Citations

Abstract Human erythropoiesis is a complex multistep process that involves the differentiation of early erythroid progenitors to mature erythrocytes. Here we show that it is feasible to differentiate and mature human embryonic stem cells (hESCs) into functional oxygen-carrying erythrocytes on a large scale (1010-1011 cells/6-well plate hESCs). We also show for the first time that the oxygen equilibrium curves of the hESC-derived cells are comparable with normal red blood cells and respond to changes in pH and 2,3-diphosphoglyerate. Although these cells mainly expressed fetal and embryonic globins, they also possessed the capacity to express the adult β-globin chain on further maturation in vitro. Polymerase chain reaction and globin chain specific immunofluorescent analysis showed that the cells increased expression of β-globin (from 0% to > 16%) after in vitro culture. Importantly, the cells underwent multiple maturation events, including a progressive decrease in size, increase in glycophorin A expression, and chromatin and nuclear condensation. This process resulted in extrusion of the pycnotic nuclei in up to more than 60% of the cells generating red blood cells with a diameter of approximately 6 to 8 μm. The results show that it is feasible to differentiate and mature hESCs into functional oxygen-carrying erythrocytes on a large scale.

Objective To review the data on long-term outcomes in women who underwent prophylactic bilateral oophorectomy, a common surgical procedure that has more than doubled in frequency since the 1960s. Study design Literature review of the published data on the consequences of prophylactic bilateral oophorectomy. Special emphasis was given to the Mayo Clinic Cohort Study of Oophorectomy and Aging. Main outcome measures Overall mortality, cardiovascular disease, cognitive impairment and dementia, parkinsonism, osteoporosis, psychological wellbeing and sexual function. Results There is a growing body of evidence suggesting that the premature loss of ovarian function caused by bilateral oophorectomy performed before natural menopause is associated with several negative outcomes. In particular, studies have revealed an increased risk of premature death, cardiovascular disease, cognitive impairment or dementia, parkinsonism, osteoporosis and bone fractures, decline in psychological wellbeing and decline in sexual function. The effects involve different organs (e.g. heart, bone, or brain), and different functions within organs (e.g. cognitive, motor, or emotional brain functions). Estrogen treatment may prevent some but not all of these negative outcomes. Conclusion The potential adverse effects of prophylactic bilateral oophorectomy on heart health, neurological health, bone health and quality of life should be carefully weighed against its potential benefits for cancer risk reduction in women at average risk of ovarian cancer.

Background— Advanced glycation end products (AGEs) are believed to increase left ventricular (LV) and vascular stiffness, in part via cross-linking proteins. We determined whether and where AGEs were increased in elderly hypertensive nondiabetic dogs and whether an AGE cross-link breaker (ALT-711) improved vascular or ventricular function. Methods and Results— Elderly dogs with experimental hypertension (old hypertensives [OH]) were randomized to receive ALT-711 (OH+ALT group; n=11; 1 mg/kg PO) or not (OH group; n=11) for 8 weeks. Conscious blood pressure measurements (weekly), echocardiography (week 8), and anesthetized study (week 8) with LV pressure–volume analysis and aortic pressure–dimension and pressure–flow assessment over a range of preloads and afterloads were performed. In LV and aorta from OH, OH+ALT, and young normal dogs, AGE content (immunohistochemistry and Western analysis for N ε -(carboxymethyl)lysine [CML]) was assessed. Aortic CML content was markedly increased in OH and OH+ALT dogs compared with young normal dogs. CML was localized to aortic and aortic vasa vasorum smooth muscle but not to collagen or elastin. CML was essentially undetectable in young normal, OH, or OH+ALT myocardium but was visible in large vessels in the LV. ALT-711 therapy was associated with lower blood pressure and pulse pressure, decreased systemic vascular resistance, increased aortic distensibility and arterial compliance, and, notably, significant aortic dilatation. Neither LV systolic nor diastolic function was different in OH+ALT versus OH dogs. Conclusions— In elderly hypertensive canines, AGE accumulation and AGE cross-link breaker effects were confined to the vasculature without evidence of myocardial accumulation or effects. The lack of AGE accumulation in collagen-rich areas suggests that the striking vascular effects may be mediated by mechanisms other than collagen cross-linking.

Purpose In men who are at high-risk of prostate cancer, progression and death from cancer after radical retropubic prostatectomy (RRP), limited prognostic information is provided by established prognostic features. The objective of this study was to develop a model predictive of outcome in this group of patients. Methods Candidate genes were identified from microarray expression data from 102 laser capture microdissected prostate tissue samples. Candidates were overexpressed in tumor compared with normal prostate and more frequently in Gleason patterns 4 and 5 than in 3. A case control study of 157 high-risk patients, matched on Gleason score and stage with systemic progression or death of prostate cancer as the end point, was used to evaluate the expression of candidate genes and build a multivariate model. Tumor was collected from the highest Gleason score in paraffin-embedded blocks and the gene expression was quantified by real-time reverse transcription polymerase chain reaction. Validation of the final model was performed on a separate case-control study of 57 high-risk patients who underwent RRP. Results A model incorporating gene expression of topoisomerase-2a, cadherin-10, the fusion status based on ERG, ETV1, and ETV4 expression, and the aneuploidy status resulted in a 0.81 area under the curve (AUC) in receiver operating characteristic statistical analysis for the identification of men with systemic progression and death from high grade prostate cancer. The AUC was 0.79 in the independent validation study. Conclusion The model can identify men with high-risk prostate cancer who may benefit from more intensive postoperative follow-up and adjuvant therapies.

It is estimated that 10% of pregnancies are affected by hypertension worldwide. Approximately one-half of all hypertensive pregnancy disorders are due to preeclampsia, a pregnancy-specific disorder, its distinctive feature being either sudden onset, or worsening of pre-existing proteinuria. It has become increasingly recognized that women with a history of preeclampsia are at increased risk for future cardiovascular disease (CVD), but the mechanisms of this increase in risk are unclear. One possible explanation is that these two conditions share several common metabolic abnormalities as risk factors, including obesity, insulin resistance, and lipid abnormalities that may lead to preeclampsia and CVD at different times of a woman's life. Recent studies have revealed that, similar to CVD, several mediators of endothelial cell dysfunction are up-regulated in preeclampsia. Free radical derived oxidative stress, various inflammatory markers, including neutrophil response, C-reactive protein, and leukocyte adhesion, may contribute to endothelial dysfunction in both preeclampsia and coronary atherosclerosis. Alternatively, preeclampsia itself may induce metabolic and vascular changes that may increase the overall future risk for CVD in affected women. Therefore, at present, it remains unclear whether preeclampsia is a formal risk factor for CVD, or identifies women at increased risk for CVD later in life. Pending large-scale studies aiming to examine the causality of this association, women with a history of preeclampsia should be counseled regarding their increased risks for hypertension and other cardiovascular sequelae later in life, followed closely and treated aggressively for modifiable CVD risk factors.