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Biomedical subjects

John P Veinot

Publications and source records attributed to John P Veinot.

At least 19 recordsLinked to original sources
PubMed2006

Cytohistopathologic hybrid renal cell carcinoma with papillary and clear cell features.

Clear cell (CRCC) and papillary (PRCC) renal cell carcinomas (RCC) are the two most frequent subtypes of RCC. In this study, we studied RCC which displayed a hybrid morphology with areas of PRCC and CRCC or which contained papillary structures with clear cell changes (CCC). Consecutive cases of RCC collected over a 12-year period were reviewed to identify RCC with papillary structures and a possible admixture between CRCC and non-oncocytic PRCC. Special stains for glycogen and immunostaining for cytokeratin 7 were applied to sections containing both areas of classical PRCC and PRCC with CCC. Of the total of 541 RCC retrieved, there were 68 non-oncocytic RCC having papillary structures that could be grouped into: (a) group 1 (15 cases), CRCC with areas of papillary formation; (b) group 2a (9 cases), PRCC with extensive CCC with areas of foamy epithelial cells or macrophages; (c) group 2b (18 cases), RCC with areas of classical PRCC with focal CCC; and (d) group 3 (26 cases), RCC with features of groups 2a and 2b and containing areas of classical CRCC. There was a high rate (12/68) of sarcomatous transformation in the study cases. Groups 2 and 3 were associated with a higher rate of vascular invasion, distant metastasis, and mortality than classical PRCC and a higher rate of lymph node metastasis than CRCC. Our study identifies two groups of RCC (referred to as groups 2 and 3) that exhibit characteristic cytohistopathologic hybrid features that set them apart from classical RCC. This type of hybrid tumor seems to be associated with a more aggressive biologic behavior, and its recognition may facilitate the classification of RCC with ambiguous morphology.

Adenocarcinoma, Clear Cell↗
PubMed2006

Fatty lesions of the atria and interatrial septum.

Lipomatous lesions of the heart involving the atria and interatrial septum are not well known. Most such lesions do not become clinically significant; however, intractable arrhythmias, blood flow obstruction, and valvular disruption may result from extensive fatty infiltration of the atrial wall or from the mass effect of benign or malignant lipomatous tumors. Some fatty lesions may be difficult to characterize radiologically, and misdiagnosis may lead to unnecessary surgical interventions. We describe the pathology of the most common fatty lesions and underscore some of the radiographic and surgical issues pertaining to the diagnosis and management of these masses.

Adipose Tissue↗
PubMed2006

Tissue-engineered injectable collagen-based matrices for improved cell delivery and vascularization of ischemic tissue using CD133+ progenitors expanded from the peripheral blood.

BACKGROUND: The use of stem and/or progenitor cells to achieve potent vasculogenesis in humans has been hindered by low cell numbers, implant capacity, and survival. This study investigated the expansion of CD133+ cells and the use of an injectable collagen-based tissue engineered matrix to support cell delivery and implantation within target ischemic tissue. METHODS AND RESULTS: Adult human CD133+ progenitor cells from the peripheral blood were generated and expanded by successive removal and culture of CD133- cell fractions, and delivered within an injectable collagen-based matrix into the ischemic hindlimb of athymic rats. Controls received injections of phosphate-buffered saline, matrix, or CD133+ cells alone. Immunohistochemistry of hindlimb muscle 2 weeks after treatment revealed that the number of CD133+ cells retained within the target site was >2-fold greater when delivered by matrix than when delivered alone (P<0.01). The transplanted CD133+ cells incorporated into vascular structures, and the matrix itself also was vascularized. Rats that received matrix and CD133+ cells demonstrated greater intramuscular arteriole and capillary density than other treatment groups (P<0.05 and P<0.01, respectively). CONCLUSIONS: Compared with other experimental approaches, treatment of ischemic muscle tissue with generated CD133+ progenitor cells delivered in an injectable collagen-based matrix significantly improved the restoration of a vascular network. This work demonstrates a novel approach for the expansion and delivery of blood CD133+ cells with resultant improvement of their implantation and vasculogenic capacity.

AC133 Antigen↗
PubMed2006

Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation.

BACKGROUND: Atrial fibrillation is the most common type of cardiac arrhythmia and a leading cause of cardiovascular morbidity, particularly stroke. The cardiac gap-junction protein connexin 40 is expressed selectively in atrial myocytes and mediates the coordinated electrical activation of the atria. We hypothesized that idiopathic atrial fibrillation has a genetic basis and that tissue-specific mutations in GJA5, the gene encoding connexin 40, may predispose the atria to fibrillation. METHODS: We sequenced GJA5 from genomic DNA isolated from resected cardiac tissue and peripheral lymphocytes from 15 patients with idiopathic atrial fibrillation. Identified GJA5 mutations were transfected into a gap-junction-deficient cell line to assess their functional effects on protein transport and intercellular electrical coupling. RESULTS: Four novel heterozygous missense mutations were identified in 4 of the 15 patients. In three patients, the mutations were found in the cardiac-tissue specimens but not in the lymphocytes, indicating a somatic source of the genetic defects. In the fourth patient, the sequence variant was detected in both cardiac tissue and lymphocytes, suggesting a germ-line origin. Analysis of the expression of mutant proteins revealed impaired intracellular transport or reduced intercellular electrical coupling. CONCLUSIONS: Mutations in GJA5 may predispose patients to idiopathic atrial fibrillation by impairing gap-junction assembly or electrical coupling. Our data suggest that common diseases traditionally considered to be idiopathic may have a genetic basis, with mutations confined to the diseased tissue.

Adult↗
PubMed2006

Papillary fibroelastoma of the pulmonary valve.

There is a lack of information regarding the diagnosis and management of papillary fibroelastoma of the pulmonary valve due to the rarity of the tumour at this location. A case of pulmonary valve papillary fibroelastoma in a 60-year-old woman is reported and the approach for diagnosis and management is described.

Female↗
PubMed2006

Comparison of processing and sectioning methodologies for arteries containing metallic stents.

The histological study of arteries with implanted metallic scaffolding devices, known as stents, remains a technical challenge. Given that the arterial response to stent implantation can sometimes lead to adverse outcomes, including the re-accumulation of tissue mass within the stent (or in-stent restenosis), overcoming these technical challenges is a priority for the advancement of research and development in this important clinical field. Essentially, the task is to section the stent-tissue interface with the least amount of disruption of tissue and cellular morphology. Although many methacrylate resin methodologies are successfully applied toward the study of endovascular stents by a variety of research laboratories, the exact formulations, as well as subsequent processing and sectioning methodology, remain largely coveted. In this paper, we describe in detail a methyl methacrylate resin-embedding methodology that can successfully be applied to tungsten carbide blade, as well as saw and grinding sectioning methods and transmission electron microscopy. In addition, we present a comparison of the two sectioning methodologies in terms of their effectiveness with regard to morphological, histochemical, and immunohistochemical analyses. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.

Acrylic Resins↗
PubMed2006

What are the most useful and trustworthy noninvasive anatomic markers of existing vascular disease?

Cardiovascular disease is the leading cause of mortality and morbidity in developed countries. Evidence challenges the notion that the severity of lesions on angiography is a predictor of future cardiac events. With the recognition that subclinical coronary artery stenoses are responsible for myocardial infarcts and sudden death, it may be important to identify patients with plaque characteristics that may place them at increased risk. Intravascular ultrasound, though invasive, remains the current imaging gold standard. Computed tomography, cardiac magnetic resonance, and single-photon emission CT positron emission tomography are evolving and promising modalities. Functional studies reflecting plaque temperature and molecular imaging reflecting plaque constituents are being developed. We review the pathology of the vulnerable atherosclerotic plaque and recent innovations in imaging modalities to assess plaque complication risk.

Atherosclerosis↗
PubMed2006

Cardiac actinomycosis: an unusual cause of an intracardiac mass.

Actinomycosis is a chronic disease characterized by abscess formation, tissue fibrosis, and draining sinuses that may involve the cervicofacial area, thorax, abdominopelvic region, or central nervous system. We describe a patient with cardiac actinomycosis presenting with pericardial disease and an intracardiac mass. The diagnosis failed to be obtained by pericardiocentesis, but was obtained after echocardiographically guided biopsy of the intracardiac mass. The patient recovered with long-term penicillin therapy. A review of the literature highlights the frequent pericardial presentation of cardiac actinomycosis, the potential difficulty in making the diagnosis, and the remarkable clinical response and good prognosis that can result when the correct diagnosis is made and appropriate antibiotic therapy administered.

Actinomycosis↗
PubMed2005

Regulation of the stepwise proteolytic cleavage and secretion of PDGF-B by the proprotein convertases.

Platelet-derived growth factor-B (PDGF-B) is important for normal tissue growth and maintenance and its overexpression has been linked to several diseases, including cancer, fibrotic disease and atherosclerosis. Here, we show that synthesized as a precursor, proPDGF-B is converted to a mature form by proteolytic cleavage at two sites and its N-terminal cleavage is a prerequisite for processing at its C-terminus. The first cleavage occurs at residues RGRR81/, and the second cleavage close to residues ARPVT190, just before the C-terminal amino-acid sequence crucial for PDGF-B retention to cell surface. Cotransfection of a Furin-deficient cell line LoVo-C5 with proPDGF-B and different PC members revealed that Furin, PACE4, PC5, and PC7 are candidate proPDGF-B convertases. This finding is consistent with the in vitro digestions of a synthetic peptide mimicking the cleavage site of proPDGF-B. The processing of proPDGF-B is blocked by site-directed mutagenesis of the RGRR81/ sequence and by various PC inhibitors. Mutation of the PDGF-A and/or PDGF-B convertase sites, revealed that processing of both A and B chains is required for the formation of mature PDGF-B dimers and that the processing of the B chain controls the level of secreted and matrix-bound PDGF-BB forms. Our findings emphasize the importance of the convertase-directed processing of proPDGF-B at the RGRR81/ sequence for PDGF-B maturation and secretion.

Amino Acid Sequence↗
PubMed2005

Furin-like proprotein convertases are central regulators of the membrane type matrix metalloproteinase-pro-matrix metalloproteinase-2 proteolytic cascade in atherosclerosis.

BACKGROUND: Accumulation of macrophages and their in situ expression of matrix metalloproteinases (MMPs) are important determinants of plaque stability. Activation of membrane-bound MT1-MMP, the major activator of pro-MMP-2, requires intracellular endoproteolytic cleavage of its precursor protein. This type of activation typically requires suitable furin-like proprotein convertases (PCs), specifically furin and PC5. The present study was done to investigate the function of MT1-MMP as well as furin-like PCs in mononuclear inflammatory cells. METHODS AND RESULTS: Macrophage differentiation of human monocytic THP-1 cells was accompanied by increased expression of furin, PC5, and MT1-MMP. Some pro-MMP-2 activation was found in macrophages, but pro-MMP-2 level or activation was not enhanced after stimulation with the proinflammatory mediators tumor necrosis factor-alpha or lipopolysaccharide. However, culturing of macrophages in conditioned medium from serum-starved vascular smooth muscle cells, which constitutively secrete pro-MMP-2, resulted in a strong pro-MMP-2 activation. Inhibition of furin-like PCs with the specific pharmacological inhibitor decanoyl-RVKR-chloromethylketone (dec-CMK) inhibited MT1-MMP activation in macrophages. Dec-CMK or furin-specific small interfering RNA significantly inhibited macrophage MT1-MMP-dependent activation of vascular smooth muscle cell-derived pro-MMP-2. Flow cytometry demonstrated that human circulating monocytes express furin and PC5, and MT1-MMP and immunohistochemistry revealed their colocalization in macrophages in advanced human atherosclerotic lesions. CONCLUSIONS: Furin-like PCs (furin and PC5) play a central role in a MT-MMP-MMP-2 proteolytic cascade, involving provision of macrophage MT1-MMP for the activation of pro-MMP-2 synthesized by other cells. Furin and PC5 are expressed in human peripheral blood mononuclear cells and colocalize with MT1-MMP in macrophages in the atherosclerotic plaque, supporting the hypothesis that they are potential targets in atherosclerosis.

Arteriosclerosis↗
PubMed2005

Immunohistochemical localization of subtilisin/kexin-like proprotein convertases in human atherosclerosis.

Integrins are heterodimeric alpha/beta receptors that link the cytoskeleton with the extracellular matrix, thereby regulating several cell functions important in atherosclerosis. In vitro, the subtilisin/kexin-like proprotein convertases (PCs), namely PC5 and furin, have been shown to be responsible for the endoproteolytic activation of the alpha(v) integrin subunit. Based on their cleavage activity, these PCs are potential targets in atherosclerosis. In the present study, we investigated the localization of furin and PC5 in different stages of human atherosclerosis. Immunohistochemical analysis of furin and PC5 revealed their presence in vascular smooth-muscle cells and endothelial cells in atherosclerotic and non-atherosclerotic lesions. However, in the more advanced lesions, furin and PC5 staining was significantly expressed in macrophages/foam cells. In vitro, THP-1 derived macrophages contained furin and PC5, and maturation of monocytes to macrophages was accompanied by enhanced alpha(v)beta3 cell-surface expression. Inhibition of furin/PC5 with the specific pharmacological furin-like PC-inhibitor dec-CMK inhibited alpha(v) endoproteolytic activation but did not abolish alpha(v)beta3 cell-surface expression. This indicates that furin/PC5 is required for alpha(v) endoproteolytic activation but not for alpha(v) routing and sorting to the cell surface. In conclusion, our study demonstrates that furin and PC5 are significantly expressed in mononuclear cells in advanced human atherosclerotic lesions, where they regulate alpha(v) endoproteolytic activation.

Arteriosclerosis↗
PubMed2005

Surgical treatment of atrial fibrillation with diathermy: an in vitro study.

OBJECTIVE: The utilization of diathermy (electrocautery) as an energy source in the treatment of chronic atrial fibrillation has generated positive early clinical results. Although this technology is available and affordable, it has not been well studied for this indication. The objectives of this study were: (1) to characterize atrial lesions created by diathermy, (2) to determine relationships between power setting, tissue contact time, and lesion depth and (3) to histologically compare diathermy and unipolar radiofrequency lesions. METHODS: Fresh bovine atrial tissue samples were used to create endocardial lesions using a unipolar diathermy system with a blade tip. A total of 120 lesions were created at varying power settings and tissue contact times. Subendocardial temperatures were recorded. All lesions were examined grossly, then fixed, sectioned and evaluated histologically by a blinded pathologist. Comparisons were made with saline irrigated unipolar radiofrequency lesions. RESULTS: Gross examination revealed extensive tissue destruction of the endocardial surface at the point of contact. Histological examination showed minimal penetrance of the lesions beyond the destroyed tissue margin of the endocardium. This was corroborated by the finding of minimal thermal penetration beyond the endocardium and superficial myocardium. There was a linear relationship between the power setting (15-55 watts), depth of penetrance (2-15 mm) at varying contact times (1-5s/cm). CONCLUSIONS: In this in vitro model, lesions created by diathermy were not transmural, even with high power settings and prolonged contact times. At these settings, significant tissue destruction was observed that may predispose to atrial perforation without achieving penetration. Diathermy did not constitute an effective energy source in the creation of transmural lesions for atrial fibrillation ablation.

Animals↗
PubMed2005

Neuroendocrine profiling of humans receiving cardiac allografts.

BACKGROUND: Several studies have investigated changes in circulating hormones and markers of cardiac status after heart transplantation in humans. As a result, plasma levels of various hormones and autocoids have been associated with cardiac allograft rejection status. However, no clear associations can be defined given the highly contradictory nature of the available literature. METHODS: In this study of 69 consecutive heart transplant patients followed for >2 years we examine the relationship between neurohumors potentially related to allograft rejection and endomyocardial biopsy grade of rejection (according to the ISHLT) and hemodynamic status. Markers assessed include brain natriuretic peptide (BNP), amino-terminal pro-BNP (N-BNP), atrial natriuretic factor (ANF), adrenomedullin, interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, troponin C and C-reactive protein. RESULTS: The highest plasma levels for most neurohumors were found shortly after surgery and showed a trend towards normalization with time. BNP and N-BNP were the only significantly elevated plasma analytes for patients with Grade 3 rejection as compared with other ISHLT grades. ANF plasma levels correlated with BNP and N-BNP in Grades 0 to 2, but not in Grade 3, suggesting that in this rejection grade the usual coordinated changes observed in BNP and ANF secretion no longer exist. Cardiac filling pressures were correlated with plasma BNP, N-BNP and ANF levels only for Grades 0 and 1. CONCLUSIONS: The timing of blood sampling after transplantation influences the level of the neurohumors measured, which may help explain the conflicting literature reports on the association between neurohumor levels and rejection grade. The significant increase in circulating levels of BNP and N-BNP observed in most cases of Grade 3 rejection occurred with no apparent relationship to post-transplantation time, which suggests a specific influence of acute rejection on BNP gene expression.

Adolescent↗
PubMed2005

Tricuspid valve chordal tissue in endomyocardial biopsy specimens of patients with significant tricuspid regurgitation.

OBJECTIVES: Tricuspid regurgitation is the most common valvular abnormality after orthotopic heart transplantation, with multiple etiologic factors implicated. The purpose of this study was to determine if the endomyocardial biopsy specimens of patients who developed significant tricuspid valve regurgitation (TVR) after cardiac transplantation had evidence of chordal tissue. METHODS: The echocardiograms of 98 patients who had cardiac transplantation between 1986 and 2002 were reviewed for evidence of significant TVR greater than mild. The biopsy specimens of all patients with significant TVR were then reviewed for histologic evidence of tricuspid chordal tissue and frequency and severity of rejection episodes. Clinical information collected included the presence of any systolic murmurs, significant dyspnea, and invasive hemodynamic measurements. RESULTS: The incidence of significant TVR was 19% (n = 19 patients). Histologic evidence of chordal tissue was present in 9 patients (47%) with significant TVR. Patients whose biopsy specimens evidenced chordal tissue tended to have a greater degree of TVR, but this was not statistically significant (odds ratio, 2.07; 95% confidence interval, 0.537-8.01, p = 0.32). There was no statistically significant difference in the number of biopsy specimens (p = 0.798), the number of rejection episodes (p = 0.73), or overall left or right ventricular systolic function between the patients with and without biopsy specimen evidence of chordal tissue disruption. Most of the patients with evidence of significant TVR after chordal tissue biopsy were clinically asymptomatic, with no significant change in their hemodynamics. CONCLUSION: Histologic evidence of chordal tissue in endomyocardial biopsy specimens was present in 47% of patients with significant TVR and did not relate to the number of biopsy procedures performed or the frequency of rejection episodes. This study provides histologic evidence that chordal tissue damage can occur after cardiac biopsy, resulting in significant TVR; however, it is clinically well tolerated by affected patients.

Adult↗
PubMed2005

Prevention of cardiac remodeling after myocardial infarction in transgenic rats deficient in brain angiotensinogen.

The brain renin-angiotensin-aldosterone system (RAAS) plays a major role in cardiac remodeling after myocardial infarction (MI). To assess the contribution of the brain RAAS in the activation of the cardiac RAAS post-MI, transgenic (TG) rats deficient in brain angiotensinogen and Wistar rats with intracerebroventricular (ICV) infusion of spironolactone were studied. An MI was induced by acute coronary artery ligation. TG and control Sprague-Dawley (SD) rats were followed for 8 weeks and Wistar rats for 6 weeks. Infarct sizes, % of left ventricle (LV) area, were in the 30-33% range. In SD rats at 8 weeks post-MI, internal circumference, interstitial and perivascular fibrosis, cardiomyocyte diameter in the LV and right ventricle (RV), laminin and fibronectin in the LV, and lung weights were increased. Aldosterone was increased markedly in both the LV and RV at 8 weeks post-MI. In TG rats, the MI-induced increases of RV internal circumference and weight were prevented and increases of lung weight and LV internal circumference were significantly inhibited. In TG rats, the post-MI increases of interstitial fibrosis and cardiomyocyte diameter were prevented in septum and RV and significantly inhibited in the peri-infarct zone of the LV. The increases in perivascular fibrosis, laminin and fibronectin were prevented in the LV. In TG rats, cardiac aldosterone did not increase. In Wistar rats at 6 weeks post-MI, aldosterone was markedly increased in the LV, but not in the RV. This increase was prevented by ICV infusion of spironolactone. These findings support the pivotal role of locally produced angiotensin II in the brain in cardiac remodeling post-MI. The brain RAAS appears to activate a cascade of events, among others an increase in cardiac aldosterone, which play a major role in cardiac remodeling post-MI.

Aldosterone↗
PubMed2005

Comparison of surgically removed cardiac valves of patients with ESRD with those of the general population.

BACKGROUND: Patients with end-stage renal disease (ESRD) have increased vascular and valvular calcification compared with the general population. Recently, 44% of renal transplant recipients were found to have vascular calcification of the medial layer of the inferior epigastric artery that was associated with deposition of bone matrix proteins. Similar findings have been reported for native and bioprosthetic cardiac valves surgically removed from patients without ESRD. METHODS: To determine whether valvular calcification in patients with ESRD is similar to that in patients without ESRD, we retrospectively examined surgically excised native cardiac valves of all hemodialysis patients and compared them pathologically with those of matched controls without renal failure. Valves were examined by using routine stains and immunohistochemistry for markers to endothelial cells, macrophages, B and T lymphocytes, alkaline phosphatase, osteopontin, and bone morphogenic protein 4. RESULTS: Histologically, 7 of 10 valves from patients with ESRD had moderate to severe inflammation compared with 1 of 10 valves from control patients. Patients with ESRD had more endothelial cells/vascularity (P = 0.002) and macrophages (P = 0.069). There was no difference between the 2 groups with respect to B and T lymphocytes, alkaline phosphatase, osteopontin, or bone morphogenic protein 4. CONCLUSION: The noncollagenous proteins bone morphogenic protein and osteopontin have been shown in surgically removed cardiac valves of patients with ESRD and the general population. However, valvular calcification in patients with ESRD is associated with enhanced inflammation, consistent with the previously reported greater C-reactive protein levels in this patient population and their increased risk for death.

Alkaline Phosphatase↗