Locally Delivered Salicylic Acid From a Poly(anhydride-ester): Impact on Diabetic Bone Regeneration

Diabetes mellitus (DM) involves metabolic changes that can impair bone repair, including a prolonged inflammatory response. A salicylic acid-based poly(anhydride-ester) (SA-PAE) provides controlled and sustained release of salicylic acid (SA) that locally resolves inflammation. This study investigates the effect of polymer-controlled SA release on bone regeneration in diabetic rats where enhanced inflammation is expected. Fifty-six Sprague–Dawley rats were randomly assigned to two groups: diabetic group induced by streptozotocin (STZ) injection or normoglycemic controls injected with citrate buffer alone. Three weeks after hyperglycemia development or vehicle injection, 5 mm critical sized defects were created at the rat mandibular angle and treated with SA-PAE/bone graft mixture or bone graft alone. Rats were euthanized 4 and 12 weeks after surgery, then bone fill percentage in the defect region was assessed by micro-computed tomography (CT) and histomorphometry. It was observed that bone fill increased significantly at 4 and 12 weeks in SA-PAE/bone graft-treated diabetic rats compared to diabetic rats receiving bone graft alone. Accelerated bone formation in normoglycemic rats caused by SA-PAE/bone graft treatment was observed at 4 weeks but not at 12 weeks. This study shows that treatment with SA-PAE enhances bone regeneration in diabetic rats and accelerates bone regeneration in normoglycemic animals

A pilot randomized clinical trial of intermittent occlusion therapy liquid crystal glasses versus traditional patching for treatment of moderate unilateral amblyopia

PURPOSE: To compare the effectiveness of intermittent occlusion therapy (IO therapy) using liquid crystal glasses and continuous occlusion therapy using traditional adhesive patches for treating amblyopia. METHODS: Children 3-8 years of age with previously untreated, moderate, unilateral amblyopia (visual acuity of 20/40 to 20/100 in the amblyopic eye) were enrolled in this randomized controlled trial. Amblyopia was associated with strabismus, anisometropia, or both. All subjects had worn any optimal refractive correction for at least 12 weeks without improvement. Subjects were randomized into two treatment groups: a 4-hour IO therapy group with liquid crystal glasses (Amblyz), set at 30-second opaque/transparent intervals (occluded 50% of wear time), and a 2-hour continuous patching group (occluded 100% of wear time). For each patient, visual acuity was measured using ATS-HOTV before and after 12 weeks of treatment. RESULTS: Data from 34 patients were available for analysis. Amblyopic eye visual acuity improvement from baseline was 0.15 ± 0.12 logMAR (95% CI, 0.09-0.15) in the IO therapy group (n = 19) and 0.15 ± 0.11 logMAR (95% CI, 0.1-0.15) in the patching group (n = 15). In both groups improvement was significant, but the difference between groups was not (P = 0.73). No adverse effects were reported. CONCLUSIONS: In this pilot study, IO therapy with liquid crystal glasses is not inferior to adhesive patching and is a promising alternative treatment for children 3-8 years of age with moderate amblyopia

A framework for evaluating the influence of climate, dispersal limitation, and biotic interactions using fossil pollen associations across the late Quaternary

Environmental conditions, dispersal lags, and interactions among species are major factors structuring communities through time and across space. Ecologists have emphasized the importance of biotic interactions in determining local patterns of species association. In contrast, abiotic limits, dispersal limitation, and historical factors have commonly been invoked to explain community structure patterns at larger spatiotemporal scales, such as the appearance of late Pleistocene no-analog communities or latitudinal gradients of species richness in both modern and fossil assemblages. Quantifying the relative influence of these processes on species co-occurrence patterns is not straightforward. We provide a framework for assessing causes of species associations by combining a null-model analysis of co-occurrence with additional analyses of climatic differences and spatial pattern for pairs of pollen taxa that are significantly associated across geographic space. We tested this framework with data on associations among 106 fossil pollen taxa and paleoclimate simulations from eastern North America across the late Quaternary. The number and proportion of significantly associated taxon pairs increased over time, but only 449 of 56 194 taxon pairs were significantly different from random. Within this significant subset of pollen taxa, biotic interactions were rarely the exclusive cause of associations. Instead, climatic or spatial differences among sites were most frequently associated with significant patterns of taxon association. Most taxon pairs that exhibited co-occurrence patterns indicative of biotic interactions at one time did not exhibit significant associations at other times. Evidence for environmental filtering and dispersal limitation was weakest for aggregated pairs between 16 and 11 kyr BP, suggesting enhanced importance of positive species interactions during this interval. The framework can thus be used to identify species associations that may reflect biotic interactions because these associations are not tied to environmental or spatial differences. Furthermore, temporally repeated analyses of spatial associations can reveal whether such associations persist through time

Pulmonary metastasectomy versus continued active monitoring in colorectal cancer (PulMiCC): a multicentre randomised clinical trial

BACKGROUND: Lung metastasectomy in the treatment of advanced colorectal cancer has been widely adopted without good evidence of survival or palliative benefit. We aimed to test its effectiveness in a randomised controlled trial (RCT). METHODS: Multidisciplinary teams in 13 hospitals recruited participants with potentially resectable lung metastases to a multicentre, two-arm RCT comparing active monitoring with or without metastasectomy. Other local or systemic treatments were decided by the local team. Randomisation was remote and stratified by site with minimisation for age, sex, primary cancer stage, interval since primary resection, prior liver involvement, the number of metastases, and carcinoembryonic antigen level. The central Trial Management Group were blind to patient allocation until completion of the analysis. Analysis was on intention to treat with a margin for non-inferiority of 10%. RESULTS: Between December 2010 and December 2016, 65 participants were randomised. Characteristics were well-matched in the two arms and similar to those in reported studies: age 35 to 86 years (interquartile range (IQR) 60 to 74); primary resection IQR 16 to 35 months previously; stage at resection T1, 2 or 3 in 3, 8 and 46; N1 or N2 in 31 and 26; unknown in 8. Lung metastases 1 to 5 (median 2); 16/65 had previous liver metastases; carcinoembryonic antigen normal in 55/65. There were no other interventions in the first 6 months, no crossovers from control to treatment, and no treatment-related deaths or major adverse events. The Hazard ratio for death within 5 years, comparing metastasectomy with control, was 0.82 (95%CI 0.43, 1.56). CONCLUSIONS: Because of poor and worsening recruitment, the study was stopped. The small number of participants in the trial (N = 65) precludes a conclusive answer to the research question given the large overlap in the confidence intervals in the proportions still alive at all time points. A widely held belief is that the 5-year absolute survival benefit with metastasectomy is about 35%: 40% after metastasectomy compared to < 5% in controls. The estimated survival in this study was 38% (23-62%) for metastasectomy patients and 29% (16-52%) in the well-matched controls. That is the new and important finding of this RCT. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT01106261. Registered on 19 April 2010

Genome sequence of an Australian kangaroo, Macropus eugenii, provides insight into the evolution of mammalian reproduction and development.

BACKGROUND: We present the genome sequence of the tammar wallaby, Macropus eugenii, which is a member of the kangaroo family and the first representative of the iconic hopping mammals that symbolize Australia to be sequenced. The tammar has many unusual biological characteristics, including the longest period of embryonic diapause of any mammal, extremely synchronized seasonal breeding and prolonged and sophisticated lactation within a well-defined pouch. Like other marsupials, it gives birth to highly altricial young, and has a small number of very large chromosomes, making it a valuable model for genomics, reproduction and development. RESULTS: The genome has been sequenced to 2 × coverage using Sanger sequencing, enhanced with additional next generation sequencing and the integration of extensive physical and linkage maps to build the genome assembly. We also sequenced the tammar transcriptome across many tissues and developmental time points. Our analyses of these data shed light on mammalian reproduction, development and genome evolution: there is innovation in reproductive and lactational genes, rapid evolution of germ cell genes, and incomplete, locus-specific X inactivation. We also observe novel retrotransposons and a highly rearranged major histocompatibility complex, with many class I genes located outside the complex. Novel microRNAs in the tammar HOX clusters uncover new potential mammalian HOX regulatory elements. CONCLUSIONS: Analyses of these resources enhance our understanding of marsupial gene evolution, identify marsupial-specific conserved non-coding elements and critical genes across a range of biological systems, including reproduction, development and immunity, and provide new insight into marsupial and mammalian biology and genome evolution

Genetic diversity in the modern horse illustrated from genome-wide SNP data

Horses were domesticated from the Eurasian steppes 5,000-6,000 years ago. Since then, the use of horses for transportation, warfare, and agriculture, as well as selection for desired traits and fitness, has resulted in diverse populations distributed across the world, many of which have become or are in the process of becoming formally organized into closed, breeding populations (breeds). This report describes the use of a genome-wide set of autosomal SNPs and 814 horses from 36 breeds to provide the first detailed description of equine breed diversity. F(ST) calculations, parsimony, and distance analysis demonstrated relationships among the breeds that largely reflect geographic origins and known breed histories. Low levels of population divergence were observed between breeds that are relatively early on in the process of breed development, and between those with high levels of within-breed diversity, whether due to large population size, ongoing outcrossing, or large within-breed phenotypic diversity. Populations with low within-breed diversity included those which have experienced population bottlenecks, have been under intense selective pressure, or are closed populations with long breed histories. These results provide new insights into the relationships among and the diversity within breeds of horses. In addition these results will facilitate future genome-wide association studies and investigations into genomic targets of selection

Genetic Diversity in the Modern Horse Illustrated from Genome-Wide SNP Data

Horses were domesticated from the Eurasian steppes 5,000–6,000 years ago. Since then, the use of horses for transportation, warfare, and agriculture, as well as selection for desired traits and fitness, has resulted in diverse populations distributed across the world, many of which have become or are in the process of becoming formally organized into closed, breeding populations (breeds). This report describes the use of a genome-wide set of autosomal SNPs and 814 horses from 36 breeds to provide the first detailed description of equine breed diversity. FST calculations, parsimony, and distance analysis demonstrated relationships among the breeds that largely reflect geographic origins and known breed histories. Low levels of population divergence were observed between breeds that are relatively early on in the process of breed development, and between those with high levels of within-breed diversity, whether due to large population size, ongoing outcrossing, or large within-breed phenotypic diversity. Populations with low within-breed diversity included those which have experienced population bottlenecks, have been under intense selective pressure, or are closed populations with long breed histories. These results provide new insights into the relationships among and the diversity within breeds of horses. In addition these results will facilitate future genome-wide association studies and investigations into genomic targets of selection

Insights into hominid evolution from the gorilla genome sequence.

Gorillas are humans' closest living relatives after chimpanzees, and are of comparable importance for the study of human origins and evolution. Here we present the assembly and analysis of a genome sequence for the western lowland gorilla, and compare the whole genomes of all extant great ape genera. We propose a synthesis of genetic and fossil evidence consistent with placing the human-chimpanzee and human-chimpanzee-gorilla speciation events at approximately 6 and 10 million years ago. In 30% of the genome, gorilla is closer to human or chimpanzee than the latter are to each other; this is rarer around coding genes, indicating pervasive selection throughout great ape evolution, and has functional consequences in gene expression. A comparison of protein coding genes reveals approximately 500 genes showing accelerated evolution on each of the gorilla, human and chimpanzee lineages, and evidence for parallel acceleration, particularly of genes involved in hearing. We also compare the western and eastern gorilla species, estimating an average sequence divergence time 1.75 million years ago, but with evidence for more recent genetic exchange and a population bottleneck in the eastern species. The use of the genome sequence in these and future analyses will promote a deeper understanding of great ape biology and evolution

Genetic Diversity in the Modern Horse Illustrated from Genome-Wide SNP Data

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