Therapeutic Potential of 25-Hydroxyvitamin D in Promoting Cardiovascular Health

Introduction: The primary focus on vitamin D therapy was to treat metabolic bone disease. Over the past decade, however, researchers have demonstrated that vitamin D may have a role in other disease processes, particularly cardiovascular diseases (CVDs). Review: Serum 25-hydroxyvitamin D (25(OH)D) deficiency is widespread, and is extremely common in kidney transplant recipients. In community surveys, lower levels of 25(OH)D were associated with significantly higher adjusted prevalence of cardiovascular risk factors and CVD. CVD patients have lower 25(OH)D levels than controls, which are associated with more severe disease and worse prognosis. 25(OH)D levels are inversely associated with insulin resistance and future risk of hyperglycemia in non-diabetic subjects. Low levels of 25(OH)D were found to be independent predictors of death and end stage renal disease (ESRD) in chronic kidney disease (CKD) patients. Supplementation with vitamin D was found to lower parathyroid hormone and increase anti-inflammatory cytokines in congestive heart failure patient. It was found to improve flow mediated vasodilatation of the brachial artery in asymptomatic vitamin D deficient subjects and diabetic patients. Vitamin D supplementation was found to reduce proteinuria, mortality and progression to dialysis in CKD patients and to reduce cardiovascular mortality in hemodialysis patients. Vitamin D and calcium supplementation was also found to reduce cancer risk in community dwelling healthy postmenopausal women. Conclusion: Low levels of vitamin D seem to have undesirable effects on health. Based on the results of recent research, the recommended lower value of serum 25(OH)D is likely to be elevated. Key Words: Vitamin D; Cardiovascular disease ; Chronic kidney diseas

Evidence to Support a Putative Role for Insulin Resistance in Chronic Kidney Disease

Introduction: The primary cause of morbidity and mortality in the renal patient is a cardiovascular event. Insulin resistance (IR) contributes to this event by increasing cardiovascular disease (CVD) and accelerating rates of decline in kidney function. Here we review the historical background of IR in patients with chronic kidney disease (CKD) and present evidence for a role of IR in accelerating cardiovascular and renal diseases. Review: The high prevalence of IR in CKD patients is well documented. It is suggested that increased IR in the renal patient is caused by uremia as well as by other known factors in the general population. Patients with CKD have an alarmingly high risk for cardiovascular morbidity and mortality. There is overwhelming evidence to support a role for IR in increased CVD morbidity and mortality in the general population, which is likely to extend to CKD patients. Some of the traditional treatment measures for IR, such as metformin, may not be applicable to the renal patient. Other options include weight reduction, exercise, treatment of anemia to improve exercise tolerance, treatment of vitamin D deficiency, thiazolidinediones, and dialysis. IR is estimated by studying the relationship between blood glucose and the concomitant insulin level. Such measurement may help identify patients at increased risk for future cardiovascular events and guide treatment measures. Conclusion: Sufficient evidence supports the increased prevalence of IR in kidney patients. Treating IR may retard the progression of CKD and decrease the incidence of cardiovascular events in this high risk population. Keywords: chronic kidney diseass, cardiovascular disease, insulin resistanc

Immunodetectable cyclin D 1 is associated with oestrogen receptor but not Ki67 in normal, cancerous and precancerous breast lesions

Cyclin D1 is associated with cell cycle regulation and has more recently been shown to stimulate the transcriptional functions of the oestrogen receptor (ER). Furthermore, in normal breast there is a negative association between expression of ER and the proliferation marker Ki67 indicating that either ER positive cells are non-dividing or that the receptor is down-regulated as cells enter cycle. This important relationship breaks down in many ER-positive cancers and precancerous breast lesions where the receptor is often detected on proliferating cells. The aims of the present study were to determine the interplay between ER, Ki67 and cyclin D 1 in individual cells within the spectrum of human breast lesions ranging from normal to invasive carcinoma by using dual staining immunofluorescence. We found that in normal breast there was a strong positive association between ER and cyclin D 1 expression. In contrast there was a strong negative association between cyclin D 1 and Ki67 expression. Similar findings were seen for the other precancerous and cancerous breast lesions. Thus immunodetectable cyclin D 1 within individual cells does not appear to be associated with cell cycle progression in the benign or malignant breast but instead may have important interactions with ER. © 2001 Cancer Research Campaign http://www.bjcancer.co

Hypersensitive K303R oestrogen receptor-α variant not found in invasive carcinomas

INTRODUCTION: Genetic abnormalities or mutations in premalignant breast lesions may have a role in progression toward malignancy or influence the behaviour of subsequent disease. The A908G (Lys303→Arg) change in the gene encoding oestrogen receptor-α (ER-α) creates a hypersensitivity to oestradiol and would have significant consequences if present in breast carcinoma, especially those treated with endocrine therapy. We have therefore examined a panel of endocrine-treated invasive carcinomas for the presence of this mutation. METHODS: Sequencing of control DNA was shown to detect mutation present in as little as 15% of the starting material. Enrichment for the mutation by using MboII restriction digestion allowed the detection of mutant present at 1% or less. We applied these techniques to genomic DNA and cDNA from 136 invasive breast carcinomas. RESULTS: No evidence of the A908G mutation was found with either technique. The incidence of this mutation in our panel of tumours is therefore significantly less than previously reported. CONCLUSION: The fact that the mutation was not found leads us to believe that this mutation is absent from most cells in invasive carcinomas and furthermore that the major expression product of the ER-α gene in cancers does not contain the K303R mutation. It is therefore unlikely to influence the effectiveness of endocrine treatment

Stop! In the name of transforming growth factor-β: keeping estrogen receptor-α-positive mammary epithelial cells from proliferating

Recent genetic and cell biological studies illustrate the importance of active transforming growth factor-β signaling in preventing the proliferation of estrogen receptor-positive cells in the normal mammary gland, and suggest how the loss of this inhibition may be important in early breast cancer progression

Compliance with guidelines is related to better local recurrence-free survival in ductal carcinoma in situ

The aim was to study the effect of compliance with guidelines on local recurrence (LR)-free survival in patients treated for ductal carcinoma in situ (DCIS). From January 1992 to December 2003, 251 consecutive patients had been treated for DCIS in two hospitals in the North Netherlands. Every case in this two-hospital sample was reviewed in retrospect for its clinical and pathological parameters. It was determined whether treatment had been carried out according to clinical guidelines, and outcomes in follow-up were assessed. In addition, all patients treated for DCIS in this region (n=1389) were studied regarding clinical parameters, in order to determine whether the two-hospital sample was representative of the entire region. In the two-hospital sample, 31.4% (n=79) of the patients had not been treated according to the guidelines. Positive margins were associated with LR (hazard ratio (HR)=4.790, 95% confidence interval (CI) 1.696–13.531). Breast-conserving surgery and deviation from the guidelines were independent predictors of LR (HR=7.842, 95% CI 2.126–28.926; HR=2.778, 95% CI 0.982–6.781, respectively). Although the guidelines changed over time, time was not a significant factor in predicting LRs (HR=1.254, 95% CI 0.272–5.776 for time period 1992–1995 and HR=1.976, 95% CI 0.526–7.421 for time period 1996–1999). Clinical guidelines for the treatment of patients with DCIS have been developed and updated from existing literature and best evidence. Compliance with the guidelines was an independent predictor of disease-free survival. These findings support the application of guidelines in the treatment of DCIS

Intravenous mycophenolate mofetil: safety, tolerability, and pharmacokinetics

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72291/1/j.1399-0012.2000.140301.x.pd

Vascular density and phenotype around ductal carcinoma in situ (DCIS) of the breast

Up to 50% of recurrences of ductal carcinoma in situ of the breast are associated with invasive carcinoma but no pathological or molecular features have yet been found to predict for the development of invasive disease. For a tumour to invade, it requires the formation of new blood vessels. Previous studies have described a vascular rim around ducts involved by ductal carcinoma in situ, raising the possibility that the characteristics of periductal vascularisation may be important in determining transformation from in situ to invasive disease. Periductal vascular density and phenotype were determined using morphometry and a panel of anti-endothelial antibodies (von Willebrand factor, CD31, CD141 and CD34) and related to the presence of invasive carcinoma and other histological features. Compared to normal lobules, pure ductal carcinoma in situ exhibited a greater density of CD34+ and CD31+ vessels but a decrease in those that were immunopositive for vWF, indicating a difference in phenotype and in density. Ductal carcinoma in situ associated with invasive carcinoma showed a profile of vascular immunostaining similar to that of pure ductal carcinoma in situ but there were significantly greater numbers of CD34+ and CD141+ vessels and fewer staining for vWF. There was a significant negative correlation between vascular density and both the cross-sectional areas of the ducts involved and the extent of the necrosis of the tumour they contained. A correlation between vascular density and nuclear grade was also noted, being highest in the intermediate grade. The greater density of CD34+ and CD141+ vessels around ductal carcinoma in situ associated with invasive carcinoma could reflect a greater predisposition to invade but a direct effect of co-existent invasive carcinoma cannot entirely be ruled out in the present study. The relationship between vascular density, grade, duct size and nuclear grade suggests that periductal angiogenesis increases with tumour growth rate but is unable to keep pace with the most rapidly growing lesions

DAX-1 expression in human breast cancer: comparison with estrogen receptors ER-α, ER-β and androgen receptor status

BACKGROUND: So far there have been no reports on the expression pattern of DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) in human breast cells and its relationship to the estrogen receptors, ER-α and ER-β, and the androgen receptor (AR). METHODS: In this study we evaluated, by immunohistochemistry and Western blot analysis, the presence and distribution of DAX-1 in benign breast disease (BBD), in situ carcinoma (CIS), and ductal and lobular breast carcinomas. RESULTS: In BBD and breast carcinomas, DAX-1 was present in both the nuclei and the cytoplasm of epithelial cells, although in infiltrative carcinomas the percentage of nuclear immunoreaction was higher than in CIS. An important relation was observed between DAX-1 and AR expression and between this orphan receptor and nodal status. CONCLUSION: DAX-1 might modify the AR and ER-β intracellular location, and because a direct positive relation between the expression of these three receptors was found it could be assumed that the presence of DAX-1 in neoplastic cells might indicate a possible failure of endocrine therapies