Improved endothelial function after endothelin receptor blockade in patients with systemic sclerosis

Objective

Impaired endothelium‐dependent vasodilator function may contribute to vascular damage in patients with systemic sclerosis (SSc). This study was undertaken to investigate whether increased activity of the endothelin 1 (ET‐1) system plays a role in the occurrence of endothelial dysfunction in patients with SSc.

Methods

In 12 patients with SSc (6 with diffuse cutaneous SSc [dcSSc] and 6 with limited cutaneous SSc [lcSSc]), forearm blood flow responses to graded doses of acetylcholine (ACh) and sodium nitroprusside (SNP) given intraarterially were assessed by plethysmography, during infusion of saline and following selective blockade of ET_A receptors with BQ‐123 (10 nmoles/minute).

Results

During saline infusion, the vasodilator response to ACh was blunted in patients with SSc as compared with that in healthy controls (P < 0.001), whereas the response to SNP was not different between groups (P = 0.27). The vasodilator effect of ET_A receptor antagonism was higher in patients than in controls (P < 0.001), indicating enhanced ET‐1–mediated vasoconstriction in SSc. In patients, ET_A receptor blockade resulted in a potentiation of the vasodilator response to ACh (P < 0.001 versus saline), but did not affect the response to SNP (P = 0.31). Notably, both the vasodilator effect of ET_A receptor antagonism and the improvement in the responsiveness to ACh following BQ‐123 infusion were higher in patients with dcSSc than in those with lcSSc (P < 0.01).

Conclusion

ET‐1–dependent vasoconstrictor tone is increased predominantly in the subgroup of SSc patients with dcSSc, in whom acute blockade of ET_A receptors was able to improve impaired endothelium‐dependent vasodilator function. Our results suggest novel vasculoprotective effects of ET_A receptor antagonism and support further exploration of strategies that target the ET‐1 pathway in SSc.

     

Water polo is associated with an apparent redistribution of bone mass and density from the lower to the upper limbs

The bone response to exercise is site-specific and load-dependent. Recent evidence suggests that an inverse relationship may exist between loaded and unloaded sites, such that the former may benefit at the expense of the latter. The present study examined this possibility in 48 males (21 water polo players, 12 handball players, and 15 sedentary controls). Water polo and handball are alike with respect to the active loading of the upper limbs during overhead throwing; however, the weight-supporting environment of water polo removes the weight-bearing effect from the lower limbs. Bone mineral content (BMC), bone projected area (Ap), and areal bone mineral density (aBMD) of the total body and of various subregions were determined by dual-energy X-ray absorptiometry. After adjusting for age, height, and weight, water polo players had higher arms BMC, Ap, and aBMD (by 22.2, 11.1, and 10.5%, respectively; P < 0.05), but lower legs aBMD (−6.3%; P < 0.05) relative to controls. On the contrary, compared to controls, handball players had higher BMC (from 11.8 to 24.3%), Ap (from 5.2 to 11.7%), and aBMD (from 6.4 to 11.9%) for the total body at all sites. Water polo athletes had increased arms and decreased legs aBMD ratios (regional-to-total) than either handball players or sedentary subjects (P < 0.001). Water polo is associated with an apparent redistribution of bone mass and density from the lower to the upper limbs, with no major effects on the rest of the body.     

Discrepancy analysis, communication, and feedback for cytotechnologist quality improvement of nongynecologic cytopathology

The Clinical Laboratory Improvement Amendments of 1988 (CLIA '88) detail the requirements for the cytotechnologist (CT) who evaluates gynecologic cytopathology specimens. However, the role of the CT in nongynecologic cytopathology is not clearly defined. Furthermore, non gynecologic cytopathology cases are diverse and the screening, interpretative, and diagnostic issues may be quite different from the gynecologic cases. At our institution, the CT and pathologist review nongynecologic cytopathology cases. Since CLIA '88 does not require the CT to screen nongynecologic cytopathology cases, there are few guidelines for quality assessment or quality improvement for the CT regarding nongynecologic cytopathology cases. To provide better understanding of the expectations of the CT and the needs of the pathologist, we developed a system comparing the CT's interpretation to the pathologist's interpretation as a means for enhanced communication and feedback. Using our Laboratory Information System (LIS), we generate a daily report that lists all cases with discrepancy in diagnoses between the CT and pathologist. The general supervisor reviews this report for diagnostic discrepancy in each case. To determine the degree of discrepancy, numerical values are assigned to each primary interpretation. Minor discrepancies are defined as differences less than +/-2.0. Major discrepancies are defined as differences greater than or equal to +/-2.0. For the entire laboratory, the overall percentage of concordant cases was consistently above 80% for each of the 6 mo analysis. Regarding the monthly discrepancies, the proportion of minor discrepancies ranged from 11.09% to 15.44% and the proportion of major discrepancies ranged from 1.40% to 3.56%. The frequency distribution of discrepancies by degree approximates a normal (Gaussian) curve and serves as baseline information that may be used for comparison when there are changes in practice or personnel. The CTs attend slide review sessions conducted by the general supervisor for discussion of cases with major discrepancies. The discrepancy data from individual CTs are useful in counseling and recommending areas for improvement. As the CT and pathologist work cooperatively and in tandem, our system allows for a mechanism by which the expectations and needs of pathologist are communicated to the CT more effectively. We believe our process is a fundamental step in improving CT performance in Nongynecologic cytopathology and keeps the CT informed of complexities of nongynecologic cytopathology.     

Mammalian reovirus, a nonfusogenic nonenveloped virus, forms size-selective pores in a model membrane

During cell entry, reovirus particles with a diameter of 70-80 nm must penetrate the cellular membrane to access the cytoplasm. The mechanism of penetration, without benefit of membrane fusion, is not well characterized for any such nonenveloped animal virus. Lysis of RBCs is an in vitro assay for the membrane perforation activity of reovirus; however, the mechanism of lysis has been unknown. In this report, osmotic-protection experiments using PEGs of different sizes revealed that reovirus-induced lysis of RBCs occurs osmotically, after formation of small size-selective lesions or "pores." Consistent results were obtained by monitoring leakage of fluorophore-tagged dextrans from the interior of resealed RBC ghosts. Gradient fractionations showed that whole virus particles, as well as the myristoylated fragment mu1N that is released from particles, are recruited to RBC membranes in association with pore formation. We propose that formation of small pores is a discrete, intermediate step in the reovirus membrane-penetration pathway, which may be shared by other nonenveloped animal viruses.     

Comparison of select cancer biomarkers in human circulating and bulk tumor cells using magnetic nanoparticles and a miniaturized micro-NMR system

Circulating tumor cells (CTC) harvested from peripheral blood have received significant interest as sources for serial sampling to gauge treatment efficacy. Nanotechnology and microfluidic based approaches are emerging to facilitate such analyses. While of considerable clinical importance, there is little information on how similar or different CTCs are from their shedding bulk tumors. In this clinical study, paired tumor fine needle aspirate and peripheral blood samples were obtained from cancer patients during image-guided biopsy. Using targeted magnetic nanoparticles and a point-of-care micro-NMR system, we compared selected biomarkers (EpCAM, EGFR, HER-2 and vimentin) in both CTC and fine needle biopsies of solid epithelial cancers. We show a weak correlation between each paired sample, suggesting that use of CTC as “liquid biopsies” and proxies to metastatic solid lesions could be misleading.From the Clinical EditorIn this clinical study, paired tumor fine needle aspirate and peripheral blood samples were obtained from patients with solid epithelial cancers during image-guided biopsy. Using targeted magnetic nanoparticles and a point-of-care micro-NMR system, the authors compared selected biomarkers in both circulating tumor cells (CTC) and fine needle biopsies, demonstrating a weak correlation between each paired sample, suggesting that use of CTC could be misleading in this context.     

A prospective study on survival in cancer patients with and without venous thromboembolism

Retrospective population-based studies showed that in cancer patients venous thromboembolism (VTE) is associated with reduced survival. Master Oncology is a multicenter study in patients with solid advanced cancer aimed at assessing (1) risk factors for VTE using a case–control design, and (2) survival in cases (patients with VTE) and controls (patients without VTE). Survival data were prospectively collected for at least 10 months. Overall, 237 cases and 339 controls were included in the analysis. The following factors were found to be associated with an increased risk of VTE: body mass index (BMI; OR 2.02; 95 % CI 1.31–3.12 for ≥26 vs. <23 kg/m²), ECOG score (OR 2.14; 95 % CI 1.47–3.11 for grade 1, and 3.32; 95 % CI 1.64–6.00 for grade 2–3, compared to grade 0) and recent diagnosis of cancer (OR 1.90; 95 % CI 1.33–2.71 for <12 vs. ≥12 months). After an average prospective observation of 8.3 months, 136 cases (57.4 %) and 127 controls (37.5 %) died with a median survival of 8.7 (95 % CI 7.5–10.9) and 14.3 months (95 % CI 12.2–18.7), respectively, (Wilcoxon = 27.72, p < 0.001; multivariate hazard ratio 1.55; 95 % CI 1.21–2.00). Median survival time was reduced for both patients with symptomatic (Wilcoxon = 35.22, p < 0.001) and asymptomatic VTE (Wilcoxon = 4.63, p = 0.031). Patients with advanced solid cancer, high BMI, high ECOG score, and recent diagnosis of cancer are associated with an increased risk for VTE. Patients with both symptomatic and asymptomatic VTE have a reduced survival compared to those without VTE.