In vivo fragmentation of heparan sulfate by heparanase overexpression renders mice resistant to amyloid protein A amyloidosis

Amyloid diseases encompass >20 medical disorders that include amyloid protein A (AA) amyloidosis, Alzheimer's disease, and type 2 diabetes. A common feature of these conditions is the selective organ deposition of disease-specific fibrillar proteins, along with the sulfated glycosaminoglycan, heparan sulfate. We have generated transgenic mice that overexpress human heparanase and have tested their susceptibility to amyloid induction. Drastic shortening of heparan sulfate chains was observed in heparanase-overproducing organs, such as liver and kidney. These sites selectively escaped amyloid deposition on experimental induction of inflammation-associated AA amyloidosis, as verified by lack of material staining with Congo Red, as well as lack of associated polysaccharide, whereas the same tissues from control animals were heavily infiltrated with amyloid. By contrast, the spleens of transgenic mice that failed to significantly overexpress heparanase contained heparan sulfate chains similar in size to those of control spleen and remained susceptible to amyloid deposition. Our findings provide direct in vivo evidence that heparan sulfate is essential for the development of amyloid disease.     

Cumulative adverse effects of diabetes mellitus and hypertension on coronary flow velocity reserve

BACKGROUND: this study aimed to assess the hypothesis that essential hypertension (EH) may increase coronary microcirculation dysfunction in patients with type 2 diabetes mellitus (DM). Microvascular dysfunction has been reported in patients with DM or EH. Discordant results have been reported on cumulative adverse effects of the simultaneous presence of DM and EH on coronary flow velocity reserve (CFR). METHODS: CFR were compared in 13 hypertensive diabetics (group 1), 12 normotensive diabetics (group 2), 11 hypertensive non diabetics (group 3) and 29 normotensive non diabetic patients (group 4). CFR was calculated using an intracoronary Doppler-tipped flow wire. RESULTS: CFR was significantly lower in patients with both DM and EH (2.2 +/- 0.4 in group 1 vs 2.8 +/- 0.5, 2.8 +/- 0.6 and 2.9 +/- 0.7 in groups 2, 3 and 4 respectively, p<0.01). The presence of hypertension reduced CFR in diabetic patients with angiographically abnormal but unobstructed coronary arteries (2.1 +/- 0.3 in hypertensive vs 3.1 +/- 0.2 in normotensive diabetic patients, p<0.02). No cumulative adverse effect was observed in diabetics with angiographically normal coronary arteries (2.3 +/- 0.6 in hypertensive vs 2.6 +/- 0.5 in normotensive diabetic patients, NS). Multivariate analysis revealed that combination of DM and EH (p<0.007) was independently related to CFR. CONCLUSIONS: the presence of hypertension appears to worsen coronary microangiopathy in diabetic patients with unobstructed coronary artery disease. The cumulative effect of EH and DM on CFR impairment has consequences for decision-making during coronary angioplasty and could identify patients at risk for cardiomyopathy.     

Correction to: Effect of Opioid Use on Immune Activation and HIV Persistence on ART

Journal of Neuroimmune Pharmacology - The original version of this article unfortunately contained mistakes.     

Is multiple SNP testing in BRCA2 and BRCA1 female carriers ready for use in clinical practice? Results from a large Genetic Centre in the UK

BRCA1 and BRCA2 are major breast cancer susceptibility genes. Nineteen single nucleotide polymorphisms (SNPs) at 18 loci have been associated with breast cancer. We aimed to determine whether these predict breast cancer incidence in women with BRCA1/BRCA2 mutations. BRCA1/2 mutation carriers identified through the Manchester genetics centre between 1996 and 2011 were included. Using published odds ratios (OR) and risk allele frequencies, we calculated an overall breast cancer risk SNP score (OBRS) for each woman. The relationship between OBRS and age at breast cancer onset was investigated using the Cox proportional hazards model, and predictive ability assessed using Harrell's C concordance statistic. In BRCA1 mutation carriers we found no association between OBRS and age at breast cancer onset: OR for the lowest risk quintile compared to the highest was 1.20 (95% CI 0.82–1.75, Harrell's C = 0.54), but in BRCA2 mutation carriers the association was significant (OR for the lowest risk quintile relative to the highest was 0.47 (95% CI 0.33–0.69, Harrell's C = 0.59). The 18 validated breast cancer SNPs differentiate breast cancer risks between women with BRCA2 mutations, but not BRCA1. It may now be appropriate to use these SNPs to help women with BRCA2 mutations make maximally informed decisions about management options.