Systemic Arterial Endothelial Function in Children and Young Adults with Idiopathic Pulmonary Arterial Hypertension: Is there a Relation to Pulmonary Endothelium-Dependent Relaxation?

Pulmonary arterial endothelial function is known to be affected in patients with idiopathic pulmonary arterial hypertension (IPAH). Current reports also detected peripheral systemic arterial dysfunction in IPAH patients. The purpose of this study was to assess whether there is a relation between pulmonary arterial and systemic arterial endothelial function. Pulmonary arterial endothelium-dependent relaxation was assessed by changes in pulmonary blood flow in response to acetylcholine which were determined using intravascular Doppler flow measurements. Pulmonary flow reserve (PFR) was calculated as the ratio of pulmonary blood flow velocity in response to acetylcholine relative to baseline values. Systemic arterial endothelial function was assessed by the vascular response to reactive hyperemia, and was recorded non-invasively by peripheral arterial finger tonometry under standardized conditions. Thirteen children and young adults [mean age 16.7 (±5.6) years] with IPAH and 13 age-/gender-matched controls were included in the study. Digital reactive hyperemic index (RHI) of the IPAH patients was 1.54 (±0.69), and of the controls was 1.67 (±0.66) [p = 0.64]. The mean baseline flow velocity in the segmental pulmonary artery of all patients was 18.5 (±5.5) cm/s, increasing to 27.4 (±12.3) cm/s (p = 0.003) during acetylcholine infusion. The calculated mean PFR was 1.48 (±0.4). There was no significant correlation between the PFR and RHI (r = 0.19; p = 0.54). According to our results, systemic arterial endothelial function assessed by peripheral arterial finger tonometry was not significantly impaired in children and young adults with IPAH compared with age-/gender-matched controls. There was no correlation between systemic arterial and pulmonary arterial endothelial function, suggesting that different mechanisms may contribute to their pathogenesis and progression.     

Adiposity and estrogen receptor-positive,postmenopausal breast cancer risk: Quantification of the mediating effects of fasting insulin and free estradiol

Adiposity increases estrogen receptor (ER)-positive postmenopausal breast cancer risk. While mechanisms underlying this relationship are uncertain, dysregulated sex-steroid hormone production and insulin signaling are likely pathways. Our aim was to quantify mediating effects of fasting insulin and free estradiol in the adiposity and ER-positive postmenopausal breast cancer association. We used data from a case–cohort study of sex hormones and insulin signaling nested within the Melbourne Collaborative Cohort Study. Eligible women, at baseline, were not diagnosed with cancer, were postmenopausal, did not use hormone therapy and had no history of diabetes or diabetes medication use. Women with ER-negative disease or breast cancer diagnosis within the first follow-up year were excluded. We analyzed the study as a cumulative sampling case–control study with 149 cases and 1,029 controls. Missing values for insulin and free estradiol were multiply imputed with chained equations. Interventional direct (IDE) and indirect (IIE) effects were estimated using regression-based multiple-mediator approach. For women with body mass index (BMI) >30 kg/m² compared to women with BMI 18.5–25 kg/m², the risk ratio (RR) of breast cancer was 1.75 (95% confidence interval [CI] 1.05–2.91). The estimated IDE (RR) not through the mediators was 1.03 (95% CI 0.43–2.48). Percentage mediated effect through free estradiol was 72% (IIE-RR 1.56; 95% CI 1.11–2.19). There was no evidence for an indirect effect through insulin (IIE-RR 1.12; 95% CI 0.68–1.84; 28% mediated). Our results suggest that circulating free estradiol plays an important mediating role in the adiposity–breast cancer relationship but does not explain all of the association.     

Theoretical potential for endometrial cancer prevention through primary risk factor modification: Estimates from the EPIC cohort

Endometrial cancer (EC) incidence rates vary ~10-fold worldwide, in part due to variation in EC risk factor profiles. Using an EC risk model previously developed in the European EPIC cohort, we evaluated the prevention potential of modified EC risk factor patterns and whether differences in EC incidence between a European population and low-risk countries can be explained by differences in these patterns. Predicted EC incidence rates were estimated over 10 years of follow-up for the cohort before and after modifying risk factor profiles. Risk factors considered were: body mass index (BMI, kg/m²), use of postmenopausal hormone therapy (HT) and oral contraceptives (OC) (potentially modifiable); and, parity, ages at first birth, menarche and menopause (environmentally conditioned, but not readily modifiable). Modeled alterations in BMI (to all ≤23 kg/m²) and HT use (to all non-HT users) profiles resulted in a 30% reduction in predicted EC incidence rates; individually, longer duration of OC use (to all ≥10 years) resulted in a 42.5% reduction. Modeled changes in not readily modifiable exposures (i.e., those not contributing to prevention potential) resulted in ≤24.6% reduction in predicted EC incidence. Women in the lowest decile of a risk score based on the evaluated exposures had risk similar to a low risk countries; however, this was driven by relatively long use of OCs (median = 23 years). Our findings support avoidance of overweight BMI and of HT use as prevention strategies for EC in a European population; OC use must be considered in the context of benefits and risks.     

Regulative mechanisms of chondrocyte adhesion

Interaction between chondrocytes and extracellular matrix is considered a key factor in the generation of grafts for matrix-associated chondrocyte transplantation. Therefore, our objective was to study the influence of differentiation status on cellular attachment. Adhesion of chondrocytes to collagen type II increased after removal from native cartilage up to the third day in monolayer in a dose-dependent manner. Following dedifferentiation after the second passage, adhesion to collagen types I (-84%) and II (-46%) decreased, whereas adhesion to fibrinogen (+59%) and fibronectin (+43%) increased. A cartilage construct was developed based on a clinically established collagen type I scaffold. In this matrix, more than 80% of the cells could be immobilized by mechanisms of adhesion, filtration, and cell entrapment. Confocal laser microscopy revealed focal adhesion sites as points of cell-matrix interaction, as well as collagen type II expression in the cartilage graft after two weeks of in vitro cultivation. Basic fibroblast growth factor (bFGF) treated chondrocytes showed increased adhesion to collagen types I and II, fibronectin, and fibrinogen. Attachment to these investigated proteins significantly enhanced cell proliferation. Matrix design in cartilage engineering must meet the biological demands of amplified cells, because adhesion of chondrocytes depends on their differentiation status and is regulated by bFGF.     

Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications

It is no a secret that we are confronted by an alarmingly increasing number of patients with progressive renal disease. There is ample evidence for the notion that angiotensin II (Ang II) is a major culprit in progression. The vasopeptide Ang II turned out to have also multiple nonhemodynamic pathophysiologic actions on the kidney, including proinflammatory and profibrogenic effects. Diverse complex Ang II generating systems have been identified, including specifically local tissue-specific renin-angiotensin systems (RAS). For example, proximal tubular cells have all components required for a functional RAS capable of synthesizing Ang II. On the other hand, Ang II is not the only effector of the RAS and other peptides generated by the RAS influence renal function and structure as well. Moreover, the discoveries that Ang II can be generated by enzymes other than angiotensin-converting enzyme (ACE) and that Ang II and other RAS derived peptides bind to various receptors with different functional consequences have further added to the complexity of this system. Several major clinical trials have clearly shown that ACE inhibitor treatment slows the progression of renal diseases, including in diabetic nephropathy. Well-controlled studies demonstrated that this effect is in part independent of blood pressure control. More recently, with Ang II type 1 receptor (AT(1)) receptor antagonists a similarly protective effect on renal function was seen in patients with type 2 diabetes. Neither ACE inhibitor treatment nor AT(1) receptor blockade completely abrogate progression of renal disease. A recently introduced novel therapeutic approach is combination treatment comprising both ACE inhibitor and AT(1) receptor antagonists. The rationale for this approach is based on several considerations. Small-scale clinical studies, mainly of crossover design, documented that combination therapy is more potent in reducing proteinuria in patients with different chronic renal diseases. Blood pressure as an important confounder was, however, significantly lower in the majority of this studies in the combination treatment arms compared to the respective monotherapies. In a recent prospective study Japanese authors avoided this confounder and demonstrated that combination therapy reduced hard end-points (end stage renal failure or doubling of serum creatinine concentration) by 50% compared to the respective monotherapies. This effect could not be explained by a more pronounced reduction of blood pressure in the combination therapy group. Although these results are encouraging, administration of combination therapy should be reserved currently to special high risk groups. Further studies are necessary to confirm these promising results. It is possible that combination therapy may increase the risk of hyperkalemia, particularly when with coadministered with medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) or spironolactone. In our opinion patients with proteinuria >1 g/day despite optimal blood pressure control under RAS-blocking monotherapy are a high-risk group which will presumably benefit from combination therapy.     

Feasibility of extension of platinum-free interval with weekly bolus topotecan and subsequent platinum retreatment outcomes in recurrent ovarian cancer

Purpose  

The goal of this study was to evaluate the outcomes and response in a cohort of patients with presumed platinum-sensitive disease who were subsequently retreated with platinum after receiving weekly bolus topotecan at the time of initial recurrence.     

Identification of Cowdria ruminantium antigens that stimulate proliferation of lymphocytes from cattle immunized by infection and treatment or with inactivated organisms

Cowdria ruminantium is an obligate intracellular pathogen that causes heartwater in ruminants. Several findings suggest that T cells play an important role in protection against the disease. In order to identify which proteins are involved in T-cell immunity, C. ruminantium proteins were fractionated by continuous-flow electrophoresis and tested for their ability to stimulate lymphocyte proliferation in vitro. C. ruminantium-infected endothelial cell lysates were fractionated at between 11 and 38 kDa and 50 and 168 kDa on 15 and 7% acrylamide gels, respectively. In an attempt to stimulate the natural infective process, peripheral blood mononuclear cells (PBMC) were obtained from two cattle rendered immune by infection and treatment and assayed in proliferation assays with fractionated proteins. In a parallel study, four cattle were immunized with inactivated C. ruminantium to determine whether their lymphocytes also responded to fractionated proteins. Proliferation assays after immunization by infection and treatment detected no C. ruminantium-specific proliferation in vitro after one vaccination. Proliferation was observed, however, between 1 and 4 weeks after challenge. This was followed by a period of no detectable response, after which the response reappeared. PBMC from animals immunized with inactivated organisms proliferated specifically in response to antigen soon after the first immunization. Only C. ruminantium proteins with low molecular masses of 11, 12, 14 to 17, and 19 to 23 kDa induced proliferative responses by lymphocytes from all six animals. These protein fractions may have potential as vaccine antigens.     

Transfusion-Transmitted Cytomegalovirus: The Part-Time Pathogen

Viral infection is a well-known risk of blood product transfusion and much work has been devoted to the detection of such well-known pathogens as human immunodeficiency virus and hepatitis viruses in blood donors. Cytomegalovirus (CMV) is found in a much larger percentage of donor units than these other viruses but will cause disease in only a minority of recipients. Many pediatric patients (especially premature infants) are at risk for transfusion-transmitted CMV. This review describes work delineating the populations of patients most at risk for transfusion-transmitted CMV, describes methods for detecting CMV in blood donors, evaluates current methods for leukodepletion of blood products, and provides recommendations for patients most likely to benefit from blood products with low risk of CMV transmission.