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Tissue advanced glycation end products (AGEs) are a measure of cumulative metabolic and oxidative stress and cytokine-driven inflammatory reactions. AGEs are thought to contribute to the cardiovascular complications of hemodialysis (HD) patients. Skin autofluorescence (SAF) is related to the tissue accumulation of AGEs and rises with age. SAF is one of the strongest prognostic markers of mortality in these patients. The content of AGEs is high in barbecue food. Due to the location in northern Sweden, there is a short intense barbecue season between June and August. The aim of this study was to investigate if seasonal variations in SAF exist in HD patients, especially during the barbecue season. SAF was measured noninvasively with an AGE Reader in 34 HD-patients (15 of those with diabetes mellitus, DM). Each time the median of three measures were used. Skin-AF was measured before and after each one HD at the end of February and May in 31 patients (22 men/9 women); the end of May and August in 28 (20 m/8 w); the end of August and March in 25 (19 m/6 w). Paired statistical analyses were performed during all four periods (n = 23, 17 m/6 w); as was HbA1c of those with DM. There was at a median 5.6% increase in skin-AF during the winter period (February-May, P = 0.004) and a 10.6% decrease in the skin-AF during the summer (May-August, P

Objective: HIV-1 infection is associated with an increased cardiovascular disease (CVD) risk. Advanced glycation end products are formed as stable markers of glycaemic and oxidative stress. Skin autofluorescence (SAF) as marker of accumulated advanced glycation end products is increased and predictive of CVD events in diabetes mellitus, chronic kidney disease (CKD), and preexisting CVD. We determined SAF levels in HIV-1 infected patients, testing the hypothesis that SAF predicts CVD events in HIV infection.Design: Single-centre prospective cohort study.Methods: In 2010-2011, SAF was measured in 91 patients. Development of CVD events was monitored during a median follow-up of 4.8 years. SAF values of the patients were expressed as a ratio (rSAF) to expected SAF levels in age-matched healthy volunteers.Results: Seventy-nine men and 12 women were included, mean age 47 years; 81 patients were on combination antiretroviral therapy. With a mean rSAF of 1.155, SAF levels in patients were 15.5% higher than predicted for their age (95% confidence interval, 10.0-20.0; PConclusion: SAF is increased in HIV-infected patients, and related with smoking, low nadir CD4(+) cell count, and MSM. Larger studies are needed to confirm whether SAF is an independent predictor of CVD events. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

Aims/hypothesis Earlier studies have shown that skin autofluorescence measured with an AGE reader estimates the accumulation of AGEs in the skin, which increases with ageing and is associated with the metabolic syndrome and type 2 diabetes. In the present study, we examined whether the measurement of skin autofluorescence can predict 4 year risk of incident type 2 diabetes, cardiovascular disease (CVD) and mortality in the general population. Methods For this prospective analysis, we included 72,880 participants of the Dutch Lifelines Cohort Study, who underwent baseline investigations between 2007 and 2013, had validated baseline skin autofluorescence values available and were not known to have diabetes or CVD. Individuals were diagnosed with incident type 2 diabetes by self-report or by a fasting blood glucose ≥7.0 mmol/l or HbA1c ≥48 mmol/mol (≥6.5%) at follow-up. Participants were diagnosed as having incident CVD (myocardial infarction, coronary interventions, cerebrovascular accident, transient ischaemic attack, intermittent claudication or vascular surgery) by self-report. Mortality was ascertained using the Municipal Personal Records Database. Results After a median follow-up of 4 years (range 0.5–10 years), 1056 participants (1.4%) had developed type 2 diabetes, 1258 individuals (1.7%) were diagnosed with CVD, while 928 (1.3%) had died. Baseline skin autofluorescence was elevated in participants with incident type 2 diabetes and/or CVD and in those who had died (all p

BACKGROUND: Skin autofluorescence (SAF) is a non-invasive marker of advanced glycation end products (AGEs). In diabetes, higher SAF levels has been positively associated with long-term complications, cardiovascular morbidity and mortality. Because little is known about the factors that influence SAF in non-diabetic individuals, we assessed the association of clinical and lifestyle parameters with SAF as well as their interactions in a large-scale, non-diabetic population and performed the same analyses in a type 2 diabetic subgroup.METHODS: In a cross-sectional study in participants from the LifeLines Cohort Study, extensive clinical and biochemical phenotyping, including SAF measurement, was assessed in 9009 subjects of whom 314 (3.5%) subjects with type 2 diabetes.RESULTS: Mean SAF was 2.04 ± 0.44 arbitrary units (AU) in non-diabetic individuals and 2.44 ± 0.55 AU in type 2 diabetic subjects (pCONCLUSIONS: In addition to the established literature on type 2 diabetes, we have demonstrated that SAF levels are associated with several clinical and lifestyle factors in the non-diabetic population. These parameters should be taken into consideration when using SAF as a screening or prediction tool for populations at risk for cardiovascular disease and diabetes. This article is protected by copyright. All rights reserved.

Background As life expectancy is increasing and healthy ageing becomes more and more important, skin ageing is a growing topic of interest from both a medical and a commercial point of view. The urgency to unravel the causes of skin ageing is rising. However, there is a lack of objective, simple, noninvasive methods to assess biological skin age - a term introduced to describe how old someone looks, covering both the appearance and function of the skin. A rapid, noninvasive assessment of biological skin age would greatly facilitate the execution of the studies required to find the causes of skin ageing.Objectives To find an objective, easy-to-apply method to assess biological skin age.Methods Skin age score (SAS) was compared with skin autofluorescence, a measure of advanced glycation end products in the skin, and several subject characteristics in 32 healthy, white women with little sun-exposed skin and no history of smoking.Results A moderate, positive correlation (R-2 = 0.32, P = 0.001) between SAS and skin autofluorescence-based biological skin age was found. However, the variation in biological skin age according to SAS could be explained better by body mass index, chronological age and hormonal status (R-2 = 0.86, P Conclusions In the current setting skin autofluorescence did not contribute better to the prediction of biological skin age than chronological age. Biological skin age was best predicted by body mass index, chronological age and hormonal status, and this approach provides a considerable simplification of the application of biological skin age.

Skin autofluorescence (AF) has been associated with complications of diabetes. We evaluated the influence of skin color and ethnicity on the association between skin AF and the presence of diabetes-related complications. In a multiethnic type 2 diabetes cohort we investigated all patients with available skin AF measurements. The associations between skin AF and hemoglobin A1c (HbA1c) and the presence of complications of diabetes were estimated, stratified for ethnicity and quartiles of ultraviolet reflectance percentage (R%). In total, 810 patients (438 native Dutch, 372 non-Dutch) were included. Because of too low an R%, 32% of black Africans and 19% of Hindustanis were excluded. Non-Dutch patients had lower AF values compared with Dutch patients (median AF=2.69 [interquartile range (IQR), 2.26-3.09] vs. 3.06 [IQR, 2.65-3.50] arbitrary units; P

Background: The metabolic syndrome (MetS) comprises several cardiometabolic risk factors associated with increased risk for both type 2 diabetes and cardiovascular disease. Skin autofluorescence (SAF), a non-invasive bio-marker of advanced glycation end products accumulation, is associated with cardiovascular complications in subjects with diabetes. The aim of the present study was to examine the association between SAF and the presence of MetS as well as its individual components in a general population.Methods: For this cross-sectional analysis, we included 78,671 non-diabetic subjects between 18 and 80 years of age who participated in the LifeLines Cohort Study and had SAF measurement obtained non-invasively using the AGE Reader. MetS was defined according to the revised NCEP ATP III criteria. Students unpaired t test was used to test differences between groups. Both logistic and linear regression analyses were performed in order to test associations between the individual MetS components and SAF.Results: Subjects with MetS had higher SAF (2.07 +/- 0.45 arbitrary units, AU) compared to individuals without MetS (1.89 +/- 0.42 AU) (p Conclusion: Skin autofluorescence was associated with the presence of MetS and some of its individual components. In addition, increasing SAF Z-scores were observed with a higher number of MetS components. Prospective studies are needed to establish whether SAF can be used as an (additional) screening tool to predict both cardiovascular disease and type 2 diabetes in high-risk populations.

Skin autofluorescence (AF) is related to the accumulation of advanced glycation end products (AGEs) and is one of the strongest prognostic markers of mortality in hemodialysis (HD) patients. The ai ...

Advanced glycation end-products (AGEs) are uremic toxins that accumulate progressively in hemodialysis (HD) patients. The aim of this study was to assess the 1-year increase in skin autofluorescence (ΔAF), a measure of AGEs accumulation and plasma markers, as predictors of mortality in HD patients. One hundred sixty-nine HD patients were enrolled in this study. Skin autofluorescence was measured twice, 1 year apart using an AGE Reader (DiagnOptics Technologies BV, Groningen, The Netherlands). Besides routine blood chemistry, additional plasma markers including superoxide dismutase, myeloperoxydase, intercellular adhesion molecule 1 (ICAM-1), C-reactive protein (hs-CRP), heart-type fatty acid binding protein (H-FABP), and von Willebrand factor were measured at baseline. The mortality of HD patients was followed for 36 months. Skin autofluorescence values of the HD patients at the two time points were significantly higher (P

Haemodialysis (HD) patients suffer from an increased risk of cardiovascular disease (CVD). Skin autofluorescence (SAF) is a strong marker for CVD. SAF indirectly measures tissue advanced glycation end products (AGE) being cumulative metabolites of oxidative stress and cytokine-driven inflammatory reactions. The dialysates often contain glucose. Autofluorescence of skin and plasma (PAF) were measured in patients on HD during standard treatment (ST) with a glucose-containing dialysate (n = 24). After that the patients were switched to a glucose-free dialysate (GFD) for a 2-week period. New measurements were performed on PAF and SAF after 1 week (M1) and 2 weeks (M2) using GFD. Nonparametric paired statistical analyses were performed between each two periods. SAF after HD increased non-significantly by 1.2% while when a GFD was used during HD at M1, a decrease of SAF by 5.2% (p = 0.002) was found. One week later (M2) the reduction of 1.6% after the HD was not significant (p = 0.33). PAF was significantly reduced during all HD sessions. Free and protein-bound PAF decreased similarly whether glucose containing or GFD was used. The HD resulted in a reduction of the total PAF of approximately 15%, the free compound of 20% and the protein bound of 10%. The protein bound part of PAF corresponded to approximately 56% of the total reduction. The protein bound concentrations after each HD showed the lowest value after 2 weeks using glucose-free dialysate (p

ObjectiveHigh density lipoprotein (HDL) particles protect apolipoprotein B-containing lipoproteins from oxidative modification. An impaired anti-oxidative functionality of HDL in type 2 diabetes mellitus (T2DM) may contribute to enhanced formation of oxidative stress products, such as Advanced Glycation Endproducts (AGEs). We tested whether in T2DM the HDL anti-oxidative capacity is related to the accumulation of AGEs in the skin.MethodsSkin autofluorescence (AF), a non-invasive read-out for AGEs, and HDL anti-oxidative capacity, i.e. the ability of HDL to protect against LDL oxidation in vitro, were assessed in 67 non-smoking T2DM patients without complications (median age: 60 (53–65), 60% males, 6.5 (5.2–8.5) years of diabetes duration).ResultsIn univariate analysis, skin AF correlated inversely with HDL anti-oxidative capacity (r=−0.305, P

Aim Advanced glycation end products play an important role in the pathophysiology of several chronic and age-related diseases, especially diabetes mellitus. Skin autofluorescence is a non-invasive method for assessing levels of tissue advanced glycation end products. This study aims to establish the normal reference value of advanced glycation end products accumulated in tissue measured by the advanced glycation end product reader-skin autofluorescence-and discusses some factors influencing it. Methods The values of autofluorescence in healthy individuals in China were determined by the advanced glycation end product reader; age, gender, skin reflectance, smoking habits and alcohol consumption of the subjects were also recorded. Results Themean reference values of autofluorescence in healthy Chinese subjects are (95% confidence interval) 20-29 years: 1.54-1.62 arbitrary units; 30-39 years: 1.66-1.75; 40-49 years: 1.78-1.89; 50-59 years: 1.87-2.03; 60-69 years: 1.86-2.09; 70-79 years: 1.97-2.31. The value of autofluorescence is strongly related to age, but no significant difference between males and females were found (all P > 0.05). Autofluorescence was higher in smokers than in non-smokers (P

Condensation. In women with a history of preeclampsia skin autofluorescence as marker of tissue AGEs accumulation is increased, supporting a common causal metabolic or vascular link between preeclampsia and cardiovascular diseases. Objective. To investigate whether skin autofluorescence (AF), as marker of tissue accumulation of advanced glycation end-products (AGEs), is elevated in women with a 4-year history of severe preeclampsia. Methods. About 17 formerly preeclamptic women and 16 controls were included. Skin AF and several traditional cardiovascular risk factors were recorded. Results. In comparison to controls, formerly preeclamptic women had higher skin AF of the legs, body mass index (BMI), blood pressure, and high-sensitivity C-reactive protein (hsCRP), HbA1C, and triglycerides in serum. Conclusion. Skin AF as well as cardiovascular risk factors is elevated in formerly preeclamptic women. These results suggest a common causal vascular link between preeclampsia and cardiovascular diseases.

Objective. To investigate whether advanced glycation endproducts (AGEs) in the skin are increased in patients with systemic sclerosis (SSc) and are related to the presence of disease-related and traditional cardiovascular risk factors.Methods. Skin autofluorescence, as a measure for the accumulation of AGEs, was assessed by measuring UV-A light excitation-emission matrices (AF-EEMS) in 41 SSc patients and 41 age- and sex-matched controls. Traditional cardiovascular risk factors and disease-related risk factors were recorded.Results. Skin AF-EEMS did not differ between SSc patients and controls (1.68±0.58 a.u. versus1.63±0.41 a.u.,P=0.684). Skin AF-EEMS in SSc patients was associated with levels of CRP (r=0.44,P=0.004), Medsger's severity scale (r=0.45,P=0.006), and use of agents intervening in the renin-angiotensin system (r=0.33,P=0.027). When analysing SSc patients and controls together, in multivariate analysis, only age and use of agents intervening in the renin-angiotensin system were independently associated with AF-EEMS.Conclusion. These data demonstrate that skin AGEs are not increased in SSc patients.

BACKGROUND: In transfusion medicine, frozen red blood cells (RBCs) are an alternative for liquid-stored RBCs. Little is known about the rheologic properties (i.e., aggregability and deformability) of thawed RBCs. In this study the rheologic properties of high-glycerol frozen RBCs and postthaw stored in saline-adenine-glucose-mannitol medium were compared to those of conventionally liquid-stored and fresh RBCs STUDY DESIGN AND METHODS: Fresh RBCs were obtained from healthy volunteers. Leukoreduced liquid-stored and thawed deglycerolized RBC units were obtained from the Sanquin Blood Bank. RBCs were tested for aggregability (aggregation index [AI]), deformability (elongation index [El]), and various hematologic variables. RESULTS: The AI of thawed RBCs was reduced, compared to fresh and liquid-stored RBCs (p

Background: Accumulation of advanced glycation end products (AGEs) is accelerated during glycemic and oxidative stress and is an important predictor of complications in diabetes mellitus (DM).Study Design: Here we both review and present original data on the relationship between skin autofluorescence (SAF), a noninvasive measure of AGEs, and short-and intermediate-term glycemic variations.Results: Acute changes in glucose levels during an oral glucose tolerance test in 56 persons with varying degrees of glucose tolerance did not influence SAF. AGE-rich meals result in a transient postprandial rise in SAF of 10% 2-4 h later. This could not be attributed to meal-induced glycemic changes and is probably caused by the AGE content of the meal. In type 1DM major intermediate-term improvements of glycemic control as depicted by multiple hemoglobin A1c (HbA1c) measurements were associated with lower skin AGE levels. In a well-controlled, stable type 2DM cohort, only a weak correlation was found between SAF and HbA1c. In both studies skin AGE/SAF levels predicted complications of diabetes with an accuracy superior to that of HbA1c. SAF has also been proposed as a new tool in diagnosing impaired glucose tolerance (IGT) and DM. It proved to be more sensitive than either fasting glucose or HbA1c.Conclusions: SAF is not influenced by short-term glycemic variations. AGE-rich meals may, however, cause a transient rise postprandially. There is a weak correlation between SAF or skin AGEs and current or time-integrated HbA1c levels. SAF has strong added value in risk prediction of complications of diabetes and is a promising tool for early detection of diabetes and IGT.

P>Background Skin autofluorescence (skin AF) is determined in part by accumulation of advanced glycation end products. Increased skin AF was shown previously to predict cardiovascular events independently of conventional risk factors. We determined the association of carotid artery intima media thickness (IMT), a marker of subclinical cardiovascular disease, with skin AF in subjects without diabetes or clinically manifest cardiovascular disease. Methods In a cross-sectional observational study, IMT, skin AF, lipids and apolipoproteins, C-reactive protein (CRP), insulin resistance and paraoxonase-1 activity were measured in 59 non-smoking, non-obese subjects without diabetes mellitus and cardiovascular disease (32 women; 12 subjects with metabolic syndrome (MetS)). Results In univariate analyses, skin AF was correlated with IMT (r = 0 center dot 265, P = 0 center dot 042), but not significantly with clinical factors, (apo)lipoproteins, CRP, insulin resistance and paraoxonase-1. In multiple linear regression analyses, IMT was determined independently by age (beta = 0 center dot 549, P

Skin autofluorescence (AF) as measured with the AGE Reader (DiagnOptics Technologies, Groningen, The Netherlands) is a noninvasive prognostic marker in diabetes mellitus and other diseases with increased cardiovascular risk. This study provides reference values of healthy Caucasian control subjects as a function of age, tobacco smoking, and gender.The results of skin AF measured in 428 healthy Caucasian control subjects by the AGE Reader (n = 211) and its nonautomated but otherwise similar predecessor, the Autofluorescence Reader (n = 217), were analyzed. Linear regression analysis was performed to obtain reference values for skin AF as a function of age. Further analysis was performed on the effect of tobacco smoking (n = 96) and gender.Skin AF was described by a linear increase with age of approximately 0.023 arbitrary units (AU) per year for subject age up to 70 years. Tobacco smoking was associated with an absolute increase of skin AF by 0.16 AU (P0.01), without a significant further increase with age (P = 0.17). Gender had no influence on skin AF in nonsmokers. Among current smokers, female subjects had a 0.2 AU higher skin AF than male subjects (P = 0.02), with no further age-related increase.The present results provide reference values of skin AF for healthy Caucasian control subjects over a broad age range. A major contribution of age and some interaction of smoking and gender were observed, resulting in reference values of skin AF suitable for clinical settings and future studies.

BACKGROUND:Red blood cell (RBC) units stored for more than 2 weeks at 4 degrees C are currently considered of impaired quality. This opinion has primarily been based on altered RBC rheologic properties (i.e., enhanced aggregability, reduced deformability, and elevated endothelial cell interaction), during prolonged storage of nonleukoreduced RBC units. In this study, the rheologic properties and cell variables of leukoreduced RBC units, during routine blood bank storage in saline-adenine-glucose-mannitol, were investigated.STUDY DESIGN AND METHODS:Ten leukoreduced RBC units were stored at the blood bank for 7 weeks at 4 degrees C. RBCs were tested weekly for aggregability, deformability, and other relevant variables.RESULTS:RBC aggregability was significantly reduced after the first week of storage but recovered during the following weeks. After 7 weeks aggregability was slightly, but significantly, reduced (46.9 +/- 2.4-44.3 +/- 2.2 aggregation index). During storage the osmotic fragility was not significantly enhanced (0.47 +/- 0.01% phosphate-buffered saline) and the deformability at shear stress of 3.9 Pa was not significantly reduced (0.36 +/- 0.01 elongation index [EI]). The deformability at 50 Pa was reduced (0.58 +/- 0.01-0.54 +/- 0.01 EI) but remained within reference values (0.53 +/- 0.04). During 5 weeks of storage, adenosine triphosphate was reduced by 54% whereas mean cell volume, pH, and mean cell hemoglobin concentration were minimally affected.CONCLUSIONS:RBC biochemical and physical alterations during storage minimally affected the RBC ability to aggregate and deform, even after prolonged storage. The rheologic properties of leukoreduced RBC units were well preserved during 7 weeks of routine blood bank storage.

The UK Prospective Diabetes Study (UKPDS) risk engine has become a standard for cardiovascular risk assessment in type 2 diabetes mellitus. Skin autofluorescence was recently introduced as an alternative tool for cardiovascular risk assessment in diabetes. We investigated the prognostic value of skin autofluorescence for cardiovascular events in combination with the UKPDS risk engine in a cohort of patients with type 2 diabetes managed in primary care.Clinical, UKPDS risk engine and skin autofluorescence data were obtained at baseline in 2001-2002 in the type 2 diabetes group (n = 973). Follow-up data concerning fatal and non-fatal cardiovascular events (primary endpoint) were obtained till 2005. Patients were classified as 'low risk' when their 10 year UKPDS risk score for fatal cardiovascular events was 10%. Skin autofluorescence was measured non-invasively with an autofluorescence reader. Skin autofluorescence was classified by the median (i.e. low risk median).The incidence of cardiovascular events was 119 (44 fatal, 75 non-fatal). In multivariate analysis, skin autofluorescence, age, sex and diabetes duration were predictors for the primary endpoint. Addition of skin autofluorescence information to that from the UKPDS risk engine resulted in re-classification of 55 of 203 patients from the low-risk to the high-risk group. The 10 year cardiovascular event rate was higher in patients with a UKPDS score > 10% when skin autofluorescence was above the median (55.8% vs 38.9%).Skin autofluorescence provides additional information to the UKPDS risk engine which can result in risk re-classification of a substantial number of patients. It furthermore identifies patients who have a particularly high risk for developing cardiovascular events.

Background. ST-elevation myocardial infarction Back, (STEMI) is associated with increased inflammation and oxidative stress, enhancing the formation of advanced glycation endproducts (AGEs). Thew , encompass characteristic fluorescence: pattern, which can be non-invasively measured as skin autofluorescence (AF). In this study we investigate whether skin AF is elevated in STEMI, its association with inflammatory and glycaemic stress,and its predictive value for future events.Methods. Skin AF was measured in 88 STEMI patients (mean age 64 +/- 13 years) within 72 hours and around six months after discharge, in 81 stable coronary artery disease (sCAD) patients (64 +/- 10 years), and in 32 healthy controls (63 +/- 11 years). The cumulative one-year incidence Of all-cause mortality and hospitalisation for myocardial infarction Or heart failure was documented.Results. Skin AF was significantly higher in STEMI compared with sCAD and controls, irrespective of: confounders, and was associated with HbA1c and C-reactive protein. Skin AF decreased significantly in STEMI patients, when measured >200 days after discharge. In STEMI patients, skin AF above g the median was predictive of future events (hazard ratio 11.6, 95% CI 1.5 to 90.8, p=0.019). Conclusion . Skin AF is elevated in STEMI, is associated with inflammation and glycaemic stress, and predicts future major adverse cardiac events. (Neth Heart J 2009;17:162-8.)

Skin autofluorescence (AF) is becoming an accepted clinical method for assessing the risk of chronic complications in diabetes mellitus (DM). In this study, the role of the excitation wavelength in the recognition of increased risk of diabetes-related chronic complications was investigated. An Excitation Emission Matrix Scanner (EEMS) was used to perform non-invasive measurements in four age-matched groups of patients with type 1 and type 2 DM, with and without chronic complications, as well as in a control group (N=97 in total). AF was calculated for excitation wavelengths in the range 355 - 405 nm. Mean spectra were assessed per group. AF values in both type 1 and type 2 DM patients with complications were increased compared to the control subjects (p

Objectives. To examine whether skin advanced glycation endproducts (AGEs) accumulation, plasma levels of AGEs-N-epsilon-carboxymethyllysine (CML) and N-epsilon-carboxyethyllysine (CEL)-and serum levels of soluble receptor for AGEs (sRAGE) are elevated in SLE patients compared with controls, and whether these parameters are related to disease activity and endothelial cell (EC) activation.Methods. Ten SLE patients (9 women, age 34 +/- 13 yrs, mean +/- S.D.) and 10 age- and sex-matched controls were included. Patients were analysed during inactive as well as active disease. Skin AGE accumulation was estimated using ultraviolet-A (UV-A) light for measurement of autofluorescence obtained by ExcitationEmission matrix Scanner (AF-EEMS). Levels of CML and CEL were determined by tandem mass spectrometry. Levels of sRAGE and of soluble vascular cell adhesion molecule-1 (sVCAM-1) were determined by ELISAs.Results. Skin AF-EEMS was increased in SLE patients compared with controls (P Conclusions. Skin AGEs and levels of sRAGE and sVCAM-1 were elevated in SLE patients, whereas levels of CML and CEL were comparable with controls. As sRAGE even further increased during endothelial activation, it might be hypothesized that sRAGE acts as a decoy receptor. Why this proposed mechanism is insufficient to prevent increased AGE accumulation in the skin of SLE patients has to be established.

OBJECTIVE—Skin autofluorescence is a noninvasive measure of the level of tissue accumulation of advanced glycation end products, representing cumulative glycemic and oxidative stress. Recent studies have already shown a relationship between skin autofluorescence and diabetes complications, as well as the predictive value of skin autofluorescence for total and cardiovascular mortality in type 2 diabetes. Our aim was to investigate the predictive value of skin autofluorescence for the development of microvascular complications in type 2 diabetes. RESEARCH DESIGN AND METHODS—At baseline, skin autofluorescence of 973 type 2 diabetic patients with well-controlled diabetes was noninvasively measured with an autofluorescence reader. The aggregate clinical outcome was defined as the development of any diabetes-associated microvascular complication of 881 surviving patients, which was assessed at baseline and at the end of follow-up. Single end points were the development of diabetes-associated retinopathy, neuropathy, and (micro)albuminuria. RESULTS—After a mean follow-up period of 3.1 years, baseline skin autofluorescence was significantly higher in patients who developed any microvascular complication, neuropathy, or (micro)albuminuria but not in those who developed retinopathy. Multivariate analyses showed skin autofluorescence as a predictor for development of any microvascular complication along with A1C, for development of neuropathy along with smoking, and for development of (micro)albuminuria together with sex, A1C, and diabetes duration. Skin autofluorescence did not have predictive value for the development of retinopathy, albeit diabetes duration did. CONCLUSIONS—Our study is the first observation of skin autofluorescence measurement as an independent predictor of development of microvascular complications in type 2 diabetes.

Introducton: Despite their unfavourable cardiovascular risk profile, patients with glycogen storage disease type Ia (GSD Ia) do not develop premature atherosclerosis. We hypothesized that this paradox might be related to a decreased formation of advanced glycation end products (AGEs) resulting from lifetime low plasma glucose levels and decreased oxidative stress. Methods: In 8 GSD Ia patients (age 20-34 years) and 30 matched controls we measured carotid intima-media thickness (IMT), skin autofluorescence (AF; a non-invasive index for AGEs), and specific AGEs (pentosidine, N-(carboxymethyl)lysine (CML), N-(carboxyethyl)lysine (CEL)) and collagen linked fluorescence (CLF, measured at excitation/emission wavelength combinations of 328/378 and 370/440 nm) in skin samples. Results: Carotid IMT was significantly lower in GSD Ia patients. Skin AF did not differ between patients and controls. The skin samples showed higher CEL levels in the patient group (p=0.008), but similar levels of pentosidine, CML, and CLF. In the total group, skin AF correlated with CML (r=0.39, p=0.031), CLF 328/378 nm (r=0.53; p=0.002) and CLF 370/440 nm (r=0.60; p=0.001). In the control group, AF also correlated with the maximum carotid IMT (r=0.6; p=0.004). Conclusion: Although our data confirm that GSD Ia patients present with a reduced burden of atherosclerosis, this phenomenon cannot be explained by differences in AGE accumulation as measured in the skin.

BackgroundTissue advanced glycation end products (AGE) are increased in hemodialysis (HD) patients, especially those with cardiovascular complications. Skin autofluorescence (skin-AF) can noninvasively estimate the accumulation of AGE in tissue. The aim was to clarify whether HD using a high-flux (HF) dialyzer favors plasma- or skin-AF removal compared to low-flux (LF) dialysis.Material and methods28 patients were treated with either an HF-HD or LF-HD but otherwise unchanged conditions in a cross-over design. A glucose containing dialysate was used. Skin-AF was measured noninvasively with an AGE reader before and after HD. Fluorescence (370 nm/465 nm) of plasma (p-AF) was determined as total and nonprotein-bound fractions. Correction for hemoconcentrations were made using the change in serum albumin. Paired and nonpaired statistical analyses were used.ResultsSkin-AF was unchanged after LF- and HF-dialysis. Total, free, and protein- bound p-AF was reduced after a single LF-HD by 21%, 28%, and 17%, respectively ( PConclusionsIn the dialysis settings used there was no significant change in skin AF after dialysis, with LF or with HF dialysis. Although only limited reduction in plasma fluorescence was observed, this was more pronounced when performing LF dialysis. These data are not in overwhelming support of the use of HF dialysis in the setting used in this study.

A series of flat ended stainless steel wires was constructed and experimentally evaluated as point targets giving a calibrated backscattering over a large range (up to 72 dB) for ultrasound frequencies in the range 2 to 10 MHz. Over a range of 36 dB, theory was strictly followed (within 1 dB), giving proportionality with the square of the frequency and the fourth power of the diameter. In this range, the relative scattering strength of targets does not depend on the frequency content of the ultrasound pulse. A deviation of maximal 5 dB at the low side is tentatively ascribed to a failure of simple theory for target diameters smaller than half a wavelength. For large diameters, backscattering is sensitive to orientation of the target: a numerical relation between misalignment and desired accuracy is proposed. A replication test for targets with a diameter of 0.24 mm gave equal scattering strengths within 0.8 dB. It is proposed to apply the targets for calibration of the dynamic range of a scanner and as point targets to establish resolution in three perpendicular directions, axial, lateral and elevational. (E-mail: jaaltje@ncrvnet.nl) (c) 2006 World Federation for Ultrasound in Medicine & Biology.

Tissue advanced glycation end products (AGE) are a measure of cumulative metabolic stress and trigger cytokines driven inflammatory reactions. AGE are thought to contribute to the chronic complications of diabetes and ESRD. Tissue autofluorescence is related to the accumulation of AGE. Therefore, skin autofluorescence (AF) may provide prognostic information on mortality in hemodialysis (HD) patients. Skin AF was measured noninvasively with an AF reader at baseline in 109 HD patients. Overall and cardiovascular mortality was monitored prospectively during a period of 3 yr. The AF reader was validated against AGE contents in skin biopsies from 29 dialysis patients. Forty-two of the 109 (38.5%) HD patients died. Cox regression analysis showed that AF was an independent predictor of overall and cardiovascular mortality (for overall mortality odds ratio [OR] 3.9), as were pre-existing cardiovascular disease (CVD; OR 3.1), C-reactive protein (OR 1.1), and serum albumin (OR 0.3). Multivariate analysis revealed that 65% of the variance in AF could be attributed to the independent effects of age, dialysis and renal failure duration, presence of diabetes, triglycerides levels, and C-reactive protein. AF was also independently linked to the presence of CVD at baseline (OR 8.8; P

Shortcomings of diffusion theory when applied to turbid media such as biological tissue makes the development of more accurate equations desirable. Several authors developed telegrapher's equations in the well known P-1 approximation. The method used in this paper is different: it is based on the asymptotic evaluation of the solutions of the equation of radiative transport with respect to place and time for all values of the albedo. Various coefficients for the telegrapher's equations were derived, restricted to the case of isotropic scattering, and their properties are discussed. A correct diffusion coefficient for the stationary case could be obtained. However, solution did not lead to the correct phase velocity. Correct phase velocities in combination with a correct diffusion coefficient were found for a dispersion relation that corresponds with anisotropic Henyey-Greenstein scattering with g = 0.22. It provides a time-dependent description of the fluence rate with validity for all values of the albedo. (c) 2005 Elsevier B.V. All rights reserved.

Aims/hypothesis: The accumulation of AGE is related to the progression of the renal, retinal and vascular complications of diabetes. However, the relationship with diabetic neuropathy remains unclear. We recently showed that skin autofluorescence, measured non-invasively with an AutoFluorescence Reader ( AFR), could be used to assess skin AGE accumulation. We evaluated the relationship between skin autofluorescence and the severity of diabetic neuropathy. Materials and methods: Skin autofluorescence in arbitrary units (AU) was assessed in 24 diabetic patients with a history of neuropathic foot ulceration (NP+), 23 diabetic patients without clinical neuropathy (NP-) and 21 control subjects, using the AFR. Arterial occlusive disease was excluded in all. The severity of foot ulceration was assessed by the Wagner score. Peripheral nerve function was assessed by neurography, measuring motor and sensory nerve conduction velocity and amplitude of the median, peroneal and sural nerves. Heart rate variability (HRV) and baroreflex sensitivity BRS) were measured by Finapres to assess autonomic nervous function. Results: Autofluorescence was increased in NP- compared with control subjects. In NP+ patients, autofluorescence was further increased and correlated with the Wagner score. Autofluorescence correlated negatively with nerve conduction velocity and amplitude, HRV and BRS in both NP+ and NP- groups. Autofluorescence correlated with age, diabetes duration, mean HbA(1)c of the previous year, serum creatinine level, presence of microalbuminuria and severity of diabetic retinopathy. Conclusions/interpretation: Skin autofluorescence correlates with the severity of peripheral and autonomic nerve abnormalities in diabetes, even before being clinically manifest. The AFR may be a convenient and rapid clinical tool for assessing risk of progression of long- term diabetic complications.

Aims/hypothesis. The accumulation of AGE is thought to play a role in the pathogenesis of chronic complications of diabetes mellitus and renal failure. All current measurements of AGE accumulation require invasive sampling. We exploited the fact that several AGE exhibit autofluorescence to develop a non-invasive tool for measuring skin AGE accumulation, the Autofluorescence Reader (AFR). We validated its use by comparing the values obtained using the AFR with the AGE content measured in extracts from skin biopsies of diabetic and control subjects.Methods. Using the AFR with an excitation light source of 300-420 nm, fluorescence of the skin was measured at the arm and lower leg in 46 patients with diabetes (Type 1 and 2) and in 46 age- and sex-matched control subjects, the majority of whom were Caucasian. Autofluorescence was defined as the average fluorescence per nm over the entire emission spectrum (420-600 nm) as ratio of the average fluorescence per nm over the 300-420-nm range. Skin biopsies were obtained from the same site of the arm, and analysed for collagen-linked fluorescence (CLF) and specific AGE: pentosidine, N-epsilon-(carboxymethyl)lysine (CML) and N-epsilon-(carboxyethyl)lysine (CEL).Results. Autofluorescence correlated with CLF, pentosidine, CML, and CEL (r=0.47-0.62, pless than or equal to0.002). In 32 of 46 diabetic patients (70%), autofluorescence values were above the 95% CI of the mean value in control subjects, and correlated with age, diabetes duration, mean HbA(1)c of the previous year and creatinine levels.Conclusions/interpretation. The AFR offers a simple alternative to invasive measurement of AGE accumulation and, to date, has been validated in non-pigmented skin. The AFR may prove to be a useful clinical tool for rapid risk assessment of AGE-related long-term complications in diabetes mellitus and in other conditions associated with AGE accumulation.

Not much is known about red cell aggregation during cardio-pulmonary bypass surgery (CPB). Blood samples from 19 patients undergoing CPB were anticoagulated with EDTA. Hematocrit was adjusted to 40%. A red blood cell aggregometer (LORCA) measured changes in light reflection from each blood sample after cessation of the rotation, and calculated an aggregation index (AI). Reflection measurements were stored. Because LORCA software failed for 87 of 171 samples, we developed new software, and applied it to the stored reflection measurements. This software failed only in 7 out of 171 cases and showed that all LORCA failures occurred for AI < 40%. The new calculations revealed that the aggregation index significantly decreased from 46.6 ± 10.1 (mean ± standard deviation) baseline to 22.8 ± 8.3 at the end of CPB and recovered to 37.1 ± 13.5 at day 1. It is concluded that the new software can be used to study decreased red cell aggregation during CPB.

Laser Doppler perfusion monitoring (LDPM) is a noninvasive technique for monitoring skin microcirculation. The aim of this article was to investigate the influence of fiber separation on clinical LDPM measurements. A dual-channel LDPM system was used in combination with a probe that consists of two sets of detection fibers, at 0.2 and 1.0 mm from the illuminating fiber. Measurements were performed at the big toe of 8 healthy subjects and 11 subjects who had vascular disorders. In most cases, fluxes detected at both fiber distances showed very similar fluctuations. For each fiber separation, flux values of healthy subjects and patients were not significantly different. Furthermore, skin temperature ( range: 22-34 degreesC) influenced the toe's pulp microcirculation markedly, increasing similarly at both probe separations, with a higher flux at a separation of 1.0 mm than at 0.2 mm. The flux ratio signal, obtained by dividing the flux at 0.2 mm by the flux at 1.0 mm, was significantly different between the two groups (p

To investigate the feasibility of instrument-independent perfusion units for laser Doppler flowmetry, a comparison was performed of two commercial fiberoptic laser Doppler perfusion monitors measuring the same flux situation for two different types of probes. In vivo measurements were performed on the cortex of pig's kidney, with an ultrasonic arterial flow meter as reference. The flow was mainly varied by internal arterial constriction using a balloon catheter. For each probe, instruments are compared in terms of the ratio of laser Doppler flux and arterial flow. For a given probe, the flux-to-flow ratios of the two instruments show a linear mutual relationship for a wide variety of arterial flows and laser Doppler fluxes. In vitro measurements were performed on an aqueous suspension of polystyrene microspheres. For the probe with interfiber distance 500 mum the ratio of the in vivo fluxes appears to agree within 16% to the value found in vitro, while for the 250-mum probe a difference of 28% was found. For a wide range of fluxes, the in vivo flux values of one instrument can be translated into flux values for the other instrument, in spite of the instrumental differences. This enables the user to render experimental results independent of the specific instrument, thus facilitating multi-center studies. (C) 2003 Elsevier Science (USA). All rights reserved.

Adhesion and activation of platelets are important steps in the thrombosis of blood after contact with a biomaterial surface and are governed, in part, by the wettability of the surface. Since most implanted devices are in contact with blood under flow conditions, it is important to study the effect of wettability of device surfaces on the behavior of platelets also under flow. To this end, wettability gradient polyethylene surfaces were prepared through glow discharge with partial shielding over a length of 5 cm, with advancing water contact angles varying from 95 to 45 degrees and a contact angle hysteresis of 30 degrees. The role of blood flow on the adhesion of platelets was examined by incubating these gradient surfaces in anticoagulated, whole human blood under static conditions or in blood under a flow of 10 or 40 ml/min through a 3 mm diameter circuit or for 5 or 15 min with either the hydrophobic or hydrophilic end upstream. Generally, more platelets adhered on the hydrophilic end of the wettability gradient than on the hydrophobic end, although the increment along the wettability gradient was dependent on both the flow conditions and direction. More platelets adhered under a flow of 10 ml/min than under static conditions, due to higher mass transport. Especially when the hydrophilic end was upstream, there was a more pronounced adhesion. This can be explained in terms of immediate platelet activation by shear stress imposed at the upstream end. During flow of 40 ml/min, platelet adhesion on an upstream hydrophilic end was less than on a downstream hydrophilic end. We conclude that platelets detach from the hydrophilic end at high shear stress due to the spherical form of adhered platelets. Platelets on the hydrophobic end could withstand detachment by strong, flat shaped platelet-material contact.

BACKGROUND: Skin autofluorescence, a biomarker for advanced glycation end products (AGEs) accumulation, has been shown to predict diabetes-related cardiovascular complications and is associated with several environmental and lifestyle factors. In the present study, we examined the association between various smoking behaviors and skin autofluorescence, as well as the association between several cotinine biomarkers and skin autofluorescence, using both epidemiological and metabolomics data.METHODS: In a cross-sectional study, we evaluated participants from the LifeLines Cohort Study and the Qatar Metabolomics Study on Diabetes (QMDiab). In the LifeLines Cohort Study smoking behavior and secondhand smoking were assessed in 8,905 individuals including 309 individuals (3.5%) with type 2 diabetes. In QMDiab, cotinine biomarkers were measured in saliva, plasma and urine in 364 individuals of whom 188 (51%) had type 2 diabetes. Skin autofluorescence was measured non-invasively in all participants using the AGE Reader.RESULTS: Skin autofluorescence levels increased with a higher number of hours being exposed to secondhand smoking. Skin autofluorescence levels of former smokers approached levels of never smokers after around 15 years of smoking cessation. Urinary cotinine N-oxide, a biomarker of nicotine exposure, was found to be positively associated with skin autofluorescence in the QMDiab study (p = 0.03).CONCLUSIONS: In the present study, we have demonstrated that secondhand smoking is associated with higher skin autofluorescence levels whereas smoking cessation has a beneficial effect on skin autofluorescence. Finally, urinary cotinine N-oxide might be used as an alternative way for questionnaires to examine the effect of (environmental) tobacco smoking on skin autofluorescence.

Aims/hypothesis Skin fluorescence (SF) is a non-invasive marker of AGEs and is associated with the long-term complications of diabetes. SF increases with age and is also greater among individuals with diabetes. A familial correlation of SF suggests that genetics may play a role. We therefore performed parallel genome-wide association studies of SF in two cohorts. Methods Cohort 1 included 1,082 participants, 35–67 years of age with type 1 diabetes. Cohort 2 included 8,721 participants without diabetes, aged 18–90 years. Results rs1495741 was significantly associated with SF in Cohort 1 (p

Chronic kidney disease (CKD), especially in its end stage, is marked by extremely high cardiovascular rates of morbidity and mortality; hemodialysis patients have a five-fold shorter life expectancy than healthy subjects of the same age. In CKD the metabolic products that accumulate in the body are so-called uremic toxins. These include advanced glycation end-products (AGE). AGE levels are markedly increased in CKD patients not only because of impaired excretion but also because of increased production. AGE formation has initially been described as a non-enzymatic reaction between proteins and glucose in the so-called Maillard reaction, but they are also more rapidly formed during oxidative stress and subsequent formation of reactive carbonyl compounds like (methyl) glyoxal. AGE accumulate in tissue where they cross-link with proteins, e. g., collagen, inducing tissue stiffening of blood vessels and skin. They may also interact with receptor of AGE (RAGE) and other receptors, which lead to activation of intracellular transduction mechanisms resulting in cytokine release and further tissue damage in CKD. The accumulation of AGE in the skin can be measured non-invasively using autofluorescence. The skin autofluorescence is a strong marker of cardiovascular mortality in CKD. The focus of this review is on the role of tissue and plasma AGE, and of skin autofluorescence as a proxy of tissue AGE accumulation, in the increase in cardiovascular disease in end stage renal disease (ESRD). This review will also present the possibility of reducing the AGE accumulation in ESRD patients using the following five methods: 1) use of low AGE peritoneal dialysis solutions; 2) use of advanced hemodialysis techniques; 3) use of AGE reducing drugs; 4) optimizing the nutrition of hemodialysis patients; and 5) renal transplantation.

Based on the analysis of an isotropic point source in an infinite, isotropically scattering turbid medium, we suggest several modifications to the well-known diffusion theory. Compared with standard diffusion theory these modifications, which require very little extra mathematics, lead to a substantially better approximation of the exact expressions. The improved expression gives reasons to reconsider the basic concept of time-resolved diffusion theory.

Skin autofluorescence (AF) is related to the accumulation of advanced glycation end products (AGEs) and is one of the strongest prognostic markers of mortality in hemodialysis (HD) patients. The aim of this pilot study was to investigate whether changes in skin AF appear after a single HD session and if they might be related to changes in plasma AF. Skin and plasma AF were measured before and after HD in 35 patients on maintenance HD therapy (nine women and 26 men, median age 68 years, range 33-83). Median dialysis time was 4 h (range 3-5.5). Skin AF was measured noninvasively with an AGE Reader, and plasma AF was measured before and after HD at 460 nm after excitation at 370 nm. The HD patients had on average a 65% higher skin AF value than age-matched healthy persons (P 0.001). Plasma AF was reduced by 14% (P 0.001), whereas skin AF was not changed after a single HD treatment. No significant influence of the reduced plasma AF on skin AF levels was found. This suggests that the measurement of skin AF can be performed during the whole dialysis period and is not directly influenced by the changes in plasma AF during HD.

Advanced glycation end-products (AGEs) are uremic toxins that accumulate progressively in hemodialysis (HD) patients. The aim of this study was to assess the 1-year increase in skin autofluorescence (ΔAF), a measure of AGEs accumulation and plasma markers, as predictors of mortality in HD patients. One hundred sixty-nine HD patients were enrolled in this study. Skin autofluorescence was measured twice, 1 year apart using an AGE Reader (DiagnOptics Technologies BV, Groningen, The Netherlands). Besides routine blood chemistry, additional plasma markers including superoxide dismutase, myeloperoxydase, intercellular adhesion molecule 1 (ICAM-1), C-reactive protein (hs-CRP), heart-type fatty acid binding protein (H-FABP), and von Willebrand factor were measured at baseline. The mortality of HD patients was followed for 36 months. Skin autofluorescence values of the HD patients at the two time points were significantly higher (P 0.001) than those of healthy subjects of the same age. Mean 1-year ΔAF of HD patients was 0.16 ± 0.06, which was around seven- to ninefold higher than 1-year ΔAF in healthy subjects. Multivariate Cox regression showed that age, hypertension, 1-year ΔAF, hs-CRP, ICAM-1, and H-FABP were independent predictors of overall mortality. Hypertension, 1-year ΔAF, hs-CRP, and H-FABP were also independent predictors of cardiovascular mortality. One-year ΔAF and plasma H-FABP, used separately and in combination, are strong predictors of overall and cardiovascular mortality in HD patients.

The similarity studied in this paper links the diffusion exponent to the reduced albedo. If F is the ratio of the diffusion exponent assumed by standard diffusion theory to the actual value of the diffusion exponent, it is shown that for forward-scattering functions, as often found in biological tissues, the values of F approach limiting curves. These curves depend on a constant in the homologous scattering patterns, which can describe Henyey-Greenstein scattering patterns, but which can also approximate Rayleigh-Gans phase functions. Finally, a practical approach for estimating the solution for mixtures of these forward-scattering phase functions with isotropic scatterers has been given.