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.     

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.     

Response of proopiomelanocortin and gonado- or lactotroph systems to in-vitro fertilisation procedures stress

Objective

To analyse for the first time the response of the corticotroph-type and the melanotroph-type pituitary proopiomelanocortin (POMC) system with regard to in-vitro fertilisation (IVF) treatment using self-developed highly specific non-cross-reacting radioimmunoassay.

Study design

Setting: University hospital. Patients: A total of 28 patients undergoing IVF oocyte retrieval. Cross sectional exploratory study, one factorial design with repeated measurements on one factor, non-parametric tests. Blood was collected before anaesthesia (t_A) (n = 28) and immediately after oocyte retrieval (t_B) (n = 28). Main outcome measure(s): β-endorphin immunoreactive material (IRM), acetyl-N-β-endorphin IRM, β-lipotropin IRM, ACTH, cortisol, estradiol, progesterone, prolactin, luteinizing hormone, and follicle-stimulating hormone. For determination of authentic β-endorphin [β-endorphin (1–31)] a highly specific two-site fluid phase immunoprecipitation radioimmunoassay was developed, which did not cross-react with any β-endorphin derivative or any other opioid peptide tested.

Results

No response of acetyl-N-β-endorphin IRM and of authentic β-endorphin (1–31) was observed to oocyte retrieval in contrast to a significant increase of corticotroph-type proopiomelanocortin derivatives. A significant rise in prolactin plasma concentration indicates a pronounced lactotroph response to oocyte retrieval stress. No significant correlation between POMC derivates and prolactin and between POMC derivatives and gonadotropins or sexual steroids except for ACTH and progesterone and for β-endorphin IRM and estradiol was observed.

Conclusion

IVF treatment stress led to significant corticotroph-type POMC and lactotroph responses, but not to responses of authentic β-endorphin or melanotroph-type POMC in women undergoing oocyte retrieval.     

Methods to determine the minimum important difference for a sexual event diary used by postmenopausal women with hypoactive sexual desire disorder

IntroductionRecently, there has been much discussion in the literature about how to determine the meaningfulness of results generated from a patient-reported outcome measure. A number of reviews have shown that there are two main approaches: anchor- and distribution-based approaches for determining the minimum important difference (MID) for a new measure. There are issues with calculating an MID using each method: Will the two approaches give the same estimate? If the estimates differ, how do you decide on one estimate? Would asking patients directly be more beneficial?AimA case study was presented to address these issues based on a newly developed diary assessing number of satisfactory sexual events (SSEs) per week in women with hypoactive sexual desire disorder (HSDD).MethodsAnchor- and distribution-based estimates were generated from data gathered in two double-blind, placebo-controlled, parallel group trials for the treatment of HSDD (N = 788). A novel interview study was used to ask women directly about an MID for SSEs (N = 77).Main Outcome MeasuresDefining the MID for an SSE diary in women with HSDD.ResultsThe estimates varied, producing a range of mean MID estimates between 0.04 and 0.46 SSEs per week.ConclusionsWe recommend that rather than defining the MID, a range should be selected from the set of estimates formed by the limits of the 95% confidence intervals. Symonds T, Spino C, Sisson M, Soni P, Martin M, Gunter L, and Patrick DL. Methods to determine the minimum important difference for a sexual event diary used by postmenopausal women with hypoactive sexual desire disorder.     

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.     

DVT-basierte virtuelle Planung und schablonengeführte Zygomaimplantation nach Hemimaxillektomie

This article presents a case of a 67-year-old female patient with an extended defect of the maxilla after tumor ablation. The defect was reconstructed with a microvascular radial forearm flap. A DVT was done to evaluate anatomy and virtually plan for the placement of one zygomatic- and four conventional implants. Zygomatic implant was inserted using a computer-manufactured template.