Osteoclast-like giant cell tumor of the pancreas with ductal adenocarcinoma: case report with novel data on histogenesis.
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Carcinoma, Pancreatic Ductal↗
Biomedical subjects
C J Kirkpatrick
Publications and source records attributed to C J Kirkpatrick.
Expression of apoptosis-related proteins, p53, and DNA fragmentation in sarcomas of the pulmonary artery.
BACKGROUND: Apoptosis is a common feature in a variety of pathologic conditions. Induction of apoptosis through apoptotic stimuli such as, chemotherapy or radiation, presents new insights into tumor biology and therapy. In particular, members of the Bcl-2 family as well as the Fas system are known to be involved in the regulation of apoptosis in different tumor entities. METHODS: In the current study, the expression of the apoptosis-related molecules p53, Bax, Bcl-2, Fas (CD95), Fas-Ligand and perforin was examined in 7 patients with a sarcoma of the pulmonary artery. Furthermore, the TUNEL-method for the detection of apoptotic cells was applied as well as sequencing of the p53 gene. RESULTS: In the TUNEL assay, approximately 10% of the sarcoma cells displayed DNA fragmentation. In addition, Bax was expressed in tumor cells. Accumulation of p53 was evident in 4 of 7 patients (pAB 240 antibody), and 2 of them were positive for the pAB 1801 antibody. Only 1 case had a point mutation in Exon 5 of the p53 sequence. A few tumor cells showed a double labeling of Bax and p53. Bcl-2 could be detected only in tumor-associated lymphocytes. Finally, several lymphocytes could be stained with perforin, but none of the specimens showed a reactivity for Fas or Fas-Ligand. CONCLUSION: The expression of Bax indicated a possible role of this molecule in programmed cell death in pulmonary sarcomas. The limited coexpression of Bax and p53 suggested that induction of Bax can occur independently of p53. The detection of perforin in lymphocytes suggested a possible role for this molecule in apoptosis of the sarcoma cells. In contrast, the Fas system did not seem to play an essential role in sarcomas of the great vessels.
Adult↗
Western blotting as a method for studying cell-biomaterial interactions: the role of protein collection.
Research of cell-biomaterial interactions is building on knowledge and methods available in cell and molecular biology. Western blotting is one of the options to characterize protein expression in cell populations. Method transfer to biomaterial model systems is not trivial because of the structure that exists in many biomaterials, preventing the collection of cell lysate by mechanical means. In this technical report, we describe the influence of different protein collection methods in a model system for cell-biomaterial interactions, consisting of endothelial cells exposed to different stimuli. In particular, the influence of trypsinization before lysis, and handling complexity were determined. The results of this study indicate that many changes in proteins occur because of the intermediate enzymatic treatment, despite the use of ice-cold solutions and protease and tyrosine phosphatase inhibitors throughout the procedure. Protein degradation and slight depressions in molecular weight were observed. The enzymatic treatment induced a changed cell status associated with detachment from the substratum. Western blotting of lysates of cells obtained through enzymatic harvest therefore can only be used with internal controls for the assessment of artifacts introduced by trypsinization, or alternative methods should be sought.
Antigens, CD↗
The Non-neuronal cholinergic system: an emerging drug target in the airways.
The non-neuronal cholinergic system is widely expressed in human airways. Choline acetyltransferase (ChAT) and/or acetylcholine are demonstrated in more or less all epithelial surface cells (goblet cells, ciliated cells, basal cells), submucosal glands and airway smooth muscle fibres. Acetylcholine is also demonstrated in the effector cells of the immune system (lymphocytes, macrophages, mast cells). Epithelial, endothelial and immune cells express nicotinic and muscarinic receptors. Thus the cytomolecule acetylcholine can contribute to the regulation of basic cell functions via auto-/paracrine mechanisms (proliferation, differentiation, ciliary activity, secretion of water, ions and mucus, organization of the cytoskeleton, cell-cell contact). Acetylcholine also modulates immune functions (release of cytokines; proliferation, activation and inhibition of immune cells). Preliminary experimental evidence suggests that mucosal inflammation may be associated with raised acetylcholine levels, impairing cell and organ homeostasis. It should be considered that anti-muscarinic drugs which are applied for the treatment of chronic airway diseases antagonize the effect of both neuronal and non-neuronal acetylcholine. Non-neuronal acetylcholine, however, is still active, possibly directly within the cell cytosol and also via nicotinic receptors localized on various non-neuronal cells. It is an essential task to clarify the pathophysiological role of the non-neuronal cholinergic system in more detail to develop new drugs which can target the synthesis, release, inactivation and cellular activity of non-neuronal acetylcholine.
Acetylcholine↗
Release of non-neuronal acetylcholine from the human placenta: difference to neuronal acetylcholine.
The synthesis and release of non-neuronal acetylcholine, a widely expressed signaling molecule, were investigated in the human placenta. This tissue is free of cholinergic neurons, i.e. a contamination of neuronal acetylcholine can be excluded. The villus showed a choline acetyltransferase (ChAT) activity of 0.65 nmol/mg protein per h and contained 500 nmol acetylcholine/g dry weight. In the absence of cholinesterase inhibitors the release of acetylcholine from isolated villus pieces amounted to 1.3 nmol/g wet weight per 10 min corresponding to a fractional release rate of 0.13% per min. The following substances did not significantly modify the release of acetylcholine: oxotremorine (1 microM), scopolamine (1 microM), (+)-tubocurarine (30 microM), forskolin (30 microM), ouabain (10 microM), 4alpha-phorbol 12,13-didecanoate (1 microM) and tetrodotoxin (1 microM). Removal of extracellular calcium, phorbol 12,13-dibutyrate (1 microM) and colchicine (100 microM) reduced the acetylcholine release between 30% and 50%. High potassium chloride (54 mM and 108 mM) increased the acetylcholine release slightly (by about 30%). A concentration of 10 microM nicotine was ineffective, but 100 microM nicotine enhanced acetylcholine release gradually over a 50-min period without desensitization of the response. The facilitatory effect of nicotine was prevented by 30 microM (+)-tubocurarine. Inhibitors of cholinesterase (physostigmine, neostigmine; 3 microM) facilitated the efflux of acetylcholine about sixfold, and a combination of both (+)-tubocurarine (30 microM) and scopolamine (1 microM) halved the enhancing effect. In conclusion, release mechanisms differ between non-neuronal and neuronal acetylcholine. Facilitatory nicotine receptors are present which are activated by applied nicotine or by blocking cholinesterase. Thus, cholinesterase inhibitors increase assayed acetylcholine by two mechanisms, protection of hydrolysis and stimulation of facilitatory nicotine receptors.
Acetylcholine↗
Expression of thrombospondin-1 in pancreatic carcinoma: correlation with microvessel density.
Thrombospondin-1 (TSP-1) is a multifunctional platelet and extracellular matrix protein that is involved in angiogenesis. Under certain pathological conditions, e.g., malignant tumors, high concentrations of TSP-1 work as an angiogenic agonist. Here we examined 98 pancreatic carcinomas with respect to TSP-1 immunoreactivity and its correlation to intratumoral microvessel density (MVD), a representation of the overall degree of angiogenesis in carcinomas. Northern blot analysis for TSP-1 mRNA was performed in seven additional cases. Eighty-seven tumors showed strong TSP-1 immunoreactivity, nine carcinomas were only weakly positive, and two lesions were negative for TSP-1. TSP-1 immunoreactivity was detected in the extracellular matrix, mostly at the invasion front of the tumor. Using Northern blot analysis, we observed high levels of TSP-1 mRNA in three out of seven pancreatic carcinomas. The mean MVD in pancreatic carcinoma was 38.8 vessels per mm2. Tumors with a high expression of TSP-1 showed a higher MVD and the correlation between TSP-1 immunoreactivity and microvessel density was highly significant (P=0.003). As a modulator of angiogenesis, TSP-1 is strongly expressed in most pancreatic adenocarcinomas and is likely to contribute to the extensive neovascularization and spread of this highly aggressive tumor.
Adenocarcinoma↗
Osteopontin expression in primary sarcomas of the pulmonary artery.
Primary tumors of the great vessels (aorta, pulmonal artery, and inferior vena cava) are rare and represent in most cases vascular leiomyosarcomas. Furthermore, there also exists a group of sarcomas arising from the intima, known as intimal sarcomas, associated with early metastasis and a very poor prognosis. Osteopontin (OPN) is an extracellular matrix protein that binds to alphav integrins, thereby promoting cell attachment, chemotaxis, and signal transduction. The reported association of OPN with malignancy and metastasis prompted us to examine the expression of this protein in seven sarcomas of the pulmonary artery. Strong OPN-specific staining could be detected in tumor cells and the adjacent extracellular matrix. Using a double labeling procedure, proliferating cells showed a strong positive reaction with antibodies against OPN. In addition, this protein could be demonstrated in the cytoplasm of macrophages. CD44, a putative receptor of OPN, was expressed on the cellular surface of tumor-associated lymphocytes. The expression of OPN in macrophages and tumor cells indicates that this molecule could possibly mediate cellular adhesion of both cell types in pulmonary sarcomas. The detection in the extracellular matrix shows that OPN is actively secreted and may interact with the corresponding receptor, CD44, on the surface of lymphocytes. Although the function of OPN is not yet fully understood, our data indicate that strong expression of this molecule in poorly differentiated sarcomas could play a role in the progression of malignancy and metastasis as described previously for carcinomas.
Adult↗
Generation of human pulmonary microvascular endothelial cell lines.
The limited lifespan of human microvascular endothelial cells in cell culture represents a major obstacle for the study of microvascular pathobiology. To date, no endothelial cell line is available that demonstrates all of the fundamental characteristics of microvascular endothelial cells. We have generated endothelial cell lines from human pulmonary microvascular endothelial cells (HPMEC) isolated from adult donors. HPMEC were cotransfected with a plasmid encoding the catalytic component of telomerase (hTERT) and a plasmid encoding the simian virus 40 (SV40) large T antigen. Cells transfected with either plasmid alone had an extended lifespan, but the cultures eventually entered crisis after several months of proliferation. Only those cells that were transfected with both plasmids acquired the capacity to grow in vitro without demonstrating major crisis, and these cells have been in culture for 24 months. HPMEC isolated from two different donors were used, generating two populations of immortalized cells, HPMEC-ST1 and HPMEC-ST2. Single cell-derived clones of the immortalized cells HPMEC-ST1 exhibited growth characteristics that were similar to those of the parental HPMEC. One selected clone, HPMEC-ST1.6R, displayed all major constitutively expressed and inducible endothelial phenotypic markers, including platelet endothelial cell adhesion molecule (PECAM-1, CD31), von Willebrand factor (vWF), and the adhesion molecules, intercellular adhesion molecule (ICAM-1), vascular adhesion molecule (VCAM-1), and E-selectin. In addition, an angiogenic response was demonstrated by sprout formation on a biological extracellular matrix (Matrigel). The HPMEC-ST1.6R cells did not form tumors in nude mice. The microvascular endothelial cell line, HPMEC-ST1.6R, will be a valuable tool for the study of microvascular endothelial physiology and pathology including gene expression, angiogenesis, and tumorigenesis.
Adult↗
Expression of cysteine proteinases cathepsins B and K and of cysteine proteinase inhibitor cystatin C in giant cell tumor of tendon sheath.
The expression of cysteine proteinases cathepsins B and K and of the endogenous inhibitor of cysteine proteinases, cystatin C, was investigated in tissue specimens of patients with giant cell tumor of tendon sheath (GCTTS). Expression of both enzymes was examined by immunohistochemistry in tissue specimens of 14 patients with GCTTS. Applying double-labeling techniques, the coexpression of cathepsin B and its major endogenous inhibitor cystatin C was additionally studied. Cells expressing the respective proteins were further characterized with the macrophage markers HAM56 and anti-CD68 (clone PG-M1). Cathepsin B could be detected in numerous HAM56-positive mononuclear cells (MC), but only in very few giant cells (GC). In contrast, cathepsin K was predominantly identified in GC that were also strongly immunoreactive for cystatin C and CD68. Coexpression of cathepsin B and cystatin C occurred only in a few MC. The strong expression of both cathepsin B and K suggests that in GCTTS, bone erosion might be mediated not only by pressure of the proliferative tissue, but also by matrix-degrading cysteine proteinases. Because previous studies showed that osteoclasts express high levels of CD68, cathepsin K, and cystatin C but not of cathepsin B, our study contributes to the view that GC of GCTTS and osteoclasts are closely associated.
Adult↗
Expression of matrix-degrading cysteine proteinase cathepsin K in cholesteatoma.
Cholesteatoma is a nonneoplastic lesion of the middle ear space or mastoid that is histologically characterized by a progressive bone erosion of the ossicles and surrounding bone. Several matrix-degrading enzymes have been implicated as mediators of this bone erosion. Because the novel cysteine proteinase cathepsin K has been shown to play a central role in bone resorption, we examined the expression of this enzyme in tissue specimens of cholesteatoma. Tissue specimens of 9 patients with cholesteatoma were obtained during middle-ear surgery. Expression of cathepsin K mRNA was determined by RT-PCR using specific primers. Immunohistochemical analysis of cathepsin K protein expression in tissue sections was performed by using the streptavidin-alkaline phosphatase technique. Expression of both cathepsin K mRNA and protein was detected in areas affected by cholesteatoma, whereas specimens of nonaffected ear cartilage and surrounding tissue were not positive. In addition, cathepsin K was detected in numerous multinucleated giant cells, particularly osteoclasts at the site of bone degradation. In contrast, keratinized squamous epithelium was negative for cathepsin K. These data demonstrate that the matrix-degrading cysteine proteinase cathepsin K may be involved in bone erosion in cholesteatoma. Strong expression of this collagenolytic enzyme in osteoclasts suggests that these cells are mainly involved in cathepsin K-mediated bone destruction.
Adult↗
Release of non-neuronal acetylcholine from the isolated human placenta is mediated by organic cation transporters.
1. The release of acetylcholine was investigated in the human placenta villus, a useful model for the characterization of the non-neuronal cholinergic system. 2. Quinine, an inhibitor of organic cation transporters (OCT), reduced acetylcholine release in a reversible and concentration-dependent manner with an IC(50) value of 5 microM. The maximal effect, inhibition by 99%, occurred at a concentration of 300 microM. 3. Procaine (100 microM), a sodium channel blocker, and vesamicol (10 microM), an inhibitor of the vesicular acetylcholine transporter, were ineffective. 4. Corticosterone, an inhibitor of OCT subtype 1, 2 and 3 reduced acetylcholine in a concentration-dependent manner with an IC(50) value of 2 microM. 5. Substrates of OCT subtype 1, 2 and 3 (amiloride, cimetidine, guanidine, noradrenaline, verapamil) inhibited acetylcholine release, whereas carnitine, a substrate of subtype OCTN2, exerted no effect. 6. Long term exposure (48 and 72 h) of villus strips to anti-sense oligonucleotides (5 microM) directed against transcription of OCT1 and OCT3 reduced the release of acetylcholine, whereas OCT2 anti-sense oliogonucleotides were ineffective. 7. It is concluded that the release of non-neuronal acetylcholine from the human placenta is mediated via organic cation transporters of the OCT1 and OCT3 subtype.
Acetylcholine↗
The expression of cathepsins in osteoclast-like giant cells of an anaplastic thyroid carcinoma with tracheal perforation.
Anaplastic carcinoma of the thyroid gland (ACT) is a rapidly growing neoplasm with a very poor prognosis. In this study, we examined an ACT with osteoclast-like giant cells expressing matrix--degrading cysteine proteinases and their endogeneous inhibitor cystatin C. Bronchoscopic evaluation of a 50-year-old man suffering from hoarseness, dysphagia, and dyspnea revealed an irregular tumor mass infiltrating into the trachea and the cricothyroid ligament region. On histological examination, a necrotizing undifferentiated anaplastic carcinoma with osteoclast-like giant cells was detected. An immunohistochemical study of the tumor tissue was performed using a panel of 15 antibodies, including double labeling techniques. Most of the osteoclast-like multinucleated giant cells (MGC) expressed CD68 and cathepsin K. Colocalization of cathepsin B and its endogenous inhibitor cystatin C occurred in the majority of MGC. Mononuclear cells (MC) were positive for cathepsin B, cystatin C, and CD 68, but only faintly for cathepsin K. Expression of cathepsins B and K in the MGC of the ACT might contribute to the invasive behavior of this tumor, thus promoting metastatic ability and destruction of the cartilagenous trachea.
Biomarkers, Tumor↗
Differential adhesion of polymorphous neutrophilic granulocytes to macro- and microvascular endothelial cells under flow conditions.
OBJECTIVE: As one of the important active barriers in the human organism, endothelial cells (EC) play a central role in the biological reaction to a variety of stimuli, e.g. during the induction and regulation of inflammation, as well as in the reaction to transplantation and biomaterial implantation. In the study of endothelial function, the most widely used in vitro model is that of human umbilical vein EC (HUVEC), i.e. an EC type of embryonic and macrovascular origin. However, many of the important pathological processes occur at microvascular level, thus questioning the validity of the HUVEC model. Moreover, the morphological and functional heterogeneity of the endothelium in the various organs, e.g. kidney, liver and lung, must be taken into consideration. The purpose of the present study was to use a dynamic cell culture system to compare the reactions of HUVEC and human pulmonary microvascular EC (HPMEC) to pro-inflammatory stimulation. METHODS: HUVEC and HPMEC in monolayer culture were stimulated by tumor necrosis factor-alpha (TNFalpha) in a parallel-plate flow chamber. Short- (4 h) and long-term (12 h) stimulation were compared. As a functional parameter, the adhesion of human peripheral blood polymorphonuclear granulocytes (PMN) to EC was quantitated both under venous and arterial flow conditions. RESULTS: Short-term (4 h) TNFalpha stimulation and venous flow conditions elicited a 32% higher PMN adhesion to HPMEC compared with HUVEC, whereas under arterial flow conditions no statistically significant differences were found. Following longer-term (12 h) TNFalpha stimulation, PMN adhesion to HPMEC was 65% higher than to HUVEC under venous flow. Under arterial flow no differences were detected. CONCLUSION: The present results provide new data on the heterogeneity of the endothelium and affect a central element in microvascular pathology, namely granulocyte-endothelial interactions. Moreover, this paper emphasizes the necessity to evaluate the in vitro models of the endothelium with respect to the extrapolation to the situation in vivo.
Cell Adhesion↗
The biological role of non-neuronal acetylcholine in plants and humans.
Acetylcholine, one of the most exemplary neurotransmitters, has been detected in bacteria, algae, protozoa, tubellariae and primitive plants, suggesting an extremely early appearance in the evolutionary process and a wide expression in non-neuronal cells. In plants (Urtica dioica), acetylcholine is involved in the regulation of water resorption and photosynthesis. In humans, acetylcholine and/or the synthesizing enzyme, choline acetyltransferase, have been demonstrated in epithelial (airways, alimentary tract, urogenital tract, epidermis), mesothelial (pleura, pericardium), endothelial, muscle and immune cells (granulocytes, lymphocytes, macrophages, mast cells). The widespread expression of non-neuronal acetylcholine is accompanied by the ubiquitous expression of cholinesterase and acetylcholine sensitive receptors (nicotinic, muscarinic). Both receptor populations interact with more or less all cellular signalling pathways. Thus, non-neuronal acetylcholine can be involved in the regulation of basic cell functions like gene expression, proliferation, differentiation, cytoskeletal organization, cell-cell contact (tight and gap junctions, desmosomes), locomotion, migration, ciliary activity, electrical activity, secretion and absorption. Non-neuronal acetylcholine also plays a role in the control of unspecific and specific immune functions. Future experiments should be designed to analyze the cellular effects of acetylcholine in greater detail and to illuminate the involvement of the non-neuronal cholinergic system in the pathogenesis of diseases such as acute and chronic inflammation, local and systemic infection, dementia, atherosclerosis, and finally cancer.
Acetylcholine↗
The non-neuronal cholinergic system in the endothelium: evidence and possible pathobiological significance.
An increasing body of knowledge indicates that the cholinergic system is not confined to the nervous system, but is practically ubiquitous. The present paper will address the question of the non-neuronal cholinergic system in vascular endothelial cells (EC). In tissue sections of human skin, immunohistochemical studies using confocal laser scanning microscopy showed ChAT (choline acetyltransferase) activity in the EC of dermal blood vessels. Positive ChAT immunoreactivity was also demonstrated in monolayer cultures of human umbilical vein EC (HUVEC) and a human angiosarcoma EC line (HAEND). That the synthesizing enzyme is not only present in EC, but also active was shown by measuring ChAT activity. Thus, in HUVEC cultures, ChAT activity amounted to 0.78 +/- 0.15 nmol x mg protein(-1) x h(-1) (n = 3), but was only partially (about 50%) inhibited by the ChAT inhibitor bromoacetylcholine (30 microM). In HPLC measurements, a concentration of 22 +/- 2 pmol acetylcholine (ACh) per 10(6) cells was found (n = 6). However, using a cholinesterase-packed analytical column to check the identity of the acetylcholine peak, the peak height was found to be reduced, although a significant peak still remained, indicating the existence of a compound closely related to ACh. Further immunocytochemical experiments indicated that EC in vitro also express the vesicular acetylcholine transporter (VAChT) system. Preliminary immunoelectron microscopic studies suggest a topographical association of VAChT with endothelial endocytotic vesicles. The presented experiments clearly demonstrate the existence of essential elements of the cholinergic system (ChAT, VAChT, ACh) in the human endothelium. The biological functions of ACh synthesized by endothelial cells are the focus of ongoing research activity.
Acetylcholine↗
Cathepsin K in aseptic hip prosthesis loosening: expression in osteoclasts without polyethylene wear particles.
OBJECTIVE: To investigate the expression of the bone matrix degrading cysteine proteinase cathepsin K and to determine the colocalization of cathepsin K with polyethylene (PE) particles in tissue specimens of patients with aseptic hip prosthesis loosening (AHPL). METHODS: The expression of cathepsin K was studied by immunohistochemistry in tissue specimens of 9 patients with aseptically loosened acetabular components of failed cementless total hip replacements. The expression of cathepsin K was compared to that of the macrophage marker CD68 by serial section analysis. Double labeling of the expression of cathepsin K or CD68 by immunohistochemistry and of PE particles by modified Oil Red staining method was performed. RESULTS: Cathepsin K could be predominantly detected in osteoclasts attached to the bone tissue, while only a few (CD68+) mononuclear and multinucleated foreign body giant cells (MGC) were positive for this enzyme. By double labeling with Oil Red staining we found the majority of CD68 positive cells of the periprosthetic tissue that were colocalized with PE particles. However, cathepsin K-expressing osteoclasts could not be stained with Oil Red. CONCLUSION: The present data suggest that in AHPL neither mononuclear cells nor MGC but rather osteoclasts are mainly involved in cathepsin K mediated bone matrix destruction. Using double labeling of immunohistochemistry and Oil Red staining we observed that the cathepsin K-expressing osteoclasts did not include PE particles.
Acetabulum↗
[Atherosclerosis--search for a new entity].
Atherogenesis is a disease of middle-sized and large caliber blood vessels that can be divided into three major phases. The initial lesions of early atherosclerosis are characterized by the adhesion and subendothelial emigration of blood-borne monocytes, which differentiate into macrophages and provide the morphological basis for the formation of foam cells and fatty streak lesions. These lesions are found in most children and teenagers in industrialized nations. The next key event in atherogenesis is the proliferation of smooth muscle cells within the intima and media, resulting in the gradual compromise of the vessel lumen. Myofibroblastic cells also contribute to lesion growth through the production of excessive amounts of extracellular matrix. Such lesions are clinically silent unless progression to the next phase continues: the lesions degenerate, forming a mostly necrotic "lipid core" consisting of extracellular lipid, cholesterol crystals, inflammatory cells and necrotic debris. A fibrous cap is formed which prevents the interaction of blood cells, particularly of platelets with the highly proaggregatory material found in the lipid core. However, continuous inflammatory activity and/or heightened mechanical stress (i.e. in hypertension) tends to weaken the fibrous caps. Eventually, plaque rupture ensues, platelets aggregate, and the lesions become clinically manifest in such dramatic events as myocardial infarction, stroke, or mesenteric ischemia. Research into lesion formation and progression is limited by the fact that lesions develop in silence over many decades and that animal models only incompletely model the situation in humans. Most currently debated concepts accept the "response to injury" hypothesis formulated by the late Russell Ross and the multifactorial nature of atherogenesis. The discussion today circles around the relative contributions of low density lipoproteins (oxidized or enzymatically modified LDL?), the immune response (adaptive or innate?), infectious agents (CMV, chlamydia pneumoniae?), and/or hereditary factors, to name only a few of the most widely debated concepts. Irrespective of the outcome of this pathomechanistic discussion, the knowledge of established risk factors (hypercholesterolemia, hypertension, diabetes, smoking, etc.) and protective interventions (lifestyle changes, physical exercise, "healthy" diets, effective dietary and pharmacological control of hyperglycemia, blood pressure or hyperlipidemia) has helped to define atherosclerosis as a "new entity" that has little to do with the archaic concept of a "degenerative" vessel disease.
Arteriosclerosis↗
Vascular pathology: a pathogenetic challenge for a new millennium.
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Forecasting↗