Dose-Dependent Prevention of Fibrosis in Aorta of Salt-Loaded Stroke-Prone Spontaneously Hypertensive Rats by Combined Delapril and Indapamide treatment.

Combined treatment with the angiotensin-converting enzyme (ACE) inhibitor delapril and the diuretic indapamide prevented vascular damage in vital organs of salt-loaded stroke-prone spontaneously hypertensive rats (SHRsp). Whether the changes occurring after long-term hypertension could also be modulated in large arteries was investigated. Two-month-old SHRsp were salt loaded and treated with the drug regimen until they reached 50 +/- 10 mortality or around midlife. In a first experiment, delapril (12 mg/kg) and indapamide (1 mg/kg) were administered daily separately or in combination. In the second dose-finding experiment, delapril (6, 3, 1.5 mg/kg) and indapamide (0.5, 0.25, 0.125 mg/kg) in decreasing dose combinations were analyzed. Ultrastructural, histomorphometric, and biochemical studies were performed on the thoracic aorta. When compared with delapril (12 mg/kg) or indapamide (1 mg/kg) administered individually for 5 months, the combination 12 + 1 mg/kg was able to prevent the increase in extracellular matrix deposition observed in other treatment groups, as assessed by histomorphometry or 4-OH-proline biochemical determination. In the second experiment, a half-dose (delapril 6 mg/kg + indapamide 0.5 mg/kg) combination was similarly effective in counteracting fibrosis, but the other doses progressively failed. In the first experiment, the combination had a stabilizing effect on hypertension and stimulated diuresis. In the second experiment, arterial blood pressure values and sodium balance were not consistently affected by the treatments that antagonized fibrosis (i.e., delapril 6 mg/kg + indapamide 0.5 mg/kg and, less efficiently, delapril 3 mg/kg + indapamide 0.25 mg/kg). These results suggest that indapamide interacts with ACE inhibitors to limit aortic fibrosis independent of any well-established mechanism

Preassociative aggregation functions

The classical property of associativity is very often considered in aggregation function theory and fuzzy logic. In this paper we provide axiomatizations of various classes of preassociative functions, where preassociativity is a generalization of associativity recently introduced by the authors. These axiomatizations are based on existing characterizations of some noteworthy classes of associative operations, such as the class of Acz\'elian semigroups and the class of t-norms.Comment: arXiv admin note: text overlap with arXiv:1309.730

Correlative Microscopy Of Bone In Implant Osteointegration Studies.

Routine morphological analyses usually include investigations by light microscopy (LM), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Each of these techniques provides specific information on tissue morphology and all the obtained results are then combined to give an in-depth morphological overview of the examined sample. The limitations of this traditional comparative microscopy lie in the fact that each technique requires a different experimental sample, so that many specimens are necessary and the combined results come from different samples. The present study describes a technical procedure of correlative microscopy, which allows us to examine the same bone section first by LM and then, after appropriate processing, by SEM or TEM. Thanks to the possibility of analyzing the same undecalcified bone sections both by LM and SEM, the approach described in the present study allows us to make very accurate evaluations of old/new bone morphology at the bone-implant interface

Homozygous microdeletion of exon 5 in ZNF277 in a girl with specific language impairment

Peer reviewedPublisher PD

A genome-wide scan for common alleles affecting risk for autism

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C

i-Rheo: Measuring the materials' linear viscoelastic properties “in a step”!

A new analytical technique for determining a materials' linear viscoelastic properties from a simple step-strain measurement is reported. The technique avoids the need for idealisation of real measurements. The technique involves evaluating the Fourier transforms of raw experimental data describing both the time-dependent stress and strain functions. A comparison with conventional linear oscillatory measurements for a diverse range of complex materials is made and the technique is shown to be superior to existing linear oscillatory measurements in all cases

Individual common variants exert weak effects on the risk for autism spectrum disorders.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm&lt; 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest

Phenotypic and genotypic characterisation of inflammatory bowel disease presenting before the age of 2 years

OBJECTIVES: Inflammatory bowel disease presenting in early childhood is extremely rare. More recently, progress has been made to identify children with monogenic forms of IBD predominantly presenting very early in life. In this study, we describe the heterogeneous phenotypes and genotypes of patients with IBD presenting before the age of two years and establish phenotypic features associated with underlying monogenicity. METHODS: Phenotype data of 62 children with disease-onset before the age of two years presenting over the last 20 years were reviewed. Children without previously established genetic diagnosis were prospectively recruited for next-generation sequencing. RESULTS: 62 patients (55% male) were identified. The median disease-onset was three months of age [IQR: 1 to 11]. Conventional IBD classification only applied to 15 patients with Crohn's disease-like (24%) and three with ulcerative colitis-like (5%) phenotype. Forty-four patients (71%) were diagnosed with otherwise unclassifiable IBD. Patients frequently required parenteral nutrition (40%), extensive immunosuppression (31%), hematopoietic stem-cell transplantation (29%) and abdominal surgery (19%). In 31% of patients underlying monogenic diseases were established (EPCAM, IL10, IL10RA, IL10RB, FOXP3, LRBA, SKIV2L, TTC37, TTC7A). Phenotypic features significantly more prevalent in monogenic IBD were: consanguinity, disease-onset before the 6(th) month of life, stunting, extensive intestinal disease and histological evidence of epithelial abnormalities. CONCLUSION: IBD in children with disease-onset before the age of two years is frequently unclassifiable into Crohn's disease and ulcerative colitis, particularly treatment resistant and can be indistinguishable from monogenic diseases with IBD-like phenotype

The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism

Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P≤2.40E-09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P≤3.83E-23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P≤4.16E-04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions