The potential role of dietary advanced glycation endproducts in the development of chronic non-infectious diseases: a narrative review.

Increasing clinical and experimental evidence accumulated during the past few decades supports an important role for dietary advanced glycation endproducts (AGE) in the pathogenesis of many chronic non-infectious diseases, such as type 2 diabetes, CVD and others, that are reaching epidemic proportions in the Western world. Although AGE are compounds widely recognised as generated in excess in the body in diabetic patients, the potential importance of exogenous AGE, mostly of dietary origin, has been largely ignored in the general nutrition audience. In the present review we aim to describe dietary AGE, their mechanisms of formation and absorption into the body as well as their main mechanisms of action. We will present in detail current evidence of their potential role in the development of several chronic non-infectious clinical conditions, some general suggestions on how to restrict them in the diet and evidence regarding the potential benefits of lowering their consumption.

The link between soda intake and asthma: science points to the high-fructose corn syrup, not the preservatives: a commentary.

Recent research conducted by investigators at the National Center for Chronic Disease Prevention and Health Promotion-a division of the US Centers for Disease Control and Prevention (CDC)-found that 'Regular-Soda Intake, Independent of Weight Status, is Associated with Asthma among US High School Students.' On the basis of their review of prior studies, researchers hypothesized that the association may be due to high intake of sodium benzoate, a commonly used preservative in US soft drinks. But a closer look at these prior research studies suggests that there is no strong scientific evidence that the preservatives in US soft drinks are associated with asthma. Importantly, other recent research suggests that the association may be with the unpaired (excess free) fructose in high fructose corn syrup.

Intake of high-fructose corn syrup sweetened soft drinks, fruit drinks and apple juice is associated with prevalent arthritis in US adults, aged 20-30 years.

OBJECTIVE: There is a link between joint and gut inflammation of unknown etiology in arthritis. Existing research indicates that regular consumption of high-fructose corn syrup sweetened (HFCS) soft drinks, but not diet soft drinks, may be associated with increased risk of seropositive rheumatoid arthritis (RA) in women, independent of other dietary and lifestyle factors. One unexplored hypothesis for this association is that fructose malabsorption, due to regular consumption of excess free fructose (EFF) and HFCS, contributes to fructose reactivity in the gastrointestinal tract and intestinal in situ formation of enFruAGEs, which once absorbed, travel beyond the intestinal boundaries to other tissues and promote inflammation. In separate studies, the accumulation of advanced glycation end-products has been associated with joint inflammation in RA. Objective of this study was to assess the association between EFF beverages intake and non-age, non-wear and tear-associated arthritis in US young adults. METHODS: In this cross sectional study of 1209 adults aged 20-30y, (Nutrition and Health Examination Surveys 2003-2006) exposure variables were high EFF beverages, including HFCS sweetened soft drinks, and any combination of HFCS sweetened soft drinks, fruit drinks (FD) and apple juice, referred to as tEFF. Analyses of diet soda and diet FD were included for comparison. The outcome was self-reported arthritis. Rao Scott Ҳ(2) was used for prevalence differences and logistic regression for associations, adjusted for confounders. RESULTS: Young adults consuming any combination of high EFF beverages (tEFF) ⩾5 times/week (but not diet soda) were three times as likely to have arthritis as non/low consumers (odds ratios=3.01; p⩽0.021; 95% confidence intervals=1.20-7.59), independent of all covariates, including physical activity, other dietary factors, blood glucose and smoking. CONCLUSION: EFF beverage intake is significantly associated with arthritis in US adults aged 20-30 years, possibly due to the intestinal in situ formation of enFruAGEs.

Bioavailability of vitamin D2 from enriched mushrooms in prediabetic adults: a randomized controlled trial.

BACKGROUND/OBJECTIVES: Based on the growing evidence of risk reduction from fresh fruit and vegetable consumption and an inverse relationship between serum 25-hydroxyvitamin D (25OHD) and the risk of type 2 diabetes (T2D), we determined the benefits of regularly consuming vitamin D-enriched mushrooms in a prediabetic cohort. Exposing edible mushrooms to ultraviolet B (UVB) light increases vitamin D2 (D2) and raises serum 25OHD2 in healthy young adults; however, their benefit to deficient prediabetics and glucose metabolism remains untested. SUBJECTS/METHODS: Forty-three prediabetic, D-deficient adults (25OHD≤20 ng/ml), BMI>25 were randomized to four groups consuming daily entrées containing 100 g fresh sliced cooked mushrooms prepared by a chef for 16 weeks. Two groups were fed UVB-treated mushrooms initially containing: 600 IU D2 or 4000 IU D2; each one also received one capsule of placebo daily. Two control groups were fed untreated mushrooms and D3 dietary supplements at two label doses: 600 IU D3 and 4000 IU D3. D2 and D3 content were analyzed in mushrooms, before and after cooking and in over-the-counter supplements. RESULTS: After 16 weeks, both D2-UVB-mushroom entrée doses, which were significantly lower after cooking, produced modest or no increases in 25OHD2 or total 25OHD relative to the positive control subjects who actually consumed about 1242 and 7320 IU per day of D3 (higher than stated on the label). CONCLUSIONS: Unanticipated D2 cooking loss from fresh UVB mushrooms and probable low absorption and/or hydroxylation may explain the smaller increase in 25OHD2 in our prediabetic overweight/obese cohort compared with past findings in younger, healthy subjects. Moreover, no dose or vitamin D source was associated with modifying T2D risk factors.

Managing chronic inflammation in the aging diabetic patient with CKD by diet or sevelamer carbonate: a modern paradigm shift.

The maintenance of normal metabolism and body defenses depends on the balance between cellular antioxidant and anti-inflammatory factors. This balance can be disrupted by agents/mechanisms in the extracellular milieu that induce excess reactive oxygen species (ROS) and inflammation. Cytopathic advanced glycation endproducts, present in ever increasing amounts in the modern diet, are one of the major environmental factors that cause excess ROS and/or inflammation at all ages and induce complications in aging, such as chronic kidney disease (CKD) and type 2 diabetes. Increased ROS and/or inflammation are present in both aging and CKD, and are associated with reduced cellular defenses against ROS and/or inflammation. Affected individuals have reduced defenses against further stress and are predisposed to organ failure, now a well-known phenomenon in aging. Thus, new methods are urgently needed to safely reduce ROS and/or inflammation in the aging type 2 diabetes patient with CKD. Studies of both normal aging and diabetic patients with kidney disease underline the fact that increased ROS and/or inflammation can be managed in these conditions by economical, safe, and effective interventions that reduce the uptake of advanced glycation endproducts by either modifying preparation of food or an oral drug. This communication reviews these data and adds new information on the efficacy of a drug, sevelamer carbonate, required to reduce ROS and/or inflammation in the aging type 2 diabetes patient complicated by CKD. If larger and longer studies confirm the hypothesis that one or both of these interventions reduce progression of CKD, it could represent a new paradigm in the management of complications in the type 2 diabetes patient with CKD.

Listeriosis outbreak caused by Latin-style fresh cheese, Bizkaia, Spain, August 2012.

Two cases of laboratory-confirmed listeriosis were detected in Bizkaia, Spain, at the end of August. The epidemiological investigation indicated that these two cases were associated with the consumption of Latin-style fresh cheese made from pasteurised milk in Portugal. Different batches of the same cheese were analysed and confirmed as contaminated with Listeria monocytogenes. The product was withdrawn from the market and the population was advised not to consume this kind of cheese.

25-OH-vitamin D deficiency and cellular alloimmunity as measured by panel of reactive T cell testing in dialysis patients.

Primed antidonor alloreactive T cells are detrimental to transplant outcome, but factors that impact the strength of this immune response prior to transplantation are unknown. We tested peripheral blood mononuclear cells from dialysis patients, against panels of allogeneic, primary B-cell lines in a newly standardized IFNγ ELISPOT panel of reactive T cell (PRT) assay. Results were correlated with known alloantibody-sensitizing events and other clinical parameters. As 25-OH-vitamin D deficiency is associated with enhanced cellular immunity, is common in dialysis patients and is correctable, we assessed the relationship between serum 25-OH-vitamin D and the PRT. Using independent test and validation cohorts we found that low serum levels of 25-OH-vitamin D (<26 ng/mL) correlated with high-PRT values (in the upper 50th percentile, OR 0.02, p = 0.01) independent of age, sex, race, previous transplant, transfusion, pregnancy, time on dialysis, panel of reactive antibody, iPTH, and treatment with 1,25-OH-vitamin D. The data provide a potential mechanism for the possible relationship between vitamin D deficiency and poor posttransplant outcome, and support studies to test the impact of 25-OH-vitamin D repletion on alloimmunity and allograft injury in kidney transplant candidates.

Advanced glycation endproducts induce podocyte apoptosis by activation of the FOXO4 transcription factor.

Advanced glycation endproducts (AGEs) and a receptor for AGEs (RAGE) have been linked in the pathogenesis of diabetic nephropathy. RAGE is usually localized to podocytes and is increased in diabetes. RAGE activation increases reactive oxygen species production, which mediates hyperglycemia-induced podocyte apoptosis in early diabetic nephropathy. Here, we examined the interaction of AGE and RAGE on podocyte apoptosis. When we exposed murine cultured podocytes to bovine serum albumin (BSA) that was modified by AGEs or to carboxymethyl-lysine BSA, more apoptosis was found when compared with unmodified BSA. Similarly, more podocytes underwent detachment and apoptosis when cultured on AGE-modified collagen IV than on native collagen IV. AGEs isolated from sera of patients with chronic kidney disease also caused apoptosis of podocytes. Apoptosis was diminished by small interference RNA (siRNA) for RAGE in podocytes exposed to AGE-BSA, but not to AGE-modified collagen IV. Both AGE- and carboxymethyl-lysine modified-BSA activated p38MAP kinase and inhibition of this kinase reduced the apoptotic effect of AGE-BSA. Exposure to AGE-BSA was associated with Akt dephosphorylation and FOXO4 transcriptional activation leading to an increase in the expression of an effector protein of apoptosis, Bim. siRNA for FOXO4 abolished AGE-BSA-induced apoptosis of podocytes. Our study suggests that an AGE-RAGE interaction contributes to podocyte apoptosis by activation of the FOXO4 transcription factor.

Review article: Bowel preparation for colonoscopy--the importance of adequate hydration.

BACKGROUND: Patient compliance with screening recommendations for colorectal cancer remains low, despite a 90% survival rate achieved with early detection. Bowel preparation is a major deterrent for patients undergoing screening colonoscopy. More than half of patients taking polyethylene glycol electrolyte lavage solution and sodium phosphate preparations experience adverse events, such as nausea and abdominal pain. Many adverse events may be associated with dehydration, including rare reports of renal toxicity in patients taking sodium phosphate products. Addressing dehydration-related safety issues through patient screening and education may improve acceptance of bowel preparations, promote compliance and increase the likelihood of a successful procedure. AIM: To evidence safety issues associated with bowel preparation are generally related to inadequate hydration. RESULTS: Dehydration-related complications may be avoided through proper patient screening, for example, renal function and comorbid conditions should be considered when choosing an appropriate bowel preparation. In addition, patient education regarding the importance of maintaining adequate hydration before, during and after bowel preparation may promote compliance with fluid volume recommendations and reduce the risk of dehydration-related adverse events. CONCLUSIONS: Proper patient screening and rigorous attention by patients and healthcare providers to hydration during bowel preparation may provide a safer, more effective screening colonoscopy.

Efficacy of reteplase in poorly functioning hemodialysis catheters.

AIM: This is a retrospective study of reteplase efficacy for restoration of flow in occluded and poorly functioning hemodialysis catheters. PATIENTS AND METHODS: From May 1, 2001 to December 31, 2001, all hemodialysis patients seen at our university dialysis center with occluded or poorly functioning (< 200 ml/min blood flow) catheters treated with reteplase were included in the study. All catheters had been in place for more than 48 hours. Reteplase 0.4 U was instilled into each port; dwell time was 30 minutes. If aspiration had not been possible, reteplase had remained in the catheter for an additional 30 minutes. If flow was established (> 200 ml/min), the catheter was used for dialysis. If flow was not adequately established after 1 hour, the patient was referred for catheter exchange. RESULTS: Reteplase (0.4 U) was used in 50 instances to restore or improve blood flow rates in a total of 23 catheters in 19 patients. Reteplase was effective in establishing adequate blood flow rates during the current and next dialysis session in 44/50 (88%) cases; 6 cases required 1-hour dwell time. Six cases (in 5 patients) required catheter exchange; in these, an anatomic or pathologic complication was responsible for catheter malfunction. No adverse events were related to reteplase instillation during the study. CONCLUSION: Data suggest that reteplase is safe and effective in restoring flow to malfunctioning hemodialysis catheters. Results are comparable to those achieved with alteplase.

Hyponatremia in peritoneal dialysis patients.

BACKGROUND: Low serum sodium is uncommon in peritoneal dialysis (PD), which is surprising in view of the important role of normal kidney function to regulate water and sodium balance. METHODS: We report 2 cases of persistent hyponatremia with balance studies in Case 1. We performed measurements of dialysate sodium and volume output over 24 hours in a group of chronic PD patients. RESULTS: The low serum sodium concentration did not vary too much with overall fluid removal via dialysis in patient 1, mainly because large quantities of sodium were removed in the dialysate. In the 24-hour studies, a significant relationship was found between net daily PD sodium removal and net daily dialysate volume removed (r = 0.65). There was no relationship between net daily PD sodium removal and serum sodium concentration. There was a linear direct correlation between serum and dialysate sodium concentration (r = 0.8) as shown by others previously. CONCLUSIONS: These results suggest that the main determinant of PD sodium loss is net dialysate ultrafiltration volume. Water loss via dialysis is necessarily associated with sodium loss. In order to maintain a normal serum sodium concentration salt intake must be proportional to the water loss induced by dialysis. The stimuli that allow dialysis patients to maintain this delicate balance between water and salt intake are of considerable interest but remain undetermined.

Treatment of "swing point stenoses" in hemodialysis arteriovenous fistulae.

AIM: This is a retrospective study of percutaneous transluminal balloon angioplasty (PTA) efficacy for treatment of surgical vein mobilization site ("swing point") stenoses in hemodialysis arteriovenous fistulae (AVF) that fail to mature or are poorly functioning. METHOD: Between February 1, 1999, and February 28, 2001, 65 non-maturing or poorly functioning AVF were studied in 63 consecutive hemodialysis patients (30 male, 33 female, aged 26-92 years). All AVF underwent contrast angiography to study the inflow artery, AVF, outflow and central veins. PTA of stenotic sites was performed to initiate or restore AVF function. RESULTS: Seventy-eight venous and 2 arterial stenoses were found and treated with PTA in the 65 AVF. All PTA were technically successful. A total of 55 stenoses were identified in the vein at the site of surgical mobilization ("swing point"). Additionally, 19 cephalic and 4 central venous stenoses were found. During the study, 13 AVF underwent repeat PTA at the "swing point". Of the 65 AVF treated, 50 were being successfully used as an access site, 4 AVF were lost during follow-up (34-688 days; mean: 258 days) and 8 patients died within the study period. The duration of functional patency of the treated AVF was 39-660 days (mean: 280 days). CONCLUSION: Non-maturing or poorly functioning AVF frequently have stenoses in the outflow vein at the original site of surgical vein mobilization. These "swing point stenoses" are amenable to PTA, which is a safe and effective treatment for prolonging AVF patency and function.

Obese and non-obese hemodialysis patients have a similar prevalence of functioning arteriovenous fistula using pre-operative vein mapping.

AIMS: The arteriovenous fistula (AVF) is the preferred hemodialysis access. Subset analyses of both the HEMO and DOPPS studies have shown that obese hemodialysis patients have a lower prevalence of functioning AVF. Doppler ultrasound may increase the prevalence of functioning AVF in obese subjects. PATIENTS AND METHODS: The effect of pre-operative vein mapping employed between 10/01/98 and 12/08/00 on the prevalence of functioning AVF in a single university hemodialysis program was studied. Preoperative ultrasound was performed to study venous and arterial systems on both arms. RESULTS: There were 50 obese patients, defined as bodymass index (BMI) > or = 27 kg/m2, and 130 patients with a lower BMI. The groups were similar in mean age and diabetes prevalence. The obese group had statistically significantly more females 34/50 versus 61/130 with p = 0.01. There was no statistically significant difference between the vein mapping parameters studied in the two BMI groups, including mean mid-forearm cephalic vein diameter, distal radial artery peak systolic velocity and subclavian vein patency. No obese patient required venography. There was no significant difference between the number of functioning AVF in both groups (22/50 obese, 48/130 lower BMI, p = 0.24). CONCLUSIONS: Pre-operative vein mapping is associated with a similar prevalence of functioning AVF in obese and lower BMI patients. Pre-operative ultrasound screening is a useful tool to promote AVF placement in obese patients.

Vascular screening prior to placement of tunnelled and cuffed hemodialysis catheters.

PURPOSE: To demonstrate the importance of venous vascular screening before the placement of tunneled and cuffed hemodialysis catheters in patients requiring hemodialysis prior to placement and/or maturation of an arteriovenous fistula (AVF) or graft (AVG). METHODS: Between October 1998 and March 2000, all patients requiring hemodialysis access placement were prospectively evaluated with duplex ultrasound for status of upper extremity vessels and central veins prior to selection of a permanent access site. When interim tunneled and cuffed hemodialysis catheters were required, they were placed on the side contralateral to proposed AVF/AVG placement. No catheters were placed without initial vascular screening. The study group was compared to historical controls during a similar period (April 1997 through September 1998) when no vascular screening was performed. RESULTS: During the study period, 234 screening duplex ultrasound examinations were performed in 244 patients. Ten patients required no screening prior to access site placement. Overall, 353 catheters were placed, 243 (69%) on the right side and 110 (31%) on the left side. During the control period, 394 catheters were placed in 255 patients, 306 (78%) right-sided and 88 (22%) left-sided. The increase in left-sided catheters with ultrasound screening and careful planning for future access sites was significant (p<0.01). CONCLUSION: Vascular-screening-directed catheter placement significantly alters the side of catheter placement when compared to a management protocol without prior screening. Such screening helps identify the side of permanent access placement, while directing interim catheters to the contralateral side such that central veins may be preserved for permanent access.

Reteplase in the treatment of thrombosed hemodialysis grafts.

PURPOSE: To prospectively evaluate the efficacy and safety of reteplase with percutaneous transluminal angioplasty (PTA) in the treatment of thrombosed polytetrafluoroethylene hemodialysis arteriovenous grafts (AVGs). MATERIALS AND METHODS: Forty-two patients were entered into the study. Sixty-two procedures in 43 grafts were performed. One unit of reteplase and 4,000 units of heparin were administered into the AVGs. Routine venography and percutaneous transluminal angioplasty (PTA) was then performed. Patients were transferred for hemodialysis immediately after the procedure. RESULTS: Technical success was achieved in 92% of the cases. Four cases involved intentional repeat thrombosis because of poor outflow and/or need for a new graft site. Minor complications occurred in 6.5% of the cases. No major complications occurred. The mean procedure time for experienced versus less-experienced interventionalists was significantly shorter (P <.001). Primary patency rates were 50%, 34%, and 34% at 30, 90, and 180 days, respectively. CONCLUSION: Reteplase in conjunction with heparin and PTA is a safe and effective means of thrombolysis of AVGs. Its efficacy is comparable to that of other available thrombolytic drugs.

Gender modulates responsiveness to recombinant erythropoietin.

Several investigators reported that individuals with diabetes and women on hemodialysis treated with recombinant erythropoietin (EPO) attained lower hematocrits than individuals without diabetes and men. It is unclear whether these observed differences in achieved hematocrits are caused by inherent biological differences in responsiveness to EPO or undetected differences in modifiable factors that affect response to EPO. Also potentially modulating response to EPO is diurnal variation in the bioavailability of serum iron. To address these issues, we studied 309 patients undergoing hemodialysis in two large facilities in New York City. Retrospective data collected monthly for 3 months included patients' hematocrit, dose of EPO, urea reduction ratio (URR), total amount of intravenous iron administered, serum albumin concentration, transferrin saturation, and time of day patient underwent dialysis. The 309 study subjects (165 women, 144 men) included 207 blacks (67%), 74 Hispanics (24%), 23 whites (7%), and 5 Asians (2%) with a mean age of 55.4 +/- 15.6 (SD) years. Despite a greater mean URR (74% +/- 6.4% versus 71% +/- 6%; P = 0.001) and a 39% greater dose of EPO (97 +/- 65 versus 59 +/- 53 U/kg; P = 0.001), women (36% +/- 3.5%) had hematocrits equivalent with men (36.5% +/- 3.7%; P = not significant [NS]). There was no difference in the amount of intravenous iron administered to men (375 +/- 389 mg) and women (377 +/- 413 mg; P = NS). Diabetes mellitus (P = 0.48) did not significantly affect the odds of attaining a hematocrit greater than 33% after adjustment for URR, EPO dose, and amount of intravenous iron administered. The time of day a patient underwent dialysis (P = 0.93) had no effect on their response to EPO. We conclude that gender, but not diabetes status or time of dialysis, modulates response to EPO in hemodialysis patients.

Hemodialysis access placement with preoperative noninvasive vascular mapping: comparison between patients with and without diabetes.

We retrospectively analyzed data on preoperative vascular mapping in 195 consecutive patients to investigate the common belief that patients with diabetes are poor candidates to have an arteriovenous fistula placed as dialysis access because they lack suitable blood vessels. There was no difference in venous diameter, arterial diameter, and arterial peak systolic velocity measurements between patients with and without diabetes. Patients with diabetes had a greater prevalence of vascular calcifications and greater cuff measurements of systolic segmental arterial pressure. In 140 of 195 patients, subsequent vascular access surgery had been performed in our institution, and 127 of these patients were on hemodialysis therapy at the end of the study period. There was no difference in the prevalence of fistula placement (66% versus 60%; chi-square = 2.6; df = 2; P = 0.28, not significant [NS]) and percentage of functioning fistulae between patients with and without diabetes (67% versus 62%; chi-square = 0.27; df = 1; P = 0.61, NS). The percentage of patients dialyzed through a temporary catheter was equal in patients with and without diabetes (18%). In summary, patients with diabetes seem to be as good candidates for arteriovenous fistula placement as patients without diabetes. Additional studies are required to determine the long-term outcome of fistulae in patients with diabetes.