Oxidative stress in patients treated with continuous ambulatory peritoneal dialysis (CAPD) and the significant role of vitamin C and E supplementation

Purpose

Chronic renal failure patients undergoing peritoneal dialysis (PD) are characterized by increased oxidative stress (OS), which is associated with enhanced cardiovascular risk. Moreover, oxidative stress also contributes to peritoneal membrane changes and ultrafiltration failure. The aim of this study was to evaluate OS in PD patients and the effect of treatment with ascorbic acid and α-tocopherol.

Methods

Plasma, erythrocyte, urine, and peritoneal effluent samples from 20 patients on PD were evaluated for glutathione peroxidase and superoxide dismutase activity, total antioxidant capacity (TAC) and malondialdehyde (MDA) levels, as well as protein carbonyl formation, before and after administration of vitamin C, alone or in combination with vitamin E, in comparison with 10 apparently healthy control individuals.

Results

All studied markers showed enhanced OS in the PD group, compared to controls. The supplementation of vitamin C and E resulted in improvements of all the OS markers, as indicated by increased erythrocyte antioxidant enzymes activity and TAC levels, as well as decreased MDA concentration and carbonyl compound formation.

Conclusions

The oral supplementation of antioxidant vitamins C and E, in combination, can lead to decreased OS, thus providing a useful and cost-effective therapeutic option in PD patients.     

Ethical Issues of Participant Recruitment in Surgical Clinical Trials

Although the historical background of ethical principles of human subjects research are the same for surgery and nonsurgical fields, surgical clinical trials raise several specific ethical issues. Placebo arms in surgical trials are problematic because the closer the sham surgery is to a real operation, the greater the risks for subjects. In order to ethically enter subjects into a clinical trial, a researcher must have equipoise—that is, uncertainty about which treatment arm is more effective. Surgeons must diligently maintain skepticism about whether new treatments are actually better until objective data are available. The dynamic of informed consent between surgeons and patients may be negatively impacted if patients are convinced that new treatments are better even when there are no objective data. Although clinical trials in surgery often are challenging to develop and complete, there is an ethical and social responsibility for surgeons to participate in clinical trials so that data can be gathered to determine what treatments are safe and effective.     

Screening performance of different methods defining fetal nasal bone hypoplasia as a single and combined marker for the detection of trisomy 21 in the second trimester

Objective: To evaluate different methods of defining fetal nasal bone hypoplasia in the second trimester for the detection of trisomy 21.

Methods: Prospective study in Greek women undergoing anomaly scan between 18?+?0 and 23?+?6 weeks. The following methods of defining nasal bone hypoplasia were evaluated, either as a single marker or in combination with others: (1) BPD to nasal bone length (NBL) ratio; (2) multiples of the median (MoM) of NBL, according to normal curves from a Greek population; (3–4) NBL?<?2.5 percentile according to normal curves (3) commonly used internationally curves and (4) curves from a Greek population.

Results: In total, 1301 singleton fetuses were evaluated???10 with trisomy 21. The best detection rate of trisomy 21 was achieved when the applied method was nasal bone percentiles adjusted to maternal ethnicity, in combination with other markers (<2.5 percentile according to normal curves from a Greek population; p?<?0.001; sensitivity 50%; specificity 94.8%; false-positive rate 5.2%; positive likelihood ratio 9.6).

Conclusion: Screening performance of fetal nasal bone hypoplasia in detecting trisomy 21 varies according to the method applied. The best screening performance is achieved by using percentiles adjusted to maternal ethnicity in combination with other markers of aneuploidy.     

Single embryo transfer in preimplantation genetic diagnosis cycles for women <36 years does not reduce delivery rate

BACKGROUND: The Belgian legislation imposes single embryo transfer (SET) on women of <36 years in their first treatment cycle to avoid multiple pregnancies. The aim of this study is to assess the impact of this legislation on the outcome of preimplantation genetic diagnosis (PGD) for inherited diseases in young women undergoing SET. METHODS: A retrospective analysis of PGD cycles for monogenic disorders and translocations in women <36 years on their first treatment cycle. Two groups of patients were defined according to the implementation of the Belgian legislation: (i) double embryo transfer (DET), January 2001-June 2003 (ii) SET, July 2003-June 2005. The primary and secondary outcome measures were delivery per embryo transfer and multiple pregnancy rates, respectively. A subgroup analysis for monogenic disorders and translocations was performed. RESULTS: 62 cycles were included in the DET group and 73 cycles in the SET group. The mean age, number of cumulus-oocyte complexes, number of fertilized oocytes, number of biopsied and cryopreserved embryos were comparable between both groups. There was no significant difference in the delivery rates between the DET and the SET groups (33.9% versus 27.4%, respectively). Multiple pregnancies were avoided when SET was performed. When monogenic disorders and chromosomal translocations were separately evaluated, no significant difference in the delivery rate after SET was observed. CONCLUSIONS: The implementation of a SET policy in young women undergoing PGD for monogenic disorders and translocations enables a significant reduction of multiple pregnancies without significantly affecting the delivery rate.     

Effect of oral administration of dydrogestrone versus vaginal administration of natural micronized progesterone on the secretory transformation of endometrium and luteal endocrine profile in patients with premature ovarian failure: a proof of concept

BACKGROUND: We aimed to explore the endometrial histology and endocrine profiles on day 21 of an artificial cycle in patients with premature ovarian failure (POF) treated with oral dydrogesterone (DG) or vaginal micronized progesterone. METHODS: The study was designed as a prospective pilot study at an academic reproductive medicine unit. Six POF patients were included in the study. After estrogen endometrial priming, patients were randomized to receive DG or progesterone in two subsequent cycles. The main outcome measure was the endometrial histology and the endocrine profiles on day 21 of the cycle. RESULTS: Development of endometrial glands corresponded to an early secretory phase in five out of six cases supplemented with DG (out-phase). In contrast, five out of six cases treated with micronized progesterone showed an endometrium corresponding to a mid-luteal phase (in-phase) (P = 0.021 versus DG). There was a significant difference in the mean progesterone value [8.6 versus 0.3 microg l(-1) (P = 0.013)], the mean LH value [12.9 versus 22.5 IU l(-1) (P = 0.049)] and the mean FSH value [13.0 versus 23.9 IU l(-1) (P = 0.047)] between the progesterone and DG group, respectively, on day 21 of the cycle. CONCLUSIONS: After estrogen endometrial priming in POF patients, exogenous vaginal micronized progesterone is more effective than oral DG in creating an 'in-phase' secretory endometrium and induces significantly higher progesterone and lower LH and FSH serum concentrations on day 21 of the cycle.     

Case for staged thyroidectomy

Recent modifications in the management of well‐differentiated thyroid cancer have resulted in significant alterations in clinical approach. Utilizing a series of preoperative and postoperative risk factors involving both the patient and the disease pathology, we offer the term “staged thyroidectomy” to help organize these risk factors for patients and the endocrine team to optimize management. This approach is intended to incorporate our latest nuanced understanding of certain endocrine pathology and may serve to optimize patient outcomes.     

Preoperative Biliary Drainage of Severely Jaundiced Patients Increases Morbidity of Pancreaticoduodenectomy: Results of a Case-Control Study

Background

Recent studies have indicated that preoperative biliary drainage (PBD) should not be routinely performed in patients suffering from obstructive jaundice before surgery. The severity of jaundice that mandates PBD has yet to be defined. Our aim was to investigate whether PBD is truly justified in severely jaundiced patients before pancreaticoduodenectomy. The parameters evaluated were overall morbidity, length of hospital stay, and total in-hospital mortality.

Methods

From January 2000 to December 2012, a total of 240 patients underwent pancreaticoduodenectomy for periampullary tumors. Group A comprised 76 patients with preoperative serum bilirubin ≥15 mg/dl who did not undergo PBD before surgery. Group B comprised another 76 patients, matched for age and tumor localization (papillary vs. pancreatic head) who underwent PBD 2–4 weeks before pancreaticoduodenectomy and were identified from the same database.

Results

Less operative time was required in the ‘no PBD’ group compared with the ‘PBD’ group (210 vs. 240 min). Total intraoperative blood loss and blood transfusions were also significantly less in the ‘no PBD’ group. There was no difference detected in the rate of pancreatic fistula or biliary fistula formation. Group A patients demonstrated significantly lower morbidity than group B (24 vs. 36 %, respectively) and therefore required briefer hospitalization (11 vs. 16 days). Mild infectious complications appear to be the main factor that enhanced morbidity in the PBD group. However, total in-hospital mortality was not significantly different between the two groups.

Conclusions

Even severe jaundice should not be considered as an indication for PBD before pancreaticoduodenectomy, as PBD increases infections and postoperative morbidity, therefore delaying definite treatment.     

Nonclinical pharmacokinetics and metabolism of EPZ‐5676, a novel DOT1L histone methyltransferase inhibitor

(2R,3R,4S,5R)‐2‐(6‐Amino‐9H‐purin‐9‐yl)‐5‐((((1r,3S)‐3‐(2‐(5‐(tert‐butyl)‐1H‐benzo[d]imidazol‐2‐yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran‐3,4‐diol (EPZ‐5676) is a novel DOT1L histone methyltransferase inhibitor currently in clinical development for the treatment of MLL‐rearranged leukemias. This report describes the preclinical pharmacokinetics and metabolism of EPZ‐5676, an aminonucleoside analog with exquisite target potency and selectivity that has shown robust and durable tumor growth inhibition in preclinical models. The in vivo pharmacokinetics in mouse, rat and dog were characterized following i.v. and p.o. administration; EPZ‐5676 had moderate to high clearance, low oral bioavailability with a steady‐state volume of distribution 2–3 fold higher than total body water. EPZ‐5676 showed biexponential kinetics following i.v. administration, giving rise to a terminal elimination half‐life (t_1/2) of 1.1, 3.7 and 13.6 h in mouse, rat and dog, respectively. The corresponding in vitro ADME parameters were also studied and utilized for in vitro–in vivo extrapolation purposes. There was good agreement between the microsomal clearance and the in vivo clearance implicating hepatic oxidative metabolism as the predominant elimination route in preclinical species. Furthermore, low renal clearance was observed in mouse, approximating to f_u‐corrected glomerular filtration rate (GFR) and thus passive glomerular filtration. The metabolic pathways across species were studied in liver microsomes in which EPZ‐5676 was metabolized to three monohydroxylated metabolites (M1, M3 and M5), one N‐dealkylated product (M4) as well as an N‐oxide (M6). Copyright © 2014 John Wiley & Sons, Ltd.     

SGLT2 inhibitors and cardioprotection: a matter of debate and multiple hypotheses

Sodium-glucose co-transporter 2 (SGLT2) inhibitors inhibit glucose re-absorption in the proximal renal tubules. Two trials have shown significant reductions of cardiovascular (CV) events with empagliflozin and canagliflozin, which could not be attributed solely to their antidiabetic effects. The aim of the review is the critical presentation of suggested mechanisms/hypotheses for the SGLT2 inhibitors' cardioprotection. The search of the literature revealed many possible cardioprotective mechanisms, because SGLT2 inhibitors (i) increase natriuresis and act as diuretics with unique properties leading to a reduction in preload and myocardial stretch (the diuretic hypothesis); (ii) decrease blood pressure and afterload (the blood pressure lowering hypothesis), (iii) favor the production of ketones, which can act as a ‘superfuel’ in the cardiac and renal tissue (the ‘thrifty substrate’ hypothesis), (iv) improve many metabolic variables (the metabolic effects hypothesis), (v) exert many anti-inflammatory effects (the anti-inflammatory effects hypothesis), (vi) can act through the angiotensin II type II receptors in the context of simultaneous renin-angiotensin-aldosterone-system (RAAS) blockade leading to vasodilation and positive inotropic effects (the RAAS hypothesis), (vii) directly decrease the activity of the upregulated in heart failure Na⁺–H⁺ exchanger in myocardial cells leading to restoration of mitochondrial calcium handling in cardiomyocytes (the sodium hypothesis). Additionally, some SGLT2 inhibitors exhibit also SGLT1 inhibitory action possibly resulting in an attenuation of oxidative stress in ischemic myocardium (the SGLT1 inhibition hypothesis). Thus, many mechanisms have been suggested (and possibly act cumulatively) for the cardioprotective effects of SGLT2 inhibitors.     

Surgical ethics and the challenge of surgical innovation

Surgical ethics as a specific discipline is relatively new to many. Surgical ethics focuses on the ethical issues that are particularly important to the care of surgical patients. Informed consent for surgical procedures, the level of responsibility that surgeons feel for their patients' outcomes, and the management of surgical innovation are specific issues that are important in surgical ethics and are different from other areas of medicine. The future of surgical progress is dependent on surgical innovation, yet the nature of surgical innovation raises specific concerns that challenge the professionalism of surgeons. These concerns will be considered in the following pages.