Advanced glycation end products induce blood-retinal barrier dysfunction in normoglycemic rats

Advanced glycation end products (AGEs) have been implicated in the progressive vascular dysfunction which occurs during diabetic retinopathy. In the current study we have examined the role of these adducts in blood-retinal barrier (BRB) breakdown and investigated expression of the vasopermeabilizing agent vascular endothelial growth factor (VEGF) in the retina. When normoglycemic rats were injected with AGE-modified albumin daily for up to 10 days there was widespread leakage of FITC-dextran and serum albumin from the retinal vasculature when compared to control animals treated with nonmodified albumin. Ultrastructural examination of the vasculature revealed areas of attenuation of the retinal vascular endothelium and increased vesicular organelles only in the AGE-exposed rats. Quantitative RT-PCR and in situ hybridization demonstrated a significant increase in retinal VEGF mRNA expression (P <0.05). These results suggest that AGEs can initiate BRB dysfunction in nondiabetic rats and a concomitant increase in retinal VEGF expression. These findings may have implications for the role of AGEs in the pathogenesis of diabetic retinopathy.

Glucose-potentiated chemotaxis in human vascular smooth muscle is dependent on cross-talk between the P13K and MAPK signalling pathways

Atheroma formation involves the movement of vascular smooth muscle cells (VSMC) into the subendothelial space. The aim of this study was to determine the involvement of PI3K and MAPK pathways and the importance of cross-talk between these pathways, in glucose-potentiated VSMC chemotaxis to serum factors. VSMC chemotaxis occurred in a serum gradient in 25 mmol/L glucose (but not in 5 mmol/L glucose) in association with increased phosphorylation (activation) of Akt and ERK1/2 in PI3K and MAPK pathways, respectively. Inhibitors of these pathways blocked chemotaxis, as did an mTOR inhibitor. VSMC expressed all class IA PI3K isoforms, but microinjection experiments demonstrated that only the p110beta isoform was involved in chemotaxis. ERK1/2 phosphorylation was reduced not only by MAPK pathway inhibitors but also by PI3K and mTOR inhibitors; when PI3K was inhibited, ERK phosphorylation could be induced by microinjected activated Akt, indicating important cross-talk between the PI3K and ERK1/2 pathways. Glucose-potentiated phosphorylation of molecules in the p38 and JNK MAPK pathways inhibited these pathways but did not affect chemotaxis. The statin, mevinolin, blocked chemotaxis through its effects on the MAPK pathway. Mevinolin-inhibited chemotaxis was restored by farnesylpyrophosphate but not by geranylgeranylpyrophosphate; in the absence of mevinolin, inhibition of farnesyltransferase reduced ERK phosphorylation and blocked chemotaxis, indicating a role for the Ras family of GTPases (MAPK pathway) under these conditions. In conclusion, glucose sensitizes VSMC to serum, inducing chemotaxis via pathways involving p110beta-PI3K, Akt, mTOR, and ERK1/2 MAPK. Cross-talk between the PI3K and MAPK pathways is necessary for VSMC chemotaxis under these conditions.

Modulation of contractile function through NPY receptors during development of cardiomyocyte hypertrophy.

Severity of left ventricular hypertrophy (LVH) correlates with elevated plasma levels of neuropeptide Y (NPY) in hypertension. NPY elicits positive and negative contractile effects in cardiomyocytes through Y(1) and Y(2) receptors, respectively. This study tested the hypothesis that NPY receptor-mediated contraction is altered during progression of LVH. Ventricular cardiomyocytes were isolated from spontaneously hypertensive rats (SHRs) pre-LVH (12 weeks), during development (16 weeks), and at established LVH (20 weeks) and age-matched normotensive Wistar Kyoto (WKY) rats. Electrically stimulated (60 V, 0.5 Hz) cell shortening was measured using edge detection and receptor expression determined at mRNA and protein level. The NPY and Y(1) receptor-selective agonist, Leu(31)Pro(34)NPY, stimulated increases in contractile amplitude, which were abolished by the Y(1) receptor-selective antagonist, BIBP3226 [R-N(2)-(diphenyl-acetyl)-N-(4-hydroxyphenyl)methyl-argininamide)], confirming Y(1) receptor involvement. Potencies of both agonists were enhanced in SHR cardiomyocytes at 20 weeks (2300- and 380-fold versus controls). Maximal responses were not attenuated. BIBP3226 unmasked a negative contraction effect of NPY, elicited over the concentration range (10(-12) to 3 x 10(-9) M) in which NPY and PYY(3-36) attenuated the positive contraction effects of isoproterenol, the potencies of which were increased in cardiomyocytes from SHRs at 20 weeks (175- and 145-fold versus controls); maximal responses were not altered. Expression of NPY-Y(1) and NPY-Y(2) receptor mRNAs was decreased (55 and 69%) in left ventricular cardiomyocytes from 20-week-old SHRs versus age-matched WKY rats; parallel decreases (32 and 80%) were observed at protein level. Enhancement of NPY potency, producing (opposing) contractile effects on cardiomyocytes together with unchanged maximal response despite reduced receptor number, enables NPY to contribute to regulating cardiac performance during compensatory LVH.

HI observations of the high-velocity cloud in the direction of M 92

We present wide-field neutral hydrogen (H I) Lovell telescope multibeam, and Dominion Radio Astrophysical Observatory Hi synthesis observations, of the high velocity cloud (HVC) located in the general direction of the globular cluster M92. This cloud is part of the larger Complex C and lies at velocities between similar to -80 and -130 km s(-1) in the Local Standard of Rest. The Lovell telescope observations, of resolution 12 arcmin spatially and 3.0 km s(-1) in velocity, fully sampling a 3.1 degrees x 12.6 degrees RA-Dec grid, have found that this part of HVC Complex C comprises two main condensations, lying approximately north-south in declination, separated by similar to2 degrees and being parallel to the Galactic plane. At this resolution, peak values of the brightness temperature and Hi column density of similar to1.4 K and similar to5 x 10(19) cm(-2) are determined, with relatively high values of the full width half maximum velocity (FWHM) of similar to 22 km s(-1) being observed, equivalent to a gas kinetic temperature, in the absence of turbulence and geometric effects of similar to 10 000 K. Each of these properties, as well as the sizes of the clouds, are similar in the two components. The DRAO observations, towards the Northern HVC condensation, are the first high-resolution Hi spectra of Complex C. When smoothed to a resolution of 3 arcmin, they identify several Hi intensity peaks with column densities in the range 4-7 x 10(19) cm(-2). Further smoothing of these data to 6 arcmin resolution tentatively indicates that parts of the HVC consist of two velocity components, of similar brightness temperature, separated by similar to7 km s(-1) in velocity, and with FWHM velocity widths of similar to5-7 km s(-1). No IRAS 60 or 100 micron flux is associated with the M92 HVC. Cloud properties are briefly discussed and compared to previous observations of HVCs.

Australia Telescope Compact Array 1.2cm Observations of the Massive Star Forming Region G305.2+0.2

We report on Australia Telescope Compact Array observations of the massive star-forming region G305.2+0.2 at 1.2 cm. We detected emission in five molecules towards G305A, confirming its hot core nature. We determined a rotational temperature of 26 K for methanol. A non-local thermodynamic equilibrium excitation calculation suggests a kinematic temperature of the order of 200 K. A time-dependent chemical model is also used to model the gas-phase chemistry of the hot core associated with G305A. A comparison with the observations suggest an age of between 2 × 104 and 1.5 × 105 yr. We also report on a feature to the south-east of G305A which may show weak Class I methanol maser emission in the line at 24.933 GHz. The more evolved source G305B does not show emission in any of the line tracers, but strong Class I methanol maser emission at 24.933 GHz is found 3 arcsec to the east. Radio continuum emission at 18.496 GHz is detected towards two H ii regions. The implications of the non-detection of radio continuum emission towards G305A and G305B are also discussed.

Unlinked vital events in census-based longitudinal studies can bias subsequent analysis

Objective: To examine the potential biases arising from the nonlinkage of census records and vital events in longitudinal studies.
Study Design and Setting: A total of 56,396 deaths of residents of Northern Ireland in the 4 years after the 2001 Census were linked to the 2001 Census records. The characteristics of matched and nonmatched death records were compared using multivariate logistic regression. Subject attributes were as recorded on the death certificate.
Results: In total, 3,392 (6.0%) deaths could not be linked to a census record. Linkage rates were lowest in young adults, males, the unmarried, people living in communal establishments, or living in areas that were more deprived or had recorded low census enumeration. For those aged less than 65 years at census, this linkage would exclude from analysis 20.2% of suicides and 19.7% of deaths by external causes.
Conclusion: The nonlinkage of census and death records is a combination of nonenumeration at census and deficient information about the deceased recorded at the time of death. Unmatched individuals may have been more disadvantaged or socially isolated, and analysis based on the linked data set may therefore show some bias and perhaps understate true social gradients.

Ancients inspire modern memory

A stencilling technique for depositing arrays of nanoscale ferroelectric capacitors on a surface could be useful in data storage devices.