Are Elevated Levels of IGF-1 Caused by Coronary Arteriesoclerosis?: Molecular and Clinical Analysis

The importance of insulin-like growth factor-1 (IGF-1) in coronary artery disease (CAD) due to wide range of its biological effects and its therapeutic potential, has already been described. Our aim was to evaluate possible influence of IGF-1 serum level changes on coronary atherosclerosis. In case of existence of such association our further aim was to verify and explain this phenomenon by examination of promoter P1 of IGF-1gene and receptor gene for IGF-1. The study was performed in 101 consecutive patients undergo for routine coronary angiography. Quantitative and qualitative assessment of coronary atherosclerosis was performed respectively by estimation of the number of culprit lesions in coronary arteries and by Gensini score calculation. IGF-1, IGFBP3 and plasma lipoproteins were measured in all patients. In addition, we evaluated DNA from 101 patients, isolated from blood cells, which was amplified by using PCR with sophisticated primers for P1 promoter of IGF-1 gene and IGF-1 receptor gene, then analyzed utilizing SSCP technique and automatically sequenced. We observed significant increase of serum IGF-1 levels in patients with “3 vessel disease” and with high score in Gensini scale when compared to those without any narrowing lesions in coronary arteries and 0 Gensini score (in group with 3 vessel disease 215.0 ± 71.3 versuss 176.7 ± 34.2 ng/ml p = 0.04 and with high Gensini score 231.4 ± 59.3 versus 181.0 ± 37.8 ng/ml p = 0.01).We found different genotypes for five P1 promoter polymorphisms of IGF-1 gene (RS35767, RS5742612, RS228837, RS11829693, RS17879774). There were no significant associations between the observed single nucleotide polymorphism (SNP) and coronary atherosclerosis nor with levels of circulating IGF-1. We found no structural polymorphism in receptor gene for IGF-1 nor in its extracellular domain(exon 2–4) nor in internal domain (exon 16–21). The effect of increased IGF-1 serum level in our study was probably independent from structural polymorphism in promoter P1 for IGF-1 or in receptor gene for IGF-1

Dysregulated expression of MIG/CXCL9, IP-10/CXCL10 and CXCL16 and their receptors in systemic sclerosis

Abstract Introduction Systemic sclerosis (SSc) is characterized by fibrosis and microvascular abnormalities including dysregulated angiogenesis. Chemokines, in addition to their chemoattractant properties, have the ability to modulate angiogenesis. Chemokines lacking the enzyme-linked receptor (ELR) motif, such as monokine induced by interferon-γ (IFN-γ) (MIG/CXCL9) and IFN-inducible protein 10 (IP-10/CXCL10), inhibit angiogenesis by binding CXCR3. In addition, CXCL16 promotes angiogenesis by binding its unique receptor CXCR6. In this study, we determined the expression of these chemokines and receptors in SSc skin and serum. Methods Immunohistology and enzyme-linked immunosorbent assays (ELISAs) were used to determine chemokine and chemokine receptor expression in the skin and serum, respectively, of SSc and normal patients. Endothelial cells (ECs) were isolated from SSc skin biopsies and chemokine and chemokine receptor expression was determined by quantitative PCR and immunofluorescence staining. Results Antiangiogenic IP-10/CXCL10 and MIG/CXCL9 were elevated in SSc serum and highly expressed in SSc skin. However, CXCR3, the receptor for these chemokines, was decreased on ECs in SSc vs. normal skin. CXCL16 was elevated in SSc serum and increased in SSc patients with early disease, pulmonary arterial hypertension, and those that died during the 36 months of the study. In addition, its receptor CXCR6 was overexpressed on ECs in SSc skin. At the mRNA and protein levels, CXCR3 was decreased while CXCR6 was increased on SSc ECs vs. human microvascular endothelial cells (HMVECs). Conclusions These results show that while the expression of MIG/CXCL9 and IP-10/CXCL10 are elevated in SSc serum, the expression of CXCR3 is downregulated on SSc dermal ECs. In contrast, CXCL16 and CXCR6 are elevated in SSc serum and on SSc dermal ECs, respectively. In all, these findings suggest angiogenic chemokine receptor expression is likely regulated in an effort to promote angiogenesis in SSc skin.http://deepblue.lib.umich.edu/bitstream/2027.42/112894/1/13075_2010_Article_3001.pd

Digital gangrene associated with anticentromere antibodies: a case report

<p>Abstract</p> <p>Introduction</p> <p>Anticentromere antibodies have been associated with peripheral vascular occlusive disease, most frequently accompanied by sclerodactyly in the context of a connective tissue disorder. We report a case of digital gangrene with no other clinical associations except positive anticentromere antibodies.</p> <p>Case presentation</p> <p>Our patient, a 53-year-old Caucasian woman, non-smoker, presented with progressive pain and blackening of the distal right third finger over the preceding five weeks. No sclerodactyly was evident. She was anticentromere antibody positive at greater than 100 U/mL. Angiography revealed diffuse distal vasculopathy in both upper extremities. Other investigations were unremarkable.</p> <p>Conclusions</p> <p>It is rare for anticentromere antibody-associated digital necrosis to develop without concomitant sclerodactyly. However, this patient's case illustrates the need to consider an autoimmune contribution to the pathogenesis of digital ischemia even in the absence of a recognizable connective tissue disease.</p

Augmented production of chemokines (monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α) and MIP-1β) in patients with systemic sclerosis: MCP-1 and MIP-1α may be involved in the development of pulmonary fibrosis

To determine the role of chemokines in the pathogenesis of systemic sclerosis (SSc), we examined serum levels, spontaneous production by peripheral blood mononuclear cells (PBMC), and histological distribution in the affected skin, of MCP-1, MIP-1α and MIP-1β in SSc patients. Serum levels of these chemokines were examined by ELISA in 58 patients with SSc and 20 normal controls. The levels of these chemokines in culture supernatants from PBMC were also measured by ELISA. Serum levels and spontaneous production levels by PBMC of MCP-1, MIP-1α, and MIP-1β were significantly elevated in patients with SSc compared with normal controls. Elevated serum levels of MCP-1 and MIP-1α significantly correlated with the presence of pulmonary fibrosis. MCP-1 expression in the skin of SSc was immunohistochemically examined using anti-MCP-1 MoAb. MCP-1 was strongly expressed in the epidermis, inflammatory mononuclear cells, and vascular endothelial cells in the sclerotic skin of SSc patients, but not expressed in any control skin. Furthermore, the MCP-1 expression in inflammatory mononuclear cells and endothelial cells significantly correlated with earlier onset of SSc. Thus, MCP-1, MIP-1α and MIP-1β may be involved in the disease process, possibly by augmenting leucocyte migration into the affected tissues in SSc. Furthermore, MCP-1 and MIP-1α may play an important role in the development of pulmonary fibrosis in SSc

Differences in sentinel lymph node pathology protocols lead to differences in surgical strategy in breast cancer patients.

Contains fulltext : 50705tjan-heijnen.pdf (publisher's version ) (Closed access)BACKGROUND: Internationally, there is no consensus on the pathology protocol to be used to examine the sentinel lymph node (SN). At present, therefore, various hospitals use different SN pathology protocols of which the effect has not been fully elucidated. We hypothesized that differences between hospitals in SN pathology protocols affect subsequent surgical treatment strategies. METHODS: Patients from four hospitals (A-D) were prospectively registered when they underwent an SN biopsy. In hospitals A, B, and C, three levels of the SN were examined pathologically, whereas in hospital D, at least seven additional levels were examined. In the absence of apparent metastases with hematoxylin and eosin examination, immunohistochemical examination was performed in all four hospitals. RESULTS: In total, 541 eligible patients were included. In hospital D, more patients were diagnosed with a positive SN (P < .001) as compared with hospitals A, B, and C, mainly because of increased detection of isolated tumor cells. This led to more completion axillary lymph node dissections in hospital D (66.3% of patients (P < .0001), compared with 29.0% in hospitals A, B, and C combined). Positive non-SNs were detected in 13.9% of patients in hospital D, compared with 9.7% in hospitals A, B, and C (P = .70). That is, in 52.4% of patients in hospital D, a negative completion axillary lymph node dissection was performed, compared with 19.3% of patients in hospitals A, B, and C combined. CONCLUSIONS: Differences in SN pathology protocols between hospitals do have a substantial effect on SN findings and subsequent surgical treatment strategies. Whether ultrastaging and, thus, additional surgery can offer better survival remains to be determined