Single exposure of mesothelial cells to glucose degradation products (GDPs) yields early advanced glycation end-products (AGEs) and a proinflammatory response.

BACKGROUND: Fluids commonly used for peritoneal dialysis (PD) have a low pH and a high glucose content. Furthermore, heat sterilization of dialysis fluids degrades some of the glucose into glucose degradation products (GDPs), such as methylglyoxal (MGO) and 3-deoxyglucosone (3-DG). Mesothelial cells (MCs) form the first line in the peritoneal cavity and are constantly exposed to these nonphysiological conditions. Since MCs play an important role in the regulation of inflammatory responses in the peritoneal cavity, we studied the kinetics of MC uptake of highly purified GDP species, along with their effect on various cellular biological and immunological parameters. METHODS: Methylglyoxal and 3-DG were purified and added to MC cultures. Complexing to medium components or uptake by MCs was analyzed over time by HPLC of the culture supernatant and by immunocytochemistry of MCs for MGO-modified proteins. Furthermore, MCs were exposed to a single dose of MGO or 3-DG and analyzed for apoptosis, proliferation by MTT assay, and [3H]-thymidine incorporation. Incorporation of [35S]-methionine was determined in order to analyze de novo protein synthesis. Expression of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1), CD44, and vascular cell adhesion molecule-1 (VCAM-1) was analyzed by cell-bound ELISA. Effects of MGO and 3-DG on cytokine production were also analyzed. RESULTS: Substitution of MGO and 3-DG in culture medium resulted in a spontaneous decrease in MGO over time, whereas 3-DG levels decreased minimally. The concentration of these GDPs was more reduced in the presence of MCs, indicating binding to and/or uptake by MCs of these GDPs. Mesothelial cells that had been cultured in the presence of MGO showed positive staining with a monoclonal that specifically recognizes MGO-modified proteins, demonstrating complexing to mesothelial cellular proteins. Cell-bound ELISA showed a two- to three-fold induction of expression of VCAM-1 by MGO and 3-DG; the expression of ICAM-1 and CD44 was not changed. Mesothelial cells showed a twofold increase in interleukin (IL)-6 and IL-8 production after exposure to 3-DG. Furthermore, incubation with MGO and 3-DG induced apoptosis and reduced the proliferation of cells, but did not influence protein synthesis. CONCLUSIONS: In the current report we demonstrate that MCs take up MGO and 3-DG and form early advanced glycation end-products. Upon short exposure to a single GDP, MCs react with enhanced cytotoxic damage and a proinflammatory response, evidenced by increased VCAM-1 expression and elevated production of IL-6 and IL-8.     

The Daily Practice of Pancreatic Enzyme Replacement Therapy After Pancreatic Surgery: a Northern European Survey

Introduction

After pancreatic surgery, up to 80?% of patients will develop exocrine insufficiency. For enzyme supplementation to be effective, prescribing an adequate dose of pancreatic enzymes is mandatory but challenging because the required dose varies. Data on the practice of enzyme replacement therapy after surgery are lacking, and therefore, we conducted this analysis.

Methods

An anonymous survey was distributed to members of the Dutch and German patient associations for pancreatic disorders. The target population consisted of patients with chronic pancreatitis or pancreatic cancer who had undergone pancreatic surgery and were using enzymes to treat exocrine insufficiency. Results were compared to a similar group of non-operated patients.

Results

Ninety-one cases were analyzed (84?% underwent a resection procedure). The median daily enzyme dose was 6, and 25?% took three or less capsules. Despite treatment, 68?% of patients reported steatorrhea-related symptoms, 48?% adhered to a non-indicated dietary fat restriction, and only 33?% had visited a dietician. The outcome was equally poor for the 91 non-operated patients.

Conclusion

Most patients suffering from exocrine insufficiency after pancreatic surgery are undertreated. To improve efficacy, physicians should be more focused on treating exocrine insufficiency and educate patients to adjust the dose according to symptoms and their diet.     

Chronic Dialysis Patients Are Depleted of Creatine: Review and Rationale for Intradialytic Creatine Supplementation

There is great need for the identification of new, potentially modifiable risk factors for the poor health-related quality of life (HRQoL) and of the excess risk of mortality in dialysis-dependent chronic kidney disease patients. Creatine is an essential contributor to cellular energy homeostasis, yet, on a daily basis, 1.6–1.7% of the total creatine pool is non-enzymatically degraded to creatinine and subsequently lost via urinary excretion, thereby necessitating a continuous supply of new creatine in order to remain in steady-state. Because of an insufficient ability to synthesize creatine, unopposed losses to the dialysis fluid, and insufficient intake due to dietary recommendations that are increasingly steered towards more plant-based diets, hemodialysis patients are prone to creatine deficiency, and may benefit from creatine supplementation. To avoid problems with compliance and fluid balance, and, furthermore, to prevent intradialytic losses of creatine to the dialysate, we aim to investigate the potential of intradialytic creatine supplementation in improving outcomes. Given the known physiological effects of creatine, intradialytic creatine supplementation may help to maintain creatine homeostasis among dialysis-dependent chronic kidney disease patients, and consequently improve muscle status, nutritional status, neurocognitive status, HRQoL. Additionally, we describe the rationale and design for a block-randomized, double-blind, placebo-controlled pilot study. The aim of the pilot study is to explore the creatine uptake in the circulation and tissues following different creatine supplementation dosages.     

Pregnancy following diagnosis of premature ovarian insufficiency: a systematic review

The aim of this review is to report the occurrence of pregnancies in women with premature ovarian insufficiency (POI), naturally or with different treatments (hormonal replacement therapy, IVF, in-vitro maturation and stem cell therapy). This study involved an exhaustive search of the electronic databases MEDLINE, PubMed and Embase covering the period January 2000 to January 2018. A combination of Medical Subject Heading and text words was used to generate a subset of citations, including studies involving POI (‘premature menopause’ or ‘premature ovarian failure’ or ‘POI’ or ‘hypergonadotrophic amenorrhoea’). This subset of citations was then combined with ‘AND’ to the Medical Subject Heading term ‘pregnancy’. Fifteen studies were included in this review. Two randomized controlled trials, two observational studies, and 11 interventional studies reporting cases of pregnancy in women with POI were included. This review reports pregnancy rates across studies ranging from 2.2% to 14.2%. Mean age in patients who achieved a pregnancy was 30 years, highlighting that oocyte quality in these patients is likely unaffected. No treatment has thus far shown its superiority in improving fertility in women with POI. Recent advances in options such as in-vitro maturation and stem-cell therapy, however, are likely to be the future of treatment and may generate new hope for these patients.     

Problem Behaviors and Psychological Distress Among Teens Seen in a National Sample of Emergency Departments

Background

Problem behaviors, such as substance use and peer aggression, frequently coexist and are common among youth seen in emergency departments (EDs). EDs are increasingly urged to screen for both psychological distress and problem behaviors.