Damage of the Endothelial Glycocalyx in Dialysis Patients

Damage to the endothelial glycocalyx, which helps maintain vascular homeostasis, heightens the sensitivity of the vasculature to atherogenic stimuli. Patients with renal failure have endothelial dysfunction and increased risk for cardiovascular morbidity and mortality, but the state of the endothelial glycocalyx in these patients is unknown. Here, we used Sidestream Darkfield imaging to detect changes in glycocalyx dimension in dialysis patients and healthy controls from in vivo recordings of the sublingual microcirculation. Dialysis patients had increased perfused boundary region and perfused diameters, consistent with deeper penetration of erythrocytes into glycocalyx, indicating a loss of glycocalyx barrier properties. These patients also had higher serum levels of the glycocalyx constituents hyaluronan and syndecan-1 and increased hyaluronidase activity, suggesting the shedding of these components. Loss of residual renal function had no influence on the imaging parameters but did associate with greater shedding of hyaluronan in blood. Furthermore, patients with higher levels of inflammation had more significant damage to the glycocalyx barrier. In conclusion, these data suggest that dialysis patients have an impaired glycocalyx barrier and shed its constituents into blood, likely contributing to the sustained endothelial cell activation observed in ESRD.Patients with chronic renal failure have endothelial dysfunction and accelerated vascular disease leading to increased morbidity and mortality as a result of cardiovascular events.^1–4 The mechanisms responsible are unclear, controversial, and presumed to be multifactorial. The vascular endothelium is coated on the luminal side by the glycocalyx, a negatively charged mesh of proteoglycans (PGs) and associated glycosaminoglycans.⁵ It is involved in mediating shear-induced release of nitric oxide and contributes to the endothelial permeability barrier, the regulation of redox state, and the inhibition of coagulation as well as leukocyte and platelet adhesion.^6–9 Perturbation of glycocalyx occurs after provocation with inflammatory or atherogenic stimuli (such as ischemia reperfusion,¹⁰ infusion of oxidized LDL,^9,11 administration of TNF-α¹² or endotoxin,¹³ and during hyperglycemia¹⁴) and after stimulation with thrombin,¹⁵ atrial natriuretic peptide,¹⁶ or abnormal blood shear stress.^17,18 Consequences of glycocalyx perturbation include a wide range of vascular abnormalities in experimental models, including increased vascular permeability followed by generation of tissue edema,¹⁹ increased rolling and adhesion of leukocytes,⁶ and increased platelet adhesion.⁹ Therefore, disruption of the glycocalyx leads to enhanced sensitivity of vasculature to atherogenic stimuli. Based on these observations, the importance of integrity of the endothelial glycocalyx in vascular homeostasis has become evident.Attempts to assess the impairment of endothelial function in vivo are a challenge given the multifunctional nature of endothelial cells and lack of standardized tools to noninvasively assess endothelial function in a patient-friendly manner. We recently developed an imaging-based method to detect changes in glycocalyx dimension from in vivo recordings of the sublingual microcirculation, enabling us to assess the microvascular glycocalyx in vivo in patients. Previous studies have shown that, in healthy volunteers, the glycocalyx is disrupted by acute hyperglycemia.¹⁴ Subsequently, a significant reduction in glycocalyx volume was found in patients with type 1 diabetes.²⁰ This disruption may contribute to the known predisposition of these patients to vascular disease.No data are available on the state of the endothelial glycocalyx in patients with chronic renal failure. However, it is reasonable to hypothesize that the endothelial glycocalyx is affected in these patients given their predisposition to endothelial dysfunction and vascular disease. A damaged glycocalyx may lead to increased vulnerability and susceptibility of endothelial cells to vascular risk factors present in uremia. Therefore, the objective of this study was to answer the following questions. (1) Is the microvascular endothelial glycocalyx damaged in patients with ESRD on both hemodialysis (HD) and peritoneal dialysis (PD) compared with age- and sex-matched healthy controls? (2) Do dialysis patients have increased serum concentrations of glycocalyx constituents reflecting increased shedding? (3) Do the changes in endothelial glycocalyx correlate with other serum markers of endothelial activation, like sE-selectin?     

Tumor Budding is an Independent Predictor of Outcome in AJCC/UICC Stage II Colorectal Cancer

Background

In colorectal cancer, the morphology of the invasive tumor margin may reflect aggressiveness of tumor growth, thus providing important prognostic information. The tumor growth pattern according to Jass and the extent of tumor budding were analyzed in patients with American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) stage II disease.

Methods

Tumors of 120 randomly selected patients with AJCC/UICC stage II disease were retrospectively reviewed for tumor growth pattern (expanding vs. infiltrating) and the extent of tumor budding, with high-grade budding reflecting presence of 10 or more budding foci scattered at the invasive tumor margin. Progression-free and cancer-specific survivals were determined by the Kaplan?CMeier method. For multivariable analysis, Cox??s proportional hazards regression models were performed.

Results

The infiltrating growth pattern was significantly associated with histological subtype and lymphovascular invasion, while high-grade budding was significantly associated with tumor grade and lymphovascular invasion. High-grade budding, but not the infiltrating growth pattern, was significantly associated with outcome in univariable analysis. Cox??s proportional hazards regression models proved tumor budding to be an independent predictor of disease progression (hazard ratio 3.91, 95?% confidence interval 1.3?C11.77; P?=?0.02) and cancer-related death (hazard ratio 5.90, 95?% confidence interval 1.62?C21.51; P?=?0.007). The combination of infiltrating growth pattern and high-grade budding did not have a stronger prognostic significance than tumor budding alone.

Conclusions

Tumor budding independently predicted patient outcome in patients with AJCC/UICC stage II colorectal cancer and may therefore be used for accurate prognostication, patient counseling, and design of clinical trials by using integrated multimodal therapy.     

MRI of superficial soft tissue masses: analysis of features useful in distinguishing between benign and malignant lesions

Aim

To identify the MRI features of superficial soft tissue masses, that may allow differentiation between malignant and non-malignant lesions.

Method

A total of 136 consecutive patients referred to a supra-regional musculoskeletal oncology center over a 10-year period with the diagnosis of a superficial soft tissue mass were included in this retrospective study. Features analyzed included patient demographics, lesion size, MRI signal characteristics, margins, lobulation, hemorrhage, necrosis, fascial edema, relationship to the fascia, as well as involvement of the skin. Comparison was then made with the final histological diagnosis.

Results

Of the patients reviewed, 58 were male and 78 were female, and the mean age was 49.9?years. The mean age for malignant lesions was 57.9?years, and that for non-neoplastic and benign conditions 41.9?years (p?<?0.001). A significant relationship was identified between malignancy and lobulation (p?<?0.01), hemorrhage (p?<?0.001), fascial edema (p?<?0.001), hemorrhage (p?<?0.0001) and necrosis (p?<?0.001). The relationship between skin thickening and skin contact and malignancy was also found to be significant. However, size was not found to be an important determining factor for malignancy, with a significant proportion of malignant superficial sarcomas measuring less than 5?cm in maximal diameter.

Conclusions

This study has shown that a significant proportion of malignant superficial sarcomas measured less than 5?cm in maximal diameter. Fascial edema, skin thickening, skin contact, hemorrhage, and necrosis were found to be highly significant factors indicative of malignancy. Lobulation and peritumoral edema were also significant MRI features.     

Identification of cause of posttransplant cachexia by PCR

TO THE EDITOR: A man, 56 years of age, was admitted to the hospital for epigastric pain, fever, and fatigue 8 years after a cardiac transplant. His immunosuppressive regimen consisted of cyclosporine A, mycophenolate mofetil, and steroids. Clinical examination revealed a 4-kg weight loss within 3 months without peripheral lymph node enlargement.     

Potential role of complementary and alternative health care providers in chronic disease prevention and health promotion: an analysis of National Health Interview Survey data

Objective

To make a preliminary assessment of the potential role of the most frequently used licensed or certified United States complementary and alternative medicine (CAM) providers in chronic disease prevention and health promotion.

Method

This was a secondary analysis of the 2007 United States National Health Interview Survey (NHIS), the most recent to include CAM use. The Adult Core Sample, Person and Adult Complementary and Alternative Medicine data files were included. NHIS's complete survey design structure (strata, cluster and survey weights) was applied in generating national population estimates for CAM usage.

Results

Chiropractic or osteopathic manipulation (8.4%) and massage (8.1%) were most commonly used; acupuncture was used by 1.4% and naturopathy by 0.3% of respondents. Substantial proportions of respondents reported using CAM for wellness and disease prevention, and informed their medical physician of use. Fifty-four percent were overweight or obese, 22.0% physically inactive, and 17.4% smokers; 18.0% reported hypertension, 19.6% high cholesterol, and 9.1% prediabetes or diabetes.

Conclusion

CAM users present with risk factors which are priority public health issues. This implies a need to train CAM providers in evidence-based health promotion counseling. CAM encounters may provide opportunities to coordinate health promotion and prevention messages with patients' primary care providers.     

Breaking up is hard to do: why disinvestment in medical technology is harder than investment

Healthcare technology is a two-edged sword - it offers new and better treatment to a wider range of people and, at the same time, is a major driver of increasing costs in health systems. Many countries have developed sophisticated systems of health technology assessment (HTA) to inform decisions about new investments in new healthcare interventions. In this paper, we question whether HTA is also the appropriate framework for guiding or informing disinvestment decisions. In exploring the issues related to disinvestment, we first discuss the various HTA frameworks which have been suggested as a means of encouraging or facilitating disinvestment. We then describe available means of identifying candidates for disinvestment (comparative effectiveness research, clinical practice variations, clinical practice guidelines) and for implementing the disinvestment process (program budgeting and marginal analysis (PBMA) and related techniques). In considering the possible reasons for the lack of progress in active disinvestment, we suggest that HTA is not the right framework as disinvestment involves a different decision making context. The key to disinvestment is not just what to stop doing but how to make it happen - that is, decision makers need to be aware of funding disincentives.