Perturbation of hyaluronan metabolism predisposes patients with type 1 diabetes mellitus to atherosclerosis

AIMS/HYPOTHESIS: Cardiovascular disease contributes to mortality in type 1 diabetes mellitus, but the specific pathophysiological mechanisms remain to be established. We recently showed that the endothelial glycocalyx, a protective layer of proteoglycans covering the endothelium, is severely perturbed in type 1 diabetes, with concomitantly increased plasma levels of hyaluronan and hyaluronidase. In the present study, we evaluated the relationship between hyaluronan and hyaluronidase with carotid intima-media thickness (cIMT), an established surrogate marker for cardiovascular disease. SUBJECTS AND METHODS: Non-smoking type 1 diabetes patients without micro- or macrovascular complications and matched controls were recruited and cIMT of both carotid arteries was measured. To evaluate the relationship between cIMT and hyaluronan and hyaluronidase as well as other parameters, uni- or multivariate regression analyses were performed. RESULTS: We included 99 type 1 diabetes patients (age 10-72 years) and 99 age- and sex-matched controls. Mean cIMT, HbA(1c), high sensitivity C-reactive protein, hyaluronan and hyaluronidase were significantly increased in type 1 diabetes vs controls. Plasma hyaluronan and hyaluronidase were correlated in type 1 diabetes. In univariate regression analyses, mean IMT was associated with plasma hyaluronan, age and male sex, whereas after multivariate analysis only age and sex remained statistically significant. CONCLUSIONS/INTERPRETATION: We conclude that type 1 diabetes patients show structural changes of the arterial wall associated with increased hyaluronan metabolism. These data may lend further support to altered glycosaminoglycan metabolism in type 1 diabetes as a potential mechanism involved in accelerated atherogenesi

On the chronological structure of the solutrean in Southern Iberia

The Solutrean techno-complex has gained particular significance over time for representing a clear demographic and techno-typological deviation from the developments occurred during the course of the Upper Paleolithic in Western Europe. Some of Solutrean's most relevant features are the diversity and techno-typological characteristics of the lithic armatures. These have been recurrently used as pivotal elements in numerous Solutrean-related debates, including the chronological organization of the techno-complex across Iberia and Southwestern France. In Southern Iberia, patterns of presence and/or absence of specific point types in stratified sequences tend to validate the classical ordering of the techno-complex into Lower, Middle and Upper phases, although some evidence, namely radiocarbon determinations, have not always been corroborative. Here we present the first comprehensive analysis of the currently available radiocarbon data for the Solutrean in Southern Iberia. We use a Bayesian statistical approach from 13 stratified sequences to compare the duration, and the start and end moments of each classic Solutrean phase across sites. We conclude that, based on the current data, the traditional organization of the Solutrean cannot be unquestionably confirmed for Southern Iberia, calling into doubt the status of the classically defined type-fossils as precise temporal markers.Fundacao para a Ciencia e Tecnologia [PTDC/HAH/64184/2006, PTDC/HIS-ARQ/117540/2010, SFRH/BD/65527/2009, SFRH/BPD/96277/2013]; National Geographic Society [8045-06]; Wenner-Gren Foundation for Anthropological Research [8290

First-line latanoprost therapy in ocular hypertension or open-angle glaucoma patients: a 3-month efficacy analysis stratified by initial intraocular pressure

<p>Abstract</p> <p>Background</p> <p>Prospective, multicenter, randomized, double-masked trials have shown latanoprost instilled once daily to be at least as effective as and generally superior to timolol administered twice daily and to be as effective as other frequently prescribed prostaglandin analogues. This study prospectively assessed the efficacy of latanoprost monotherapy in a large cohort of treatment-naive patients with a broad range of baseline intraocular pressure (IOP) levels treated in actual clinical practice settings.</p> <p>Methods</p> <p>This prospective, open-label, multicenter, uncontrolled, phase IV study included treatment-naive ocular hypertension or open-angle glaucoma subjects initiating latanoprost once daily (evening). IOP levels were measured at baseline and after 1 and 3 months. The primary efficacy outcome was mean change in IOP from baseline to month 3. Analyses were stratified by baseline IOP: ≥ 20 and <24 mmHg <it>vs </it>≥ 24 mmHg.</p> <p>Results</p> <p>Efficacy analyses (intent to treat) included 572 subjects: 20 to <24 mmHg group, N = 252; ≥ 24 mmHg group, N = 320. Mean baseline IOP levels were 22.2 ± 0.9 mmHg and 26.7 ± 2.8 mmHg, respectively. At month 3, significant IOP reductions were seen in both groups (p < 0.0001, within-group differences); reductions were smaller in the 20 to <24 mmHg group (-6.3 ± 2.4 <it>vs </it>-9.2 ± 3.7 mmHg, respectively; -28.0 ± 10.6% <it>vs </it>-34.1 ± 11.9%, respectively). An IOP reduction of ≥ 30% from baseline to month 3 was noted in 48.4% and 65.6% of subjects, respectively (p < 0.0001). At month 3, targets IOPs of ≤ 18 mmHg were achieved by ≥ 70% of subjects in both groups. Latanoprost was well tolerated with an adverse event profile similar to that reported in the literature.</p> <p>Conclusions</p> <p>This "real world" study found once-daily latanoprost to be effective and safe in treatment-naive ocular hypertension or open-angle glaucoma patients. Patients with baseline IOP levels of 20 to <24 mmHg as well as ≥ 24 mmHg benefitted from initial latanoprost therapy.</p> <p>Trial Registration</p> <p>Trial Registration Number: NCT00647101</p

High Salt Intake Down-Regulates Colonic Mineralocorticoid Receptors, Epithelial Sodium Channels and 11β-Hydroxysteroid Dehydrogenase Type 2

Besides the kidneys, the gastrointestinal tract is the principal organ responsible for sodium homeostasis. For sodium transport across the cell membranes the epithelial sodium channel (ENaC) is of pivotal relevance. The ENaC is mainly regulated by mineralocorticoid receptor mediated actions. The MR activation by endogenous 11β-hydroxy-glucocorticoids is modulated by the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). Here we present evidence for intestinal segment specific 11β-HSD2 expression and hypothesize that a high salt intake and/or uninephrectomy (UNX) affects colonic 11β-HSD2, MR and ENaC expression. The 11β-HSD2 activity was measured by means of 3H-corticosterone conversion into 3H-11-dehydrocorticosterone in Sprague Dawley rats on a normal and high salt diet. The activity increased steadily from the ileum to the distal colon by a factor of about 3, an observation in line with the relevance of the distal colon for sodium handling. High salt intake diminished mRNA and protein of 11β-HSD2 by about 50% (p<0.001) and reduced the expression of the MR (p<0.01). The functionally relevant ENaC-β and ENaC-γ expression, a measure of mineralocorticoid action, diminished by more than 50% by high salt intake (p<0.001). The observed changes were present in rats with and without UNX. Thus, colonic epithelial cells appear to contribute to the protective armamentarium of the mammalian body against salt overload, a mechanism not modulated by UNX

Dietary Blue Pigments Derived from Genipin, Attenuate Inflammation by Inhibiting LPS-Induced iNOS and COX-2 Expression via the NF-κB Inactivation

The edible blue pigments produced by gardenia fruits have been used as value-added colorants for foods in East Asia for 20 years. However, the biological activity of the blue pigments derived from genipin has not been reported.The anti-inflammatory effect of blue pigments was studied in lipopolysaccharide (LPS) stimulated RAW 264.7 macrophage in vitro. The secretions of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) were inhibited in concentration-dependent manner by blue pigments. Real-time reverse-transcription polymerase chain reaction (Real-time RT-PCR) analyses demonstrated that the mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin (IL)-6, and tumor necrosis factor alpha (TNF-α) was inhibited, moreover, ELISA results showed that the productions of IL-6 and TNF-α were inhibited. Cell-based ELISA revealed the COX-2 protein expression was inhibited. The proteome profiler array showed that 12 cytokines and chemokines involved in the inflammatory process were down-regulated by blue pigments. Blue pigments inhibited the nuclear transcription factor kappa-B (NF-κB) activation induced by LPS, and this was associated with decreasing the DNA-binding activity of p65 and p50. Furthermore, blue pigments suppressed the degradation of inhibitor of κB (IκB) α, Inhibitor of NF-κB Kinase (IKK) α, IKK-β, and phosphorylation of IκB-α. The anti-inflammatory effect of blue pigments in vivo was studied in carrageenan-induced paw edema and LPS-injecting ICR mice. Finally, blue pigments significantly inhibited paw swelling and reduced plasma TNF-α and IL-6 production in vivo.These results suggest that the anti-inflammatory properties of blue pigments might be the results from the inhibition of iNOS, COX-2, IL-6, IL-1β, and TNF-α expression through the down-regulation of NF-κB activation, which will provide strong scientific evidence for the edible blue pigments to be developed as a new health-enhancing nutritional food for the prevention and treatment of inflammatory diseases

SuRankCo: supervised ranking of contigs in de novo assemblies

Background: Evaluating the quality and reliability of a de novo assembly and of single contigs in particular is challenging since commonly a ground truth is not readily available and numerous factors may influence results. Currently available procedures provide assembly scores but lack a comparative quality ranking of contigs within an assembly. Results: We present SuRankCo, which relies on a machine learning approach to predict quality scores for contigs and to enable the ranking of contigs within an assembly. The result is a sorted contig set which allows selective contig usage in downstream analysis. Benchmarking on datasets with known ground truth shows promising sensitivity and specificity and favorable comparison to existing methodology. Conclusions: SuRankCo analyzes the reliability of de novo assemblies on the contig level and thereby allows quality control and ranking prior to further downstream and validation experiments

Estimation of the Effective Permeability of Heterogeneous Porous Media by Using Percolation Concepts

In this paper we present new methods to estimate the effective permeability (k_eff) of heterogeneous porous media with a wide distribution of permeabilities and various underlying structures, using percolation concepts. We first set a threshold permeability (k_th) on the permeability density function (pdf) and use standard algorithms from percolation theory to check whether the high permeable grid blocks (i.e. those with permeability higher than k_th) with occupied fraction of “p” first forms a cluster connecting two opposite sides of the system in the direction of the flow (high permeability flow pathway). Then we estimate the effective permeability of the heterogeneous porous media in different ways: a power law (k_eff=k_th p^m), a weighted power average (k_eff=[p.k_th^m+(1-p).k_g^m ]^(1/m) with k_g the geometric average of the permeability distribution) and a characteristic shape factor multiplied by the permeability threshold value. We found that the characteristic parameters (i.e. the exponent “m”) can be inferred either from the statistics and properties of percolation sub-networks at the threshold point (i.e. high and low permeable regions corresponding to those permeabilities above and below the threshold permeability value) or by comparing the system properties with an uncorrelated random field having the same permeability distribution. These physically based approaches do not need fitting to the experimental data of effective permeability measurements to estimate the model parameter (i.e. exponent m) as is usually necessary in empirical methods. We examine the order of accuracy of these methods on different layers of 10th SPE model and found very good estimates as compared to the values determined from the commercial flow simulators