Dysfunction of endothelial progenitor cells under diabetic conditions and its underlying mechanisms

Cardiovascular complications have been major concerns in the treatment of diabetes, and up to 80% of all deaths in diabetic patients are linked to cardiovascular problems. Impaired angiogenesis is one of the most serious symptoms associated with diabetes, resulting in delayed wound healing and lower limb amputation. Endothelial progenitor cells (EPCs), a subpopulation of adult stem cells, are recruited from bone marrow to the injured vessel to promote endothelial regeneration and neovascularization, playing an important role in angiogenesis. Interestingly, several clinical studies have showed that the number of recruited EPCs is reduced and their function is decreased under diabetic conditions, implying that diabetic EPC dysfunction may contribute to defective angiogenesis and resultant cardiovascular complications in diabetes. To recover the functional abilities of diabetic EPCs and to address possible application of EPC cell therapy to diabetic patients, some studies provided explanations for diabetic EPC dysfunction including increased oxidative stress, involvement of the inflammatory response, alteration in the nitric oxide pathway and reduced signals for EPC recruitment. This review discusses clinical evidence of impairment of EPC functions under diabetic conditions and the suggested mechanisms for diabetic EPC dysfunction.     

Ambidextrous magnetic nanovectors for synchronous gene transfection and labeling of human MSCs

The synchronization of gene expression and cell trafficking in transfected stem cells is crucial for augmentation of stem cell functions (differentiation and neurotropic factor secretion) and real time in vivo monitoring. We report a magnetic nanoparticle-based gene delivery system that can ensure simultaneous gene delivery and in vivo cell trafficking by high resolution MR imaging. The polar aprotic solvent soluble MnFe?O? nanoparticles were enveloped using cationic polymers (branched polyethyleneimine, PEI) by the solvent shifting method for a gene loading. Using our magnetic nanovector system (PEI-coated MnFe?O? nanoparticles), thus, we synchronized stem cell migration and its gene expression in a rat stroke model.     

Exploration of Optimal Dosing Regimens of Haloperidol,a D<Subscript>2</Subscript> Antagonist, <Emphasis Type="Italic">via</Emphasis> Modeling and Simulation Analysis in a D<Subscript>2</Subscript> Receptor Occupancy Study

Purpose

To evaluate the potential usage of D₂ receptor occupancy (D2RO) measured by positron emission tomography (PET) in antipsychotic development.

Methods

In this randomized, parallel group study, eight healthy male volunteers received oral doses of 0.5 (n?=?3), 1 (n?=?2), or 3 mg (n?=?3) of haloperidol once daily for 7 days. PET’s were scanned before haloperidol, and on days 8, 12, with serial pharmacokinetic sampling on day 7. Pharmacokinetics and binding potential to D₂ receptor in putamen and caudate nucleus over time were analyzed using NONMEM, and simulations for the profiles of D2RO over time on various regimens of haloperidol were conducted to find the optimal dosing regimens.

Results

One compartment model with a saturable binding compartment, and inhibitory E_max model in the effect compartment best described the data. Plasma haloperidol concentrations at half-maximal inhibition were 0.791 and 0.650 ng/ml, in putamen and caudate nucleus. Simulation suggested haloperidol 2 mg every 12 h is near the optimal dose.

Conclusion

This study showed that sparse D2RO measurements in steady state pharmacodynamic design after multiple dosing could reveal the possibility of treatment effect of D₂ antagonist, and could identify the potential optimal doses for later clinical studies by modeling and simulation.

     

Protective role of NAD(P)H:quinone oxidoreductase 1 (NQO1) in cisplatin-induced nephrotoxicity

Although cisplatin is widely used as an anti-cancer agent, its use is significantly limited because of its tendency to induce nephrotoxicity through poorly understood mechanisms. NAD(P)H:quinone oxidoreductase 1 (NQO1) is well known to regulate ROS generation. The purpose of this study was to investigate whether NQO1 modulates cisplatin-induced renal failure associated with NADPH oxidase (NOX)-derived ROS production in an animal model. NQO1^−/− mice were treated with cisplatin (18 mg/kg) and renal function, oxidative stress, and tubular apoptosis were assessed. NQO1^−/− mice showed increased blood urea nitrogen and creatinine levels, tubular damage, oxidative stress, and apoptosis. In accordance with these results, the cellular NADPH/NADP ratio and NOX activity were markedly increased in the kidneys of NQO1^−/− mice compared to NQO1^+/+ mice. In addition, activation of NQO1 by βL treatment significantly improved renal dysfunction and reduced tubular cell damage, oxidative stress, and apoptosis. This study demonstrates that NQO1 protects cells against renal failure induced by cisplatin, and that this effect is mediated by decreased NOX activity via cellular NADPH/NADP modulation. These results provide convincing evidence that NQO1 might be beneficial for ameliorating renal failure induced by cisplatin.     

Pregnancy Outcomes Following Laparoscopic and Open Surgery in Pelvis during Pregnancy: a Nationwide Population-based Study in Korea

BackgroundNon-obstetric surgery during pregnancy is associated with adverse obstetric and fetal outcomes. The aim of this study was to investigate the risk of adverse pregnancy outcomes for women who underwent non-obstetric pelvic surgery during pregnancy compared with that of women that did not undergo surgery.MethodsStudy data from women who gave birth in Korea were collected from the Korea National Health Insurance claims database between 2006 and 2016. We identified pregnant women who underwent abdominal non-obstetric pelvic surgery by laparoscopy or laparotomy from the database. Pregnancy outcomes including preterm birth, low birth weight (LBW), cesarean section (C/S), gestational hypertension, gestational diabetes, and postpartum hemorrhage were identified. The adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the pregnancy outcomes were estimated by multivariate regression models.ResultsData from 4,439,778 women were collected for this study. From 2006–2016, 9,417 women from the initial cohort underwent non-obstetric pelvic surgery (adnexal mass resection, appendectomy) during pregnancy. Multivariate logistic regression analysis indicated that preterm birth (HR, 2.01; 95% CI, 1.81–2.23), LBW (HR, 1.62; 95% CI, 1.46–1.79), C/S (HR, 1.13; 95% CI, 1.08–1.18), and gestational hypertension (HR, 1.35; 95% CI, 1.18–1.55) were significantly more frequent in women who underwent non-obstetric surgery during pregnancy compared to pregnant women who did not undergo surgery. When the laparoscopic and laparotomy groups were compared for risk of fetal outcomes, the risk of LBW was significantly decreased in laparoscopic adnexal resection during pregnancy compared to laparotomy (odds ratio, 0.62; 95% CI, 0.40–0.95).ConclusionNon-obstetric pelvic surgery during pregnancy was associated with a higher risk of preterm birth, LBW, gestational hypertension, placenta previa, placental abruption, and C/S. Although the benefits and safety of laparoscopy during pregnancy appear similar to those of laparotomy in regard to pregnancy outcomes, laparoscopic adnexal mass resection was associated with a lower risk of LBW.     

Grade of Ductal Carcinoma In Situ Accompanying Infiltrating Ductal Carcinoma As an Independent Prognostic Factor

BackgroundSeveral studies about the relationship between IDC and DCIS have been reported, but no consensus has been reached regarding clinical characteristics and prognostic value.Patients and MethodsWe reviewed the medical records of patients who underwent surgery for IDC between 2006 and 2008. DCIS adjacent to IDC was pathologically classified as either high-grade DCIS or non–high-grade DCIS.ResultsAmong 1751 IDC patients within the study period, 1384 patients (79.0%) had concomitant DCIS. There was no survival difference between patients with pure IDC and those with IDC and concomitant DCIS. However, patients with high-grade DCIS had worse survival than did patients with non–high-grade DCIS or pure IDC (5-year recurrence-free survival rates for IDC with non–high-grade DCIS, pure IDC without DCIS, and IDC with high-grade DCIS were 97%, 93%, and 86%, respectively; P = .001). This tendency was maintained regardless of estrogen receptor status or histologic grade of IDC. In a Cox regression model, patients with IDC and accompanying high-grade DCIS had a 2.5-fold higher probability of local or distant relapse than did those with IDC and low-grade DCIS (hazard ratio, 2.51; 95% confidence interval, 1.12–5.64).ConclusionsThe prognosis of patients with invasive breast cancer differed according to the grade of concomitant adjacent DCIS. Accordingly, the grade of adjacent DCIS should be considered as a prognostic factor in the clinical management of patients with breast cancer. However, in our study, the follow-up periods were short to confirm prognostic effect. Further studies are needed.