Evaluation of glycated insulin in diabetic animals using immunocytochemistry and radioimmunoassay

Glycated insulin was evaluated in plasma and biological tissues of diabetic animal models by immuno. cytochemistry (ICC) and a novel radioimmunoassay. Glycated insulin circulated at 0.10 +/-0.04 ng/ml and 2.20 +/-0.14 ng/ml in lean and diabetic obese (ob/ob) mice, corresponding to 12.5 and 9.8% total plasma insulin, respectively. The concentration of glycated insulin was elevated 22-fold in obese mice compared to controls (P10 and 83 +/-4 ng/g wt (P0.17 mug/g wt). ICC revealed fluorescent positively stained cells in pancreatic islets from hydrocortisone (HC)treated diabetic rats. Fasting of HC-treated rats, resulted in 3-fold and 15-fold reductions in plasma glycated insulin (P

WASP-4b: A 12th magnitude transiting hot Jupiter in the southern hemisphere

We report the discovery of WASP-4b, a large transiting gas-giant planet with an orbital period of 1.34 days. This is the first planet to be discovered by the SuperWASP-South observatory and CORALIE collaboration and the first planet orbiting a star brighter than 16th magnitude to be discovered in the southern hemisphere. A simultaneous fit to high-quality light curves and precision radial velocity measurements leads to a planetary mass of 1.22(-0.08)(+0.09) M-Jup and a planetary radius of 1.42(-0.04)(+0.07) R-Jup. The host star is USNO-B1.0 0479-0948995, a G7 V star of visual magnitude 12.5. As a result of the short orbital period, the predicted surface temperature of the planet is 1761 K, making it an ideal candidate for detections of the secondary eclipse at infrared wavelengths.

A comparative electrochemical study of diffusion in room temperature ionic liquid solvents versus acetonitrile

Measurements on the diffusion coefficient of the neutral molecule N,N,N',N'-tetramethyl-para-phenylenediamine and the radical cation and dication generated by its one- and two-electron oxidation, respectively, are reported over the range 298-348 K in both acetonitrile and four room temperature ionic liquids (RTILs). Data were collected using single and double potential step chronamperometry at a gold disk electrode of micrometer dimension, and analysed via fitting to the appropriate analytical expression or, where necessary, to simulation. The variation of diffusion coefficient with temperature was found to occur in an Arrhenius-type manner for all combinations of solute and solvent. For a given ionic liquid, the diffusional activation energies of each species were not only closely equivalent to each other, but also to the RTIL's activation energy of viscous flow. In acetonitrile supported with 0.1 M tetrabutylammonium perchlorate, the ratio in diffusion coefficients of the radial cation and dication tot he neutral molecule were calculated as 0.89 +/- 0.05 and 0.51 +/- 0.03, respectively. In contrast, amongst the ionic liquids the same ratios were determined to be on average 0.53 +/- 0.04 and 0.33 +/- 0.03. The consequences of this dissimilarity are considered in terms of the modelling of voltammetric data gathered within ionic liquid solvents.

Investigation of DNA polymorphisms in SMAD genes for genetic predisposition to diabetic nephropathy in patients with type 1 diabetes mellitus

Aims/hypothesis: SMAD proteins are involved in multiple signalling pathways and are key modulators of gene expression. We hypothesised that genetic variation in selected SMAD genes contributes to susceptibility to diabetic nephropathy. Methods: We selected 13 haplotype tag (ht) single nucleotide polymorphisms (SNPs) from 67 variants identified by resequencing the SMAD2 and SMAD3 genes. For SMAD1, SMAD4 and SMAD5 genes, genotype data were downloaded for 217 SNPs from Phase II of the International HapMap project. Of these, 85 SNPs met our inclusion criteria, resulting in the selection of 13 tag SNPs for further investigation. A case-control approach was employed, using 267 nephropathic patients and 442 controls with type 1 diabetes from Ireland. Two further populations (totalling 1,407 patients, 2,238 controls) were genotyped to validate initial findings. Genotyping was conducted using iPLEX, TaqMan and gel electrophoresis.
Results: The distribution of genotypes was in Hardy-Weinberg equilibrium. Analysis by the ? 2 test of genotype and allele frequencies in patients versus controls in the Irish population (n?=?709) revealed evidence for the association of one allele at 5% level of significance (rs10515478, p uncorrected?=?0.006; p corrected?=?0.04). This finding represents a relatively small difference in allele frequency of 6.4% in the patient group compared with 10.7% in the control group; this difference was not supported in subsequent investigations using DNA from European individuals with similar phenotypic characteristics.
Conclusions/interpretation: We selected an appropriate subset of variants for the investigation of common genetic risk factors and assessed SMAD1 to SMAD5 genes for association with diabetic nephropathy. We conclude that common polymorphisms in these genes do not strongly influence genetic susceptibility to diabetic nephropathy in white individuals with type 1 diabetes mellitus.

Evaluation of N (epsilon)-(3-formyl-3,4-dehydropiperidino)lysine as a novel biomarker for the severity of diabetic retinopathy.

AIMS/HYPOTHESIS: Recent studies suggest that oxidative stress should be monitored alongside HbA(1c) to identify subgroups of diabetic patients at high risk of initiation or progression of retinopathy. The acrolein-derived advanced lipoxidation end-product (ALE), [Formula: see text]-(3-formyl-3,4-dehydropiperidino)lysine (FDP-lysine), is a useful biomarker that reflects the cumulative burden of oxidative stress over long periods of time. The purpose of the present study was to investigate whether serum and haemoglobin levels of FDP-lysine are associated with the severity of diabetic retinopathy in type 1 and type 2 diabetic patients.

METHODS: Serum and haemoglobin levels of FDP-lysine were measured by competitive ELISA in 59 type 1 and 76 type 2 diabetic patients with no retinopathy, non-proliferative retinopathy or proliferative retinopathy (mean age [+/-SEM] 54.3 +/- 1.3 years), and in 47 non-diabetic control individuals (mean age 51.9 +/- 2.1 years).

RESULTS: Serum and haemoglobin levels of FDP-lysine were significantly increased in diabetic patients compared with control individuals (p = 0.04 and p = 0.002, respectively). However, no significant association was found between levels of serum FDP-lysine and the severity of diabetic retinopathy (p = 0.97). In contrast, increased haemoglobin FDP-lysine levels were observed in patients with proliferative retinopathy compared with patients without retinopathy and with non-proliferative retinopathy (p = 0.04). The relationship of FDP-lysine with proliferative retinopathy was unaltered after adjustment for HbA(1c), or other clinical parameters.

CONCLUSIONS/INTERPRETATION: Our data suggest that haemoglobin FDP-lysine may provide a useful risk marker for the development of proliferative diabetic retinopathy independently of HbA(1c), and that elevated intracellular ALE formation may be involved in the pathogenesis of this sight-threatening complication of diabetes.

The component masses of the cataclysmic variable V347 Puppis

We present time-resolved spectroscopy and photometry of the double-lined eclipsing cataclysmic variable V347 Pup ( = LB 1800). There is evidence of irradiation on the inner hemisphere of the secondary star, which we correct for using a model to give a secondary-star radial velocity of K R = 198 +/- 5 km s(-1). The rotational velocity of the secondary star in V347 Pup is found to be v sin i = 131 +/- 5 km s(-1) and the system inclination is i = 84degrees.0 +/- 2degrees.3. From these parameters we obtain masses of M-1 = 0.63 +/- 0.04 M for the white dwarf primary and M-2 = 0.52 +/- 0.06 M for the M0.5V secondary star, giving a mass ratio of q = 0.83 +/- 0.05. On the basis of the component masses, and the spectral type and radius of the secondary star in V347 Pup, we find tentative evidence for an evolved companion. V347 Pup shows many of the characteristics of the SW Sex stars, exhibiting single-peaked emission lines, high-velocity S-wave components and phase-offsets in the radial velocity curve. We find spiral arms in the accretion disc of V347 Pup and measure the disc radius to be close to the maximum allowed in a pressureless disc.

The masses of the cataclysmic variables AC Cancri and V363 Aurigae

We present time-resolved spectroscopy and photometry of the double-lined eclipsing cataclysmic variables AC Cnc and V363 Aur (=Lanning 10). There is evidence of irradiation on the inner hemisphere of the secondary star in both systems, which we correct for using a model that reproduces the observations remarkably well. We find the radial velocity of the secondary star in AC Cnc to be K-R=176+/-3 km s(-1) and its rotational velocity to be v sin i=135+/-3 km s(-1). From these parameters we obtain masses of M-1=0.76+/-0.03 M-circle dot for the white-dwarf primary and M-2=0.77+/-0.05 M-circle dot for the K2+/-1 V secondary star, giving a mass ratio of q=1.02+/-0.04. We measure the radial and rotational velocities of the G7+/-2V secondary star in V363 Aur to be K-R=168+/-5 km s(-1) and v sin i=143+/-5 km s(-1), respectively. The component masses of V363 Aur are M-1=0.90+/-0.06M(circle dot) and M-2=1.06+/-0.11 M-circle dot giving a mass ratio of q=1.17+/-0.07. The mass ratios for AC Cnc and V363 Aur fall within the theoretical limits for dynamically and thermally stable mass transfer. Both systems are similar to the SW Sex stars, exhibiting single-peaked emission lines with transient absorption features, high-velocity S-wave components and phase-offsets in their radial-velocity curves. The Balmer lines in V363 Aur show a rapid increase in flux around phase 0 followed by a rapid decrease, which we attribute to the eclipse of an optically thick region at the centre of the disc. This model could also account for the behaviour of other SW Sex stars where the Balmer lines show only a shallow eclipse compared to the continuum.

A Transit Timing Analysis of Mine RISE Light Curves of the Exoplanet System TrES-3

We present nine newly observed transits of TrES-3, taken as part of a transit timing program using the RISE instrument on the Liverpool Telescope. A Markov-Chain Monte Carlo analysis was used to determine the planet star radius ratio and inclination of the system, which were found to be R-p/R-star = 0.1664(-0.0018)(+0.0011) and i = 81.73(-0.04)(+0.13), respectively, consistent with previous results. The central transit times and uncertainties were also calculated, using a residual-permutation algorithm as an independent check on the errors. A re-analysis of eight previously published TrES-3 light curves was conducted to determine the transit times and uncertainties using consistent techniques. Whilst the transit times were not found to be in agreement with a linear ephemeris, giving chi(2) = 35.07 for 15 degrees of freedom, we interpret this to be the result of systematics in the light curves rather than a real transit timing variation. This is because the light curves that show the largest deviation from a constant period either have relatively little out-of-transit coverage or have clear systematics. A new ephemeris was calculated using the transit times and was found to be T-c(0) = 2454632.62610 +/- 0.00006 HJD and P = 1.3061864 +/- 0.0000005 days. The transit times were then used to place upper mass limits as a function of the period ratio of a potential perturbing planet, showing that our data are sufficiently sensitive to have probed sub-Earth mass planets in both interior and exterior 2:1 resonances, assuming that the additional planet is in an initially circular orbit.

Low-fat versus low-carbohydrate weight reduction diets:Effects on weight loss, insulin resistance, and cardiovascular risk: a randomized control trial

OBJECTIVE Low-fat hypocaloric diets reduce insulin resistance and prevent type 2 diabetes in those at risk. Low-carbohydrate, high-fat diets are advocated as an alternative, but reciprocal increases in dietary fat may have detrimental effects on insulin resistance and offset the benefits of weight reduction.

RESEARCH DESIGN AND METHODS We investigated a low-fat (20% fat, 60% carbohydrate) versus a low-carbohydrate (60% fat, 20% carbohydrate) weight reduction diet in 24 overweight/obese subjects ([mean ± SD] BMI 33.6 ± 3.7 kg/m2, aged 39 ± 10 years) in an 8-week randomized controlled trial. All food was weighed and distributed, and intake was calculated to produce a 500 kcal/day energy deficit. Insulin action was assessed by the euglycemic clamp and insulin secretion by meal tolerance test. Body composition, adipokine levels, and vascular compliance by pulse-wave analysis were also measured.

RESULTS Significant weight loss occurred in both groups (P < 0.01), with no difference between groups (P = 0.40). Peripheral glucose uptake increased, but there was no difference between groups (P = 0.28), and suppression of endogenous glucose production was also similar between groups. Meal tolerance–related insulin secretion decreased with weight loss with no difference between groups (P = 0.71). The change in overall systemic arterial stiffness was, however, significantly different between diets (P = 0.04); this reflected a significant decrease in augmentation index following the low-fat diet, compared with a nonsignificant increase within the low-carbohydrate group.

CONCLUSIONS This study demonstrates comparable effects on insulin resistance of low-fat and low-carbohydrate diets independent of macronutrient content. The difference in augmentation index may imply a negative effect of low-carbohydrate diets on vascular risk.

Increases in energy, protein and fat intake following the addition of sauce to an older person's meal

Energy intake in 15-20% of the UK older population is currently thought to be inadequate for health. Based on the suggestion that increases in food pleasantness and familiarity can increase intake, this study investigated the impact of the addition of sauce to an older person's meal on subsequent intake. Twenty-eight older people consumed two meals with sauce and the same two meals without sauce on different occasions, and amount consumed in terms of weight, energy and energy consumed from carbohydrate, fat and protein were compared. Pre-meal hunger and desire to eat, post-meal pleasantness and familiarity and participants' expectations of the effects of sauces were also measured. Compared to meals without sauce, meals with sauce were found to result in greater intakes of energy, energy consumed from protein and energy consumed from fat (smallest t(27)=2.13, p=0.04). No differences between conditions were found in measures of pre-meal hunger and desire to eat, or post-meal pleasantness and familiarity (largest t(27) = 1.47, p = 0.15). Similar effects were also found when participant expectations were taken into account, and no differences between participants who expected sauces to affect intake vs. those who did not expect sauces to affect intake were found (largest F(1, 26) = 1.70, p=0.20). These findings suggest that the addition of sauce to an older person's meal can result in increases in intake and may be beneficial for preventing or treating under-nutrition in these individuals, although the mechanisms by which sauces can increase intake are unlikely to be related to pleasantness and familiarity. (c) 2008 Elsevier Ltd. All rights reserved.

Modelling the impact of antibiotic use and infection control practices on the incidence of hospital-acquired methicillin-resistant Staphylococcus aureus: a time-series analysis

Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen worldwide. A wide range of factors have been suggested to influence the spread of MRSA. The objective of this study was to evaluate the effect of antimicrobial drug use and infection control practices on nosocomial MRSA incidence in a 426-bed general teaching hospital in Northern Ireland.

Methods: The present research involved the retrospective collection of monthly data on the usage of antibiotics and on infection control practices within the hospital over a 5 year period (January 2000–December 2004). A multivariate ARIMA (time-series analysis) model was built to relate MRSA incidence with antibiotic use and infection control practices.

Results: Analysis of the 5 year data set showed that temporal variations in MRSA incidence followed temporal variations in the use of fluoroquinolones, third-generation cephalosporins, macrolides and amoxicillin/clavulanic acid (coefficients = 0.005, 0.03, 0.002 and 0.003, respectively, with various time lags). Temporal relationships were also observed between MRSA incidence and infection control practices, i.e. the number of patients actively screened for MRSA (coefficient = -0.007), the use of alcohol-impregnated wipes (coefficient = -0.0003) and the bulk orders of alcohol-based handrub (coefficients = -0.04 and -0.08), with increased infection control activity being associated with decreased MRSA incidence, and between MRSA incidence and the number of new patients admitted with MRSA (coefficient = 0.22). The model explained 78.4% of the variance in the monthly incidence of MRSA.

Conclusions: The results of this study confirm the value of infection control policies as well as suggest the usefulness of restricting the use of certain antimicrobial classes to control MRSA.

Effect of pioglitazone on endothelial function in impaired glucose tolerance

Aim: Flow-mediated dilation (FMD) is a surrogate marker of endothelial function, which has been proposed as a barometer of vascular health. Impaired microvascular response to reactive hyperaemia is thought to be the mechanism behind reduced shear stress and subsequently impaired FMD, which has been associated with cardiovascular events. This study aims to assess the effect of pioglitazone on the vasculature of patients with impaired glucose tolerance (IGT).

Materials and Methods: Forty IGT patients with no cardiovascular disease were compared with 24 healthy age- and sex-matched controls. Endothelial function was assessed using FMD of the brachial artery. Adiponectin (ADN) levels were measured and insulin sensitivity was calculated using homeostasis model assessment of insulin resistance (HOMA-IR). A randomised double-blind placebo-controlled trial of the IGT subjects was then performed, with subjects receiving either pioglitazone 30 mg od or matched placebo for 12 weeks before the measurements were repeated.

Results: The IGT subjects had a significantly impaired FMD compared with the controls (p < 0.001). Diastolic shear stress (DSS) was also significantly reduced in IGT (p = 0.04). High molecular weight (HMW) ADN was significantly lower in the IGT group than in controls (p = 0.03). On analysis of the IGT group after 12 weeks treatment, FMD was significantly increased in the pioglitazone group compared with placebo (p = 0.03) as was endothelium-independent dilation (EID) (p = 0.03). A significant increase in total ADN (p < 0.001), HMW ADN (p < 0.001) and HMW/total ratio (p = 0.001) occurred in the pioglitazone group compared with placebo.

Conclusions: Pioglitazone improved endothelial function in IGT. Treatment with pioglitazone may reduce the risk of cardiovascular disease in this patient group.

A randomized clinical trial of hydroxymethylglutaryl-Coenzyme A reductase inhibition for Acute Lung Injury (The HARP study)

Rationale: There is no effective pharmacological treatment for acute lung injury (ALI). Statins are a potential new therapy because they modify many of the underlying processes important in ALI.

Objectives: To test whether simvastatin improves physiological and biological outcomes in ALI.

Methods: We conducted a randomized, double-blinded, placebo-controlled trial in patients with ALI. Patients received 80 mg simvastatin or placebo until cessation of mechanical ventilation or up to 14 days. Extravascular lung water was measured using thermodilution. Measures of pulmonary and nonpulmonary organ function were assessed daily. Pulmonary and systemic inflammation was assessed by bronchoalveolar lavage fluid and plasma cytokines. Systemic inflammation was also measured by plasma C-reactive protein.

Measurements and Main Results: Sixty patients were recruited. Baseline characteristics, including demographics and severity of illness scores, were similar in both groups. At Day 7, there was no difference in extravascular lung water. By Day 14, the simvastatin-treated group had improvements in nonpulmonary organ dysfunction. Oxygenation and respiratory mechanics improved, although these parameters failed to reach statistical significance. Intensive care unit mortality was 30% in both groups. Simvastatin was well tolerated, with no increase in adverse events. Simvastatin decreased bronchoalveolar lavage IL-8 by 2.5-fold (P = 0.04). Plasma C-reactive protein decreased in both groups but failed to achieve significance in the placebo-treated group.

Conclusions: Treatment with simvastatin appears to be safe and may be associated with an improvement in organ dysfunction in ALI. These clinical effects may be mediated by a reduction in pulmonary and systemic inflammation.

Maternal Glucose at 28 Weeks of Gestation Is Not Associated With Obesity in 2-Year-Old Offspring:The Belfast Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Family Study

OBJECTIVE:Diabetes during pregnancy is a strong risk factor for obesity in the offspring, but the age at which this association becomes apparent is unknown. The purpose of this study was to examine the relation of glycemia during pregnancy with anthropometry in offspring of nondiabetic pregnant women from the Belfast U.K. center of the multinational Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study.
RESEARCH DESIGN AND METHODS: Women from the HAPO Study were invited to participate in follow-up of their offspring aged 2 years. Measurements included height, weight, and thickness of triceps, subscapular, and suprailiac skinfolds. RESULTS: A total of 1,165 offspring (73% of eligible children; 598 boys and 567 girls) were seen from ages 22-30 completed months. The only association that reached statistical significance was between categories of maternal 1-h glucose and BMI Z score =85th percentile at 2 years (P = 0.017). Overall the correlations between maternal glucose during pregnancy and BMI Z score at age 2 years were weak (fasting glucose r = 0.05, P = 0.08; 1-h glucose r = 0.04, P = 0.22; 2-h glucose r = 0.03, P = 0.36; and area under the curve for glucose r = 0.04, P = 0.18).
CONCLUSIONS: This study found little association between maternal glucose during pregnancy and obesity in the offspring at this young age. These findings are not unexpected given that study results for young offspring whose mothers had diabetes during pregnancy were indistinguishable from those for normal offspring at this age. It will be interesting to see whether, as these children age, maternal glucose during pregnancy in the ranges included in the HAPO Study will be associated with obesity in their children. © 2010 by the American Diabetes Association.

An Ecological Correlation Study of Late Age-Related Macular Degeneration and the Complement Factor H Y402H Polymorphism

PURPOSE:
To investigate whether variation in the distribution of the risk allele frequency of the Y402H single-nucleotide polymorphism (SNP) across various ethnicities and geographic regions reflects differences in the prevalence of late age-related macular degeneration (AMD) in those ethnicities.

METHODS:
Published data were obtained via a systematic search. Study samples were grouped into clusters by ethnicity and geographic location and the Spearman correlation coefficient of the prevalence of late AMD and risk allele frequencies was calculated across clusters.

RESULTS:
Across all ethnicities, AMD prevalence was seen to increase with age. Populations of European descent had both higher risk allele frequencies and prevalence of late AMD than did Japanese, Chinese, and Hispanic descendants. Results for African descendants were anomalous: although allele frequency was similar to that in European populations, the age-specific prevalence of late AMD was considerably lower. The correlation coefficient for the association between allele frequency and AMD prevalence was 0.40 (95% confidence interval [CI] = -0.36 to 0.84, P = 0.28) in all populations combined and 0.71 (95% CI = 0.02-0.94, P = 0.04) when people of African descent were excluded.

CONCLUSIONS:
Evidence was found at the population level to support a positive association between the Y204H risk allele and the prevalence of AMD after exclusion of studies undertaken on persons of African ancestry. Data in African, Middle Eastern, and South American populations are needed to provide a better understanding of the association of late AMD genetic risk across ethnicities.