Skin autofluorescence in people with type 1 diabetes and people without diabetes: An eight-decade cross-sectional study with evidence of accelerated aging and associations with complications.

AIM: To measure skin autofluorescence in youth (<18 y.o.) and adults (≥18 y.o.) and to assess its relationship with type 1 diabetes, chronic complications and smoking. METHODS: In a cross-sectional study (n = 383) skin autofluorescence was measured in 269 people with type 1 diabetes (67 with vascular complications) and 114 people without diabetes, covering eight decades of age. Associations of skin autofluorescence with demographics and traditional risk factors were assessed. RESULTS: Skin autofluorescence increased with age in people with diabetes: for those with complications it increased by a mean ± se of 0.029 ± 0.003 arbitrary units per year (r = 0.76) and, for those without complications, it increased by 0.028 ± 0.002 arbitrary units (r = 0.77). These increases were higher than for people without diabetes, whose skin autofluorescence increased by 0.022 ± 0.002 arbitrary units (r = 0.78) per year (p = 0.004). Mean ±se age-adjusted skin autofluorescence was higher in people with diabetes complications vs people without diabetes complications (1.85 ± 0.04 vs 1.66 ± 0.02 arbitrary units) and people without diabetes (1.48 ± 0.03 arbitrary units; all P < 0.0001). Age-adjusted skin autofluorescence was higher in current smokers and recent ex-smokers vs non-smokers and longer-term ex-smokers (1.86 ± 0.06 vs 1.63 ± 0.02 arbitrary units; P = 0.0005). Skin autofluorescence area under the receiver-operating characteristic curve was 0.89 (95% CI 0.85-0.94) for retinopathy and 0.56 (95% CI 0.47-0.65) for nephropathy. CONCLUSIONS: Skin autofluorescence increases with age, but faster in people with diabetes, particularly in those with complications and in smokers, consistent with accelerated aging. Skin autofluorescence may facilitate complication screening and prediction. Longitudinal studies are merited.

Closed-Loop Intravenous Drug Administration Using Photoplethysmography.

An optically-based injection control system has been developed for preclinical use for an intravenous drug delivery application. Current clinical drug delivery for oncology typically provides for intravenous administration without an awareness of achieved plasma concentration, yet interpatient variability produces consequences ranging from toxicity to ineffectual treatments. We report a closed-loop injection system integrating a pulse-photoplethysmograph to measure the concentration of an injected agent in the circulating blood system using a previously described technique. A proportional-derivative (PD) controller manages the injection rate in real-time. The target function for the controller is the population estimate of the pharmacokinetic model developed using Bayesian statistics describing the injection phase of a calibration set of 22 injections in mice. The controlled set of eight injections showed a reduction in variance from the target injection phase concentration profile of 74.8%.

Asymmetric changes in circulating insulin levels after an increase compared with a reduction in insulin pump basal rate in people with Type 1 diabetes.

AIMS: To investigate circulating insulin profiles after a clinically relevant insulin pump basal rate increase vs a reduction, and the associated glucose responses. METHODS: A cohort of 12 adults with Type 1 diabetes undertook this two-stage university hospital study using Accu-Chek pumps (Roche Diagnostics, Mannheim, Germany) and insulin aspart. An insulin basal rate change of 0.2 unit/h (increase in first stage, reduction in second stage) was implemented at ~09:30 h, after a single overnight basal rate (without bolus insulin), while fasting participants rested. Frequent venous samples for the assessment of plasma free insulin, glucose and cortisol were collected from 60 min before until 300 min after rate change. The primary outcome was time to steady-state insulin. RESULTS: The 0.2-unit/h rate change represented a mean ± sd alteration of 23 ± 6%. After the rate increase, the median (interquartile range) times to 80% and 90% steady-state insulin were 170 (45) min and 197 (87) min, respectively. By contrast, after rate reduction, 80% steady-state insulin was not achieved. After the rate increase, mean ± se insulin levels increased by 4.3 ± 3.1%, 12.0 ± 2.9% and 25.6 ± 2.6% at 60, 120 and 300 min, respectively (with no significant difference until 180 min). After the rate reduction, insulin decreased by 8.3 ± 3.0% at 300 min (with no significant difference until 300 min). After rate reduction, glucose levels paradoxically declined by 17.4 ± 3.7% after 300 min; cortisol levels also fell during observation (P = 0.0003). CONCLUSIONS: The time to circulating insulin change after a 0.2-unit/h basal rate change was substantial, and was greater after a reduction than after an increase. Counter-regulatory hormone circadian variation may affect glycaemia when implementing minor changes at low basal rates. Both direction of basal rate change, and time of day, warrant consideration when anticipating the clinical effects of basal rate changes.

Impact of insulin initiation on glycaemic variability and glucose profiles in a primary healthcare Type 2 diabetes cohort: analysis of continuous glucose monitoring data from the INITIATION study.

AIM: To use continuous glucose monitoring to examine the effects of insulin initiation with glargine, with or without glulisine, on glycaemic variability and glycaemia in a cohort of people with Type 2 diabetes receiving maximum oral hypoglycaemic agents in primary healthcare. METHODS: We conducted a post hoc analysis of continuous glucose monitoring data from 89 participants at baseline and at 24 weeks after insulin commencement. Indicators of glycaemic variability (standard deviation, J-index and mean amplitude of glycaemic excursion) and glycaemia (HbA1c , mean glucose, area under the glucose-time curve) were assessed. Multi-level regression analysis was used to identify the predictors of change. RESULTS: Complete glycaemic variability data were available for 78 participants. Of these participants, 41% were women, their mean (sd) age was 59.2 (10.4) years, the median (interquartile range) diabetes duration was 10.4 (6.5, 13.3) years and the median (interquartile range) baseline HbA1c was 82.5 (71.6, 96.7) mmol/mol [9.7 (8.7, 11.0)%]. At baseline, BMI correlated negatively with standard deviation (r = -0.30) and mean amplitude of glycaemic excursion (r = -0.26), but not with J-index; HbA1c correlated with J-index (r = 0.61) but not with mean amplitude of glycaemic excursion and standard deviation. After insulin initiation the mean (sd) glucose level decreased [from 12.0 (3.0) to 8.5 (1.6) mmol/l; P < 0.001], as did the median (interquartile range) J-index [from 66.9 (47.7, 95.1) to 36.9 (27.6, 49.8) mmol/l; P < 0.001]. Baseline HbA1c correlated with a greater J-index reduction (r = -0.45; P < 0.001). The mean amplitude of glycaemic excursion and standard deviation values were unchanged. The baseline temporal profile, showing elevated postprandial morning glucose levels, was unchanged after insulin initiation, despite an overall reduction in glycaemia. CONCLUSION: Insulin initiation reduced hyperglycaemia but did not alter glycaemic variability in adults with Type 2 diabetes receiving maximum oral hypoglycaemic agents. The most significant postprandial excursions were seen in the morning, which identifies prebreakfast as the most effective target for short-acting insulin therapy.

Enemies and turncoats: bovine tuberculosis exposes pathogenic potential of Rift Valley fever virus in a common host, African buffalo (Syncerus caffer).

The ubiquity and importance of parasite co-infections in populations of free-living animals is beginning to be recognized, but few studies have demonstrated differential fitness effects of single infection versus co-infection in free-living populations. We investigated interactions between the emerging bacterial disease bovine tuberculosis (BTB) and the previously existing viral disease Rift Valley fever (RVF) in a competent reservoir host, African buffalo, combining data from a natural outbreak of RVF in captive buffalo at a buffalo breeding facility in 2008 with data collected from a neighbouring free-living herd of African buffalo in Kruger National Park. RVF infection was twice as likely in individual BTB+ buffalo as in BTB- buffalo, which, according to a mathematical model, may increase RVF outbreak size at the population level. In addition, co-infection was associated with a far higher rate of fetal abortion than other infection states. Immune interactions between BTB and RVF may underlie both of these interactions, since animals with BTB had decreased innate immunity and increased pro-inflammatory immune responses. This study is one of the first to demonstrate how the consequences of emerging infections extend beyond direct effects on host health, potentially altering the dynamics and fitness effects of infectious diseases that had previously existed in the ecosystem on free-ranging wildlife populations.

Healthcare professional requirements for the care of adult diabetes patients managed with insulin pumps in Australia.

BACKGROUND: Healthcare professional (HCP) time supporting insulin pump therapy (IPT) has not been documented, yet it is important in planning and allocating resources for effective care. AIM: This study aims to determine HCP time spent in IPT patient care to inform resource planning for optimal IPT delivery. METHODS: Twenty-four Australian adult IPT-experienced institutions (14 government funded, seven private, three both) collected data between April 2012 and January 2013 prospectively, including: patient demographics, HCP classification, purpose of HCP-patient interaction, interaction mode and HCP time with the patient. A subset of patients was tracked from pre-pump education until stable on IPT. RESULTS: Data on 2577 HCP-adult patient interactions (62% face-to-face, 29% remote, 9% administrative) were collected over 12.2 ± 6.4 weeks for 895 patients; age 35.4 ± 14.2 years; 67% female; 99% type 1 diabetes, representing 25% of all IPT patients of the institutions. Time (hours) spent on IPT interactions per centre per week were: nurses 5.4 ± 2.8, dietitians 0.4 ± 0.2 and doctors 1.0 ± 0.5. IPT starts accounted for 48% of IPT interaction time. The percentage of available diabetes clinic time spent on outpatient IPT interactions was 20.4%, 4.6% and 2.7% for nurses, dietitians and doctors respectively. Fifteen patients tracked from pre-pump to stabilisation over 11.8 ± 4.5 weeks, required a median (range) of 9.2 (3.0-20.9), 2.4 (0.5-6.0) and 1.8 (0.5-5.4) hours per patient from nurses, dietitians and doctors respectively. CONCLUSIONS: IPT patient care represents a substantial investment in HCP time, particularly for nurses. Funding models for IPT care need urgent review to ensure this now mainstream therapy integrates well into healthcare resources.

Feasibility of Energy Dispersive X-Ray Fluorescence Determination of Gold in Soft Tissue for Clinical Applications.

The feasibility of using EDXRF for a rapid quantitative analysis of gold in tumor tissue has been investigated. The protocol described here demonstrates that sample biopsies can be analyzed in as little as 8 hours, with minimal sample preparation. Samples were prepared by drying a 35 µL aliquot of tissue dissolved in KOH in a standard EDXRF cup on a Prolene® support, producing a thin sample. Calibration curves of XRF peak intensity (CPS/mA) to the gold concentration (0-50 PPM) were prepared for liver, tumor, and a mix of tissue types. A linear regression demonstrated an R2 correlation of 0.93. Analysis of experimental samples showed that gold accumulation in tumors (5.8-41.3 PPM) was in agreement with previous studies, where samples were processed using INAA or ICP-MS. This report provides guidance for elemental analysis of gold in tissue in a shorter time span, showing potential for its use in a clinical setting.

Simulation of transport and extravasation of nanoparticles in tumors which exhibit enhanced permeability and retention effect.

Determining the factors that influence the delivery of sub-micron particles to tumors and understanding the relative importance of each of these factors is fundamental to the optimization of the particle delivery process. In this paper, a model that combines random walk with the pressure driven movement of nanoparticles in a tumor vasculature is presented. Nanoparticle movement in a cylindrical tube with dimensions similar to the tumor's blood capillary with a single pore is simulated. Nanoparticle velocities are calculated as a pressure driven flow over imposed to Brownian motion. The number and percentage of nanoparticles leaving the blood vessel through a single pore is obtained as a function of pore size, nanoparticle size and concentration, interstitial pressure, and blood pressure. The model presented here is able to determine the importance of these controllable parameters and thus it can be used to understand the process and predict the best conditions for nanoparticle-based treatment. The results indicate that the nanoparticle delivery gradually increases with pore size and decreases with nanoparticle size for tumors with high interstitial fluid pressure (in this work we found this behavior for head and neck carcinoma and for metastatic melanoma with interstitial pressures of 18mmHg and 19mmHg, respectively). For tumors with lower interstitial fluid pressure (rectal carcinoma with 15.3mmHg) however, delivery is observed to have little sensitivity to particle size for almost the entire nanoparticle size range. Though an increase in nanoparticle concentration increases the number of nanoparticles being delivered, the efficiency of the delivery (percentage of nanoparticles delivered) is found to remain closely unaffected.

Non-invasive measures of tissue autofluorescence are increased in Type 1 diabetes complications and correlate with a non-invasive measure of vascular dysfunction.

OBJECTIVE: To determine if ocular and skin autofluorescence, reflecting advanced glycation end-products, and vascular stiffness correlate in non-diabetic and Type 1 diabetic subjects and if levels differ by diabetes status. RESEARCH DESIGN AND METHODS: Patients with Type 1 diabetes (n = 69, 19 with and 50 without vascular complications) and 60 subjects without diabetes (control) had ocular and skin autofluorescence and pulse-wave analysis performed in the fasted state. Correlations between measures within groups used the Pearson or Spearman correlation-coefficient and measures between groups were compared by ANOVA. RESULTS: Lens and skin autofluorescence correlated in control (r = 0.58, P = 0.0001) and in Type 1 diabetes (r = 0.53, P = 0.001). Corneal autofluorescence correlated with lens (r = 0.53, r = 0.52, P = 0.0001) and skin autofluorescence (r = 0.34, P = 0.01 and r = 0.49, P = 0.00001) in control and Type 1 diabetes respectively. In Type 1 diabetes, small and large artery elasticity correlated inversely and systemic vascular resistance correlated positively with skin autofluorescence (all P = 0.001), and with lens and corneal autofluorescence (all P < 0.03). In Type 1 diabetes tissue advanced glycation end-products correlated with C-reactive protein and inversely with the estimated glucose disposal rate and with circulating advanced glycation end-product levels. Relative to non-diabetic subjects, lens, corneal and skin fluorescence were increased (all P < 0.001) and small artery elasticity was decreased in diabetes (P = 0.04). Lens, corneal and skin autofluorescence were greater (all P = 0.0001) in patients with Type 1 diabetes with complications compared to those without complications, but small artery elasticity did not differ significantly. CONCLUSIONS: Ocular and skin autofluorescence and vascular stiffness correlate in non-diabetic and Type 1 diabetes subjects and are increased in Type 1 diabetes. Tissue advanced glycation end-products correlate with vascular risk factors, including circulating advanced glycation end-products.

Three-wavelength murine photoplethysmography for estimation of vascular gold nanorod concentration.

Nanoparticle-assisted photo-thermal (NAPT) ablation has become a new and attractive modality for the treatment of cancerous tumors. This therapy exploits the passive accumulation of intravenously delivered optically resonant metal nanoparticles into tumors, however, the circulating bioavailability of these particles is often unknown. We present a non-invasive optical device capable of monitoring the circulation of optically resonant gold nanorods. The device, referred to as a pulse photometer, uses the technique of multi-wavelength photoplethysmography. We simultaneously report the circulation of gold nanorods and oximetry for six hours post-injection in mice with no anesthesia and remove the probe when not collecting data. The instrument shows good agreement (R(2) = 0.903, n = 30) with ex vivo spectrophotometric analysis of blood samples. The real-time feedback provided has a strong potential for reducing variability and thus improving the efficacy of similar clinical therapies.

Murine photoplethysmography for in vivo estimation of vascular gold nanoshell concentration.

There is an urgent clinical need to monitor the intravenous delivery and bioavailability of circulating nanoparticles used in cancer therapy. This work presents the use of photoplethysmography for the noninvasive real-time estimation of vascular gold nanoshell concentration in a murine subject. We develop a pulse photometer capable of accurately measuring the photoplethysmogram in mice and determining the ratio of pulsatile changes in optical extinction between 805 and 940 nm, commonly referred to as R. These wavelengths are selected to correspond to the extinction properties of gold nanoshells. Six 30-s measurements (5 min, 2, 4, 6, 8, 10 h) are taken under light anesthesia to observe the change in R as the nanoparticles clear from the circulation. Our model describes the linear fit (R(2)=0.85) between R and the concentration of nanoparticles measured via ex vivo spectrophotometric and instrumental neutron activation analysis. This demonstrates the utility of this technique in support of clinical nanoparticle therapies.

Feasibility of using a two-wavelength photometer to estimate the concentration of circulating near-infrared extinguishing nanoparticles.

We demonstrate a photometer based on pulse oximeter technology designed to test the feasibility of using non-invasive optics to quantify in vivo circulation parameters of optically-active particles by measuring changes in optical extinction introduced by the particles in a murine animal model. A real-time estimate of relative concentration was produced by collecting log-scaled bandpass pulsatile and non-pulsatile intensity (760 nm or 940 nm) near the extinction peak of the employed gold nanoshells and mathematically subtracting the pre-injection intensity through the murine subject. The circulation half-lives in four mice were estimated between 3 and 43 minutes compared to direct optical measurement of 5 microL blood draws with UV/Vis spectrophotometry which demonstrated nanoparticle extinctions ranging from 0.246 to 7.408 optical density (OD). A linear model fit relating the two methods produced an R2 value of 0.75. The 1.795 OD negative bias (-4.98 x 10(9) nanoparticles/ml) between the two methods describes the 35.5% (or 12.0 minutes) average error of prediction of the half-life. This report demonstrates that the circulation parameters of optically-active particles employed at therapeutically-relevant concentrations can be monitored in real-time using non-invasive optical techniques and advises further refinement.

Layer-by-Layer-Coated Gelatin Nanoparticles as a Vehicle for Delivery of Natural Polyphenols.

Natural polyphenols with previously demonstrated anticancer potential, epigallocatechin gallate (EGCG), tannic acid, curcumin, and theaflavin, were encased into gelatin-based 200 nm nanoparticles consisting of a soft gel-like interior with or without a surrounding LbL shell of polyelectrolytes (polystyrene sulfonate/polyallylamine hydrochloride, polyglutamic acid/poly-l-lysine, dextran sulfate/protamine sulfate, carboxymethyl cellulose/gelatin, type A) assembled using the layer-by-layer technique. The characteristics of polyphenol loading and factors affecting their release from the nanocapsules were investigated. Nanoparticle-encapsulated EGCG retained its biological activity and blocked hepatocyte growth factor (HGF)-induced intracellular signaling in the breast cancer cell line MBA-MD-231 as potently as free EGCG.

Quantitative comparison of delta P1 versus optical diffusion approximations for modeling near-infrared gold nanoshell heating.

Laser induced thermal therapy combined with the wavelength dependent optical absorption and heating power of gold-coated silica nanoshells can achieve therapeutic heating localized to a tumor volume. Accurate modeling of the spatiotemperal thermal distribution associated with this heating is essential for accurate thermal therapy treatment planning. The optical diffusion approximation (ODA), used in numerous applications of laser fluence in biology, is compared to the delta P1 optical approximation in phantoms containing different concentrations of nanoshells for several laser powers. Results are compared with temperature maps generated by magnetic resonance temperature imaging techniques and show that the delta P1 approximation is more effective than ODA at modeling the thermal distribution. The discrepancy between the two is especially prominent in phantoms with higher nanoshell concentrations where ODA was shown to give unsatisfactory results.

Glycaemic impact of patient-led use of sensor-guided pump therapy in type 1 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: The objective of this study was to assess the impact of patient-led sensor-guided pump management on glycaemic control, and compare the effect with that of standard insulin pump therapy. METHODS: An open multicentre parallel randomised controlled trial was conducted at five tertiary diabetes centres. Participants aged 13.0-40.0 years with well-controlled type 1 diabetes were randomised 1:1 to either study group for 3 months. Randomisation was carried out using a central computer-generated schedule. Participants in the intervention group used sensor-guided pump management; no instructive guidelines in interpreting real-time data were provided ('patient-led' use). Participants in the control group continued their original insulin pump regimen. Continuous glucose monitoring (CGM) and HbA(1c) level were used to assess outcomes. The primary outcome was the difference in the proportion of time in the target glycaemic range during the 3 month study period (derived from CGM, target range 4-10 mmol/l). Secondary outcomes were difference in HbA(1c), time in hypoglycaemic (< or =3.9 mmol/l) and hyperglycaemic (> or =10.1 mmol/l) ranges and glycaemic variability. RESULTS: Sixty-two participants were recruited and randomised; 5/31 and 2/31 withdrew from intervention and control groups, respectively, leaving 26/31 and 29/31 for the intention-to-treat analyses. When adjusted for baseline values, the mean end-of-study HbA(1c) was 0.43% lower in the intervention group compared with the control group (95% CI 0.19 to 0.75%; p = 0.009). No difference was observed in CGM-derived time in target (measured difference 1.72; 95% CI -5.37 to 8.81), hypoglycaemic (0.54; 95% CI -3.48 to 4.55) or hyperglycaemic (-2.18; 95% CI -10.0 to 5.69) range or in glycaemic variability (-0.29; 95% CI -0.34 to 0.28). Within the intervention group, HbA(1c) was 0.51% lower in participants with sensor use > or =70% compared with participants with sensor use <70% (95% CI -0.98 to -0.04, p = 0.04). Five episodes of device malfunction occurred. CONCLUSIONS/INTERPRETATION: Individuals established on insulin pump therapy can employ sensor-guided pump management to improve glycaemic control. An apparent dose-dependent effect of sensor usage was noted; however, frequent use of this technology (> or =70%) was not universally acceptable. TRIAL REGISTRATION: ACTRN12606000049572

Australian Aboriginal people and Torres Strait Islanders have an atherogenic lipid profile that is characterised by low HDL-cholesterol level and small LDL particles.

AIM: To characterise lipid profiles for Australian Aboriginal people and Torres Strait Islanders. METHODS: Community-based, cross-sectional surveys in 1995-1997 including: 407 female and 322 male Australian Aboriginal people and 207 female and 186 male Torres Strait Islanders over 15 years old. A comparator of 78 female (44 with diabetes) and 148 male (73 with diabetes) non-indigenous participants recruited to clinical epidemiological studies was used. Lipids were determined by standard assays and LDL diameter by gradient gel electrophoresis. RESULTS: Diabetes prevalence was 14.8% and 22.6% among Aboriginal people and Torres Strait Islanders, respectively. LDL size (mean [95% CI (confidence interval)]) was smaller (P<0.05) in non-diabetic Aboriginal (26.02 [25.96-26.07] nm) and Torres Strait Islander women (26.01 [25.92-26.09] nm) than in non-diabetic non-indigenous women (26.29 [26.13-26.44] nm). LDL size correlated (P<0.0005) inversely with triglyceride, WHR, and fasting insulin and positively with HDL-cholesterol. HDL-cholesterol (mean [95% CI] mmol/L) was lower (P<0.0005) in indigenous Australians than in non-indigenous subjects, independent of age, sex, diabetes, WHR, insulin, triglyceride, and LDL size: Aboriginal (non-diabetic women, 0.86 [0.84-0.88]; diabetic women, 0.76 [0.72-0.80]; non-diabetic men, 0.79 [0.76-0.81]; diabetic men, 0.76 [0.71-0.82]); Torres Strait Islander (non-diabetic women, 1.00 [0.95-1.04]; diabetic women, 0.89 [0.83-0.96]; non-diabetic men, 1.00 [0.95-1.04]; diabetic men, 0.87 [0.79-0.96]); non-indigenous (non-diabetic women, 1.49 [1.33-1.67]; diabetic women, 1.12 [1.03-1.21]; non-diabetic men, 1.18 [1.11-1.25]; diabetic men, 1.05 [0.98-1.12]). CONCLUSIONS: Indigenous Australians have a dyslipidaemia which includes small LDL and very low HDL-cholesterol levels. The dyslipidaemia was equally severe in both genders. Strategies aimed at increasing HDL-cholesterol and LDL size may reduce high CVD risk for indigenous populations.

Increased serum pigment epithelium-derived factor is associated with microvascular complications, vascular stiffness and inflammation in Type 1 diabetes.

AIMS: To determine in Type 1 diabetes patients if levels of pigment epithelium-derived factor (PEDF), an anti-angiogenic, anti-inflammatory and antioxidant factor, are increased in individuals with complications and positively related to vascular and renal dysfunction, body mass index, glycated haemoglobin, lipids, inflammation and oxidative stress. METHODS: Serum PEDF levels were measured by ELISA in a cross-sectional study of 123 Type 1 diabetic patients (71 without and 52 with microvascular complications) and 31 non-diabetic control subjects. PEDF associations with complication status, pulse-wave analysis and biochemical results were explored. RESULTS: PEDF levels [geometric mean (95% CI)] were increased in patients with complications 8.2 (7.0-9.6) microg/ml, vs. complication-free patients [5.3 (4.7-6.0) microg/ml, P < 0.001] and control subjects [5.3 (4.6-6.1) microg/ml, P < 0.001; anova between three groups, P < 0.001], but did not differ significantly between control subjects and complication-free patients (P > 0.05). In diabetes, PEDF levels correlated (all P < 0.001) with systolic blood pressure (r = 0.317), pulse pressure (r = 0.337), small artery elasticity (r = -0.269), glycated haemoglobin (r = 0.245), body mass index (r = 0.362), renal dysfunction [including serum creatinine (r = 0.491), cystatin C (r = 0.500)], triglycerides (r = 0.367), and inflammation [including log(e)C-reactive protein (CRP; r = 0.329), and soluble vascular cell adhesion molecule-1 (r = 0.363)]. Age, blood urea nitrogen, systolic blood pressure, pulse pressure and log(e)CRP correlated with PEDF levels in control subjects (all P < 0.04). PEDF levels were not significantly correlated with measures of oxidative stress: isoprostanes, oxidized low-density lipoprotein or paraoxonase-1 activity. On stepwise linear regression analysis (all subjects), independent determinants of PEDF levels were renal function, triglycerides, inflammation, small artery elasticity and age (r(2) = 0.427). CONCLUSIONS: In Type 1 diabetes, serum PEDF levels are associated with microvascular complications, poor vascular health, hyperglycaemia, adiposity and inflammation.

Quantitative estimation of gold nanoshell concentrations in whole blood using dynamic light scattering.

We demonstrate a new nondestructive optical assay to estimate submicron solid particle concentrations in whole blood. We use dynamic light scattering (DLS), commonly used to estimate nanoparticle characteristics such as size, surface charge, and degree of aggregation, to quantitatively estimate concentration and thereby estimate the actual delivered dose of intravenously injected nanoparticles and the longitudinal clearance rate. Triton X-100 is added to blood samples containing gold (Au) nanoshells to act as a quantitative scattering standard and blood lysing agent. The concentration of nanoshells was determined to be linearly proportional (R(2) = 0.998) to the relative light scattering attributed to nanoshells via DLS as compared with the Triton X-100 micelles in calibration samples. This relationship was found to remain valid (R(2) = 0.9) when estimating the concentration of circulating nanoshells in 15-muL blood samples taken from a murine tumor model as confirmed by neutron activation analysis. Au nanoshells are similar in size and shape to other types of nanoparticles delivered intravascularly in biomedical applications, and given the pervasiveness of DLS in nanoscale particle manufacturing, this simple technique should have wide applicability toward estimating the circulation time of other solid nanoparticles.

Near infrared laser-tissue welding using nanoshells as an exogenous absorber.

BACKGROUND AND OBJECTIVE: Gold nanoshells are a new class of nanoparticles that can be designed to strongly absorb light in the near infrared (NIR). These particles provide much larger absorption cross-sections and efficiency than can be achieved with currently used chemical chromophores without photobleaching. In these studies, we have investigated the use of gold nanoshells as exogenous NIR absorbers to facilitate NIR laser-tissue welding. STUDY DESIGN/MATERIALS AND METHODS: Gold nanoshells with peak extinction matching the NIR wavelength of the laser being used were manufactured and suspended in an albumin solder. Optimization work was performed on ex vivo muscle samples and then translated into testing in an in vivo rat skin wound-healing model. Mechanical testing of the muscle samples was immediately performed and compared to intact tissue mechanical properties. In the in vivo study, full thickness incisions in the dorsal skin of rats were welded, and samples of skin were excised at 0, 5, 10, 21, and 32 days for analysis of strength and wound healing response. RESULTS: Mechanical testing of nanoshell-solder welds in muscle revealed successful fusion of tissues with tensile strengths of the weld site equal to the uncut tissue. No welding was accomplished with this light source when using solder formulations without nanoshells. Mechanical testing of the skin wounds showed sufficient strength for closure and strength increased over time. Histological examination showed good wound-healing response in the soldered skin. CONCLUSIONS: The use of nanoshells as an exogenous absorber allows the usage of light sources that are minimally absorbed by tissue components, thereby, minimizing damage to surrounding tissue and allowing welding of thicker tissues.

Plasma low-molecular weight fluorescence in type 1 diabetes mellitus.

Characteristic tissue fluorescence is associated with advanced glycation end product (AGE) accumulation in experimental diabetes models, but its utility in patients with type 1 diabetes remains to be established. We studied 148 patients with type 1 diabetes and 77 healthy age-matched control subjects. Low-molecular weight (LMW) fluorophore levels were estimated in plasma samples obtained after an overnight fast. Intra- and interassay coefficients of variation were 4.7% and 6.4%, respectively. LMW fluorophore levels were significantly higher in patients with diabetes than in control subjects (6.3 +/- 0.6 AU/mL vs. 4.1 +/- 0.3; P = 0.007). However, all of this difference came from patients with microvascular complications (n = 67, 7.5 +/- 1.3). There was no significant difference in LMW fluorescence between complication-free patients (4.4 +/- 0.2) and control subjects (P > 0.05). On multivariate analysis, LMW fluorophores correlated with measures of renal function (P < 0.05) but not with diabetes per se. In addition, there was no correlation between LMW fluorophores and the markers of oxidative stress or systemic inflammation. Longitudinal and interventional studies are required to determine whether the association between LMW fluorophores and nephropathy is cause or effect.