Vascular endothelial growth factor is associated with histological instability of carotid plaques

Background: Vascular endothelial growth factor (VEGF) promotes events favouring carotid plaque instability: inflammatory chemoattraction, thrombogenesis, and upregulation of matrix metalloproteinases and cell adhesion molecules. The aim of this study was to assess neovascularization, VEGF and its receptors in high‐grade stable and unstable carotid plaques. Methods: Immunohistochemical staining for CD34, VEGF, VEGF receptor (VEGFR) 1 and VEGFR2 was performed in 34 intact carotid endarterectomy specimens, and compared in sections demonstrating maximal histological instability (cap rupture/thinning) or, if stable, maximal stenosis. Results: VEGF staining was increased in 12 unstable compared with 22 stable plaques (median (interquartile range, i.q.r.) plaque score 4·0 (4·0–4·0) versus 3·0 (2·0–3·0); P = 0·002) with upregulation of VEGFR1 (plaque score 4·0 (2·0–4·0) versus 2·0 (1·0–3·0); P = 0·016). In unstable plaques this was associated with increased microvessel density in the cap (median (i.q.r.) 12·1 (4·0–30·0) versus 1·1 (0·0–7·3) microvessels/mm²; P = 0·017) and shoulder regions (7·7 (3·4–21·4) versus 3·1 (0·4–10·8) microvessels/mm²; P = 0·176). Conclusion: Increased VEGF and receptor staining were seen in histologically unstable carotid plaques. Although these differences could reflect cytokine‐driven inflammatory events accompanying plaque instability, VEGF and VEGFR1 could be key mediators. Copyright © 2008 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.     

Comparison of the EuroQol and short form 6D in Singapore multiethnic Asian knee osteoarthritis patients scheduled for total knee replacement

OBJECTIVE: To compare the EuroQol (EQ-5D) and Short Form 6D (SF-6D) among multiethnic Asian patients with knee osteoarthritis (OA) scheduled for total knee replacement in Singapore. METHODS: Patients were asked to complete questionnaires including the EQ-5D, Short Form 36, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Lequesne knee index. EQ-5D and SF-6D utility scores were calculated using the scoring algorithms developed from the UK general population. Agreement between the 2 instruments was assessed by comparing their score distributions, means, medians, intraclass correlation coefficients (ICCs), and a Bland-Altman plot. Correlations of the EQ-5D and SF-6D with WOMAC and Lequesne knee index scores were also examined. RESULTS: A consecutive sample of 258 knee OA patients (127 English-speaking and 131 Chinese-speaking) participated. The mean +/- SD EQ-5D utility score was 0.49 +/- 0.31 (range -0.25-1.00) and the mean SF-6D utility score was 0.63 +/- 0.12 (range 0.32-0.89). In a hypothetical example, this 0.14-point difference in mean utility scores yielded a difference of $10,000/quality-adjusted life year (QALY) in cost-effectiveness ratios. The score distribution was bimodal for the EQ-5D and normal for the SF-6D. This poor agreement was also demonstrated by the Bland-Altman plot and the low ICC (range 0.18-0.54). Correlations of the WOMAC and Lequesne index with the EQ-5D were higher than with the SF-6D. CONCLUSION: Using different preference-based health-related quality of life instruments may yield different utility scores, which could have a great impact on QALY estimates. This highlights the importance of selecting appropriate instruments for economic evaluation. Additional research is needed to determine which instrument (the EQ-5D or the SF-6D) should be used in OA patients.     

Immunologic evidence for lack of heterologous protection following resolution of HCV in patients with non-genotype 1 infection

Chronic hepatitis C virus (HCV) infection is typically characterized by a lack of virus-specific CD4(+) T-cell-proliferative responses, but strong responses have been described in a subset of persons with persistent viremia. One possible explanation for these responses is that they were primed by an earlier resolved infection and do not recognize the current circulating virus. We defined all targeted epitopes using overlapping peptides corresponding to a genotype 1a strain in 44 patients chronically infected with different HCV genotypes (GT). Surprisingly, more HCV-specific CD4(+) T-cell responses were detected in patients with chronic non-GT1 infection compared with patients with chronic GT1 infection (P = .017). Notably, we found serologic evidence of a previous exposure to GT1 in 4 patients with non-GT1 infection, and these persons also demonstrated significantly more responses than non-GT1 patients in whom genotype and HCV serotype were identical (P < .001). Comparison of recognition of GT1-specific peptides to peptides representing autologous virus revealed the absence of cross-recognition of the autologous circulating virus. These data indicate that persistent HCV infection can occur in the presence of an HCV-specific T-cell response primed against a heterologous HCV strain, and suggest that clearance of 1 GT does not necessarily protect against subsequent exposure to a second GT.     

The immune thrombocytopenic purpura (ITP) bleeding score: assessment of bleeding in patients with ITP

A method for objective quantification of bleeding symptoms in immune thrombocytopenic purpura (ITP) has not been established. The ITP Bleeding Scale (IBLS) is a novel bleeding assessment system comprising 11 site-specific grades. Implementation of the IBLS on 100 patient visits revealed that although platelet count and large platelet count correlated well with bleeding symptoms overall, this relationship disappeared in marked thrombocytopenia. The IBLS is a useful clinical tool for monitoring bleeding and may be used to aid the development of laboratory parameters that correlate with underlying bleeding propensity in thrombocytopenia.     

Restraining influence of A2 neurons in chronic control of arterial pressure in spontaneously hypertensive rats

OBJECTIVES: The role of A2 noradrenergic neurons in regulating cardiovascular homeostasis chronically is poorly understood. We aimed to genetically target A2 neurons and induce expression of a potassium channel to reduce their electrical excitability and study how this impacts on long-term blood pressure control. METHODS: We used a lentiviral vector with PRSx8 promoter for targeting noradrenergic neurons to express a human inwardly rectifying potassium channel, hK(ir)2.1. The dorsal vagal complex containing the A2 cell group was microinjected with the PRSx8-hK(ir)2.1 lentivirus in both normotensive Wistar rats and spontaneously hypertensive rats fitted with radio telemetry devices. RESULTS: In Wistar rats expression of hKir2.1 increased lability of arterial pressure between 7 to 21 days post-injection with mean arterial pressure not increasing significantly until day 21 (+11+/-1 mmHg; p<0.001; dark phase). Urine output and water intake were both decreased. In contrast, in spontaneously hypertensive rats not only the lability of arterial pressure but also the mean arterial pressure increased by day 7 and persisted during the 21 day recording period (+13+/-1 mmHg; p<0.001 at day 21). In contrast to Wistar rats, body fluid homeostasis was un-affected in hypertensive rats. Neither cardiac baroreceptor reflex gain nor heart rate variability changed in either rat strain. Plasma osmolality levels were also unaffected. CONCLUSIONS: Our data indicate a role for A2 neurons in the chronic regulation of arterial pressure independent of the cardiac baroreceptor reflex. The activity of A2 neurons may constitute an essential part of the central circuitry underpinning chronic regulation of arterial pressure in both, normo- and hypertensive rats.     

Ductal carcinoma in situ: biology, diagnosis, and new therapies

The incidence of ductal carcinoma in situ (DCIS) has markedly increased as a result of the use of screening mammography. Whether DCIS is a premalignant lesion or a cancer remains a cause of debate, but evidence supports the idea that DCIS evolves into invasive breast cancer based on histologic patterns, similar risk factors, and genetic similarities. Microcalcifications identified during mammography generally raise the suspicion of DCIS, and biopsy, often by core needle, confirms such a diagnosis. The extent of disease can be further delineated by breast magnetic resonance imaging. Radiation therapy in breast-conserving treatment, along with tamoxifen, decreases the overall rate of local recurrence in patients with DCIS. Studies in the treatment of DCIS exploring partial breast radiation and trastuzumab are under way. Ongoing investigations with comparative genomic hybridization suggest that there are independent, evolutionary genetic pathways within DCIS. Genome-wide microarray-based gene expression analyses are now providing new opportunities to discover genes that are specifically activated or inactivated during the course of breast cancer progression.     

Patients with IgA nephropathy have increased serum galactose-deficient IgA1 levels

Immunoglobulin A (IgA) nephropathy is the most prevalent form of glomerulonephritis worldwide. A renal biopsy is required for an accurate diagnosis, as no convenient biomarker is currently available. We developed a serological test based upon the observation that this nephropathy is characterized by undergalactosylated IgA1 in the circulation and in mesangial immune deposits. In the absence of galactose, the terminal saccharide of O-linked chains in the hinge region of IgA1 is terminal or sialylated N-acetylgalactosamine. A lectin from Helix aspersa, recognizing N-acetylgalactosamine, was used to develop an enzyme-linked immunosorbent assay that measures galactose-deficient IgA1 in serum. The median serum lectin-binding IgA1 level was significantly higher for 153 Caucasian adult patients with IgA nephropathy without progression to end-stage renal disease as compared with that for 150 healthy Caucasian adult controls. As the lectin-binding IgA1 levels for the controls were not normally distributed, the 90th percentile was used for determination of significant elevation. Using a value of 1076 U/ml as the upper limit of normal, 117 of the 153 patients with IgA nephropathy had an elevated serum lectin-binding IgA1 level. The sensitivity as a diagnostic test was 76.5%, with specificity 94%; the positive predictive value was 88.6% and the negative predictive value was 78.9%. We conclude that this lectin-binding assay may have potential as a noninvasive diagnostic test for IgA nephropathy.