes were significantly and independently associated with stroke history. The odds of stroke increased with the number of high-risk genotypes: carrying 1 proinflammatory gene variant conferred a risk of 3.3 (1.6 to 6.9), whereas individuals concomitantly carrying 2 and 3 proinflammatory gene variants had adjusted odds ratios of 21.0 (7.6 to 57.5) and 50.3 (10.2 to 248.1), respectively. CONCLUSIONS: Proinflammatory genetic profiles are significantly more common in subjects with stroke history. Synergistic effects between proinflammatory genotypes might be potential markers for cerebrovascular diseases.

Aged↗
PubMed2004

Polymorphisms of the macrophage inhibitory factor and C-reactive protein genes in subjects with Alzheimer's dementia.

Neuroinflammation is a central feature of Alzheimer's disease (AD). C-reactive protein (CRP) is a key molecule of the acute phase of inflammation that has been localized in the two characteristic lesions of AD brain, senile plaque and neurofibrillary tangles. On the other hand, the macrophage migration inhibitory factor (MIF) is a cytokine with multiple biological activities, including the ability to act as potent amyloid beta (A-beta)-binding protein. Two common polymorphisms have been recently detected in the genes encoding for CRP and MIF and have been associated with significant modifications of plasma levels and activity of the corresponding proteins. Following these observations, we hypothesized that CRP and MIF gene polymorphisms might contribute to the development and progression of neurodegenerative disorders and evaluated their association with AD. CRP and MIF gene polymorphisms were examined by polymerase chain reaction and restriction enzyme analysis in 116 Italian subjects affected by probable AD and 184 age- and sex-matched controls. We did not find a statistically significant difference in the distribution of CRP and MIF genotypes and alleles between AD subjects and controls. Although these data need further confirmation, they indicate that CRP and MIF gene polymorphisms are not associated with AD.

Acute Disease↗
PubMed2004

CagA-positive cytotoxic H. pylori strains as a link between plaque instability and atherosclerotic stroke.

AIMS: Previous studies suggested an association between infection by cytotoxic CagA-positive Helicobacter pylori strains and atherosclerotic stroke. It has been hypothesized that CagA strains could increase the risk for stroke by affecting carotid plaque irregularity. Our aims were: (1) to confirm the association between CagA strains and atherosclerotic stroke, and (2) to assess the association between CagA strains and carotid plaque irregularity. METHODS AND RESULTS: We enrolled 105 consecutive patients affected by atherosclerotic stroke and 130 sex, age, social background-matched controls without relevant vascular diseases. Risk factors for atherosclerotic stroke, H. pylori infection and CagA status were evaluated in all subjects. The presence of plaque instability was evaluated by colour Doppler ultrasound. The prevalence of CagA-positive strains was significantly higher in patients than in controls (adjusted OR 2.99, 95% CI 1.52-5.88, P=0.002). The CagA seropositivity was the only factor independently associated with carotid plaque irregularity (adjusted OR 8.42, 95% CI 1.58-44.64, P=0.004). CONCLUSION: The evidence of significant associations between CagA-positive H. pylori strains and the presence of carotid plaque instability support their possible involvement in the pathophysiology of atherosclerotic stroke.

Aged↗
PubMed2004

Monocyte chemoattractant protein-1 (MCP-1) gene polymorphism and risk of Alzheimer's disease in Italians.

Monocyte chemoattractant protein-1 (MCP-1) is a key molecule for monocyte chemotaxis and tissue extravasation and for the modulation of leukocyte function during inflammation. Upregulation of MCP-1 may occur in the brain of subjects affected by Alzheimer's disease (AD) and MCP-1 levels in plasma and cerebrospinal fluid have been proposed as biological markers for the inflammatory process that accompanies AD pathogenesis. Importantly, serum levels and biological activity of MCP-1 protein are strongly influenced by a single nucleotide polymorphism occurring at position -2518 of the MCP-1 gene promoter. A recent study has investigated the possible association between this gene polymorphism and AD in a Spanish population, with negative results. Here, we performed a case-control study to test whether the risk for AD might be influenced by the -2518 A/G polymorphism of the MCP-1 gene in an ethnically homogeneous Italian population. The GG genotype and the G allele of the MCP-1 gene polymorphism were significantly more common in the AD group than in control individuals (P<0.0001) A logistic regression analysis indicated that the GG genotype was an independent risk factor for AD in our population. This effect was not influenced by the presence of the APOE 4 high-risk allele, nor by the presence of other gene variations associated with a pro-inflammatory phenotype. These findings indicate that the -2518 A/G polymorphism of the MCP-1 gene is associated with AD in Italians and confirm that inflammatory gene variations may be important contributors in the development and progression of neurodegenerative disorders.

Aged↗
PubMed2004

Age-dependent modifications of expression level of VEGF and its receptors in the inner ear.

The mechanisms responsible for age-associated hearing loss are still incompletely characterized. In this study, we used a murine model of age-dependent hearing loss and evaluated whether this condition is associated with vascular modifications of the structures of the inner ear. We used old C57BL/6J mice that are affected by rapid and severe age-related hearing loss, and analyzed the expression pattern of vascular endothelial growth factor (VEGF), a prototypical angiogenic cytokine, and its receptors Flt-1 and Flk-1 in the inner ear. We report for the first time morphological and quantitative data about the expression of these crucial angiogenic molecules in the murine cochlea. We also show that in this animal model, cochlear VEGF expression is significantly reduced as a function of age. Our findings provide new evidence of possible interdependent relationships between aging, VEGF, and presbycusis, suggesting that vascular abnormalities might play a role in aging-associated hearing loss, with potentially important fundamental and clinical implications.

Aging↗
PubMed2004

Treatment of ischemic ulcers of the lower limbs with alprostadil (prostaglandin E1).

BACKGROUND: Hemodynamic, hemorheologic, and metabolic changes are main determinants in the genesis of ischemic leg ulcers. Because prostaglandin E1 (alprostadil) could successfully counteract these changes, it has been intravenously used in the treatment of this disease. OBJECTIVE: The aim of this study was to evaluate the efficacy of alprostadil in the treatment of ischemic ulcers and to compare subcutaneous with intravenous administration. METHODS: Eighty patients were enrolled. Twenty-five were treated by injecting low doses of alprostadil around ischemic ulcers of the leg and saline solution intravenously and 25 were treated with intravenous alprostadil and local injections of saline solution; the control group was composed of 30 patients who received saline solution around the ulcers and intravenously. RESULTS: All patients showed a statistically significant improvement in ulcer diameter, pain, and transcutaneous oxygen pressure compared to the control group. No relevant differences in the clinical outcome in the two treated groups were found, but patients treated with subcutaneous alprostadil experienced no side effects and showed higher values of transcutaneous oxygen pressure. CONCLUSIONS: Both intravenous and local subcutaneous alprostadil are useful in the treatment of ischemic leg ulcers, but subcutaneous administration is less expensive and easier to perform.

Aged↗
PubMed2003

Postnatal recapitulation of embryonic hedgehog pathway in response to skeletal muscle ischemia.

BACKGROUND: Hedgehog (Hh) proteins are morphogens regulating epithelial-mesenchymal signaling during several crucial processes of embryonic development, including muscle patterning. Sonic (Shh), Indian (Ihh), and Desert (Dhh) hedgehog constitute the repertoire of Hh genes in humans. The activities of all 3 are transduced via the Patched (Ptc1) receptor. Recent observations indicate that exogenous administration of Shh induces angiogenesis. Here, we studied whether the endogenous Hh pathway, in addition to its functions during embryogenesis, plays a physiological role in muscle regeneration after ischemia in adults. METHODS AND RESULTS: We found that skeletal muscle ischemia induces strong local upregulation of Shh mRNA and protein. In addition, the Ptc1 receptor is activated in interstitial mesenchymal cells within the ischemic area, indicating that these cells respond to Shh and that the Shh pathway is functional. We also found that Shh-responding cells produce vascular endothelial growth factor under ischemic conditions and that systemic treatment with a Shh-blocking antibody inhibits the local angiogenic response and the upregulation of vascular endothelial growth factor. CONCLUSIONS: Our study shows that the Hh signaling may be recapitulated postnatally in adult and fully differentiated muscular tissues and has a regulatory role on angiogenesis during muscle regeneration after ischemia. These findings demonstrate a novel biological activity for the Hh pathway with both fundamental and potential therapeutic implications.

Animals↗
PubMed2003

Risks of using internal thoracic artery grafts in patients in chronic hemodialysis via upper extremity arteriovenous fistula.

BACKGROUND: In patients in chronic hemodialysis via upper extremity arteriovenous fistula in whom ipsilateral internal thoracic artery graft was used for myocardial revascularization, hemodynamic interference between the fistula and the graft during dialysis can be hypothesized. METHODS AND RESULTS: In 5 patients undergoing chronic hemodialysis via upper extremity arteriovenous fistula, ipsilateral to an internal thoracic to left anterior descending graft mammary flow was studied by means of transthoracic echo-color Doppler at baseline and during hemodialysis. Flow in the contralateral mammary artery was used as control. Transthoracic echocardiography was performed in concomitance with flow evaluation to assess eventual modifications of left ventricular segmental wall motion. Immediately after hemodialysis pump start there was a marked reduction of peak systolic and end-diastolic velocities and time average mean velocity and flow in the ITA ipsilateral to the fistula, whereas no substantial hemodynamic modification was evident in the contralateral artery. Dialysis-induced reduction of ipsilateral ITA flow was accompanied by evidence of hypokinesia of the anterior left ventricular wall. Three cases also experienced clinical angina. CONCLUSIONS: Hemodynamically evident flow steal and consequent myocardial ischemia develop during hemodialysis in patients with upper extremity arteriovenous fistula and ipsilateral internal thoracic artery to coronary graft. These data have major implications for patients' management, both for nephrologists and cardiac surgeons.

Arteriovenous Shunt, Surgical↗