Low Bone Turnover in Chronic Kidney Disease is associated with decreased VEGF-A expression and osteoblast differentiation

Background: Low turnover bone (low bone formation rates (BFRs)) with decreased osteoblast number is common in patients with chronic kidney disease (CKD) and attributed to ‘over-suppression' of the parathyroid hormone (PTH) despite supra-physiologic levels. An alternative hypothesis is abnormal osteoblast differentiation, resulting in low BFRs due to reduced VEGF-A. Methods: We analyzed the expression of VEGF-A and mesenchymal stem cell (MSC) differentiation factors in freshly isolated bone marrow (BM) cells, and in BM cell-derived MSC in rats with different levels of BFRs and PTH (modulated by calcium and zoledronic acid). The regulators of VEGF in MSC were also determined. Results: VEGF-A expression was reduced in the BM cells from CKD vs. normal animals (p < 0.02). In BM-derived MSC from CKD, there were decreased osteoblast transcription factors and mineralization. In CKD animals, the BM VEGF-A expression was positively correlated with BFR (r = 0.80, p < 0.001). Reducing BFRs in CKD animals led to reductions in VEGF-A expression and osteoblast transcription factors regardless of the PTH level. We therefore examined other regulators of VEGF-A and found decreased expression of hypoxia-inducible factor-1α and the master transcription factor of antioxidants nuclear factor (erythroid-derived 2)-like 2 in CKD animals with low PTH. Conclusion: Low BFRs in CKD are associated with a basal decrease in VEGF-A expression in BM that may be driven by altered hypoxia and oxidative stress

Automating the packing heuristic design process with genetic programming

The literature shows that one-, two-, and three-dimensional bin packing and knapsack packing are difficult problems in operational research. Many techniques, including exact, heuristic, and metaheuristic approaches, have been investigated to solve these problems and it is often not clear which method to use when presented with a new instance. This paper presents an approach which is motivated by the goal of building computer systems which can design heuristic methods. The overall aim is to explore the possibilities for automating the heuristic design process. We present a genetic programming system to automatically generate a good quality heuristic for each instance. It is not necessary to change the methodology depending on the problem type (one-, two-, or three-dimensional knapsack and bin packing problems), and it therefore has a level of generality unmatched by other systems in the literature. We carry out an extensive suite of experiments and compare with the best human designed heuristics in the literature. Note that our heuristic design methodology uses the same parameters for all the experiments. The contribution of this paper is to present a more general packing methodology than those currently available, and to show that, by using this methodology, it is possible for a computer system to design heuristics which are competitive with the human designed heuristics from the literature. This represents the first packing algorithm in the literature able to claim human competitive results in such a wide variety of packing domains

Association of cannabis with glutamatergic levels in patients with early psychosis: Evidence for altered volume striatal glutamate relationships in patients with a history of cannabis use in early psychosis

The associative striatum, an established substrate in psychosis, receives widespread glutamatergic projections. We sought to see if glutamatergic indices are altered between early psychosis patients with and without a history of cannabis use and characterise the relationship to grey matter. 92 participants were scanned: Early Psychosis with a history of cannabis use (EPC\u2009=\u200929); Early Psychosis with minimal cannabis use (EPMC\u2009=\u200925); Controls with a history of cannabis use (HCC\u2009=\u200916) and Controls with minimal use (HCMC\u2009=\u200922). Whole brain T1 weighted MR images and localised proton MR spectra were acquired from head of caudate, anterior cingulate and hippocampus. We examined relationships in regions with known high cannabinoid 1 receptor (CB1R) expression (grey matter, cortex, hippocampus, amygdala) and low expression (white matter, ventricles, brainstem) to caudate Glutamine+Glutamate (Glx). Patients were well matched in symptoms, function and medication. There was no significant group difference in Glx in any region. In EPC grey matter volume explained 31.9% of the variance of caudate Glx (p\u2009=\u20090.003) and amygdala volume explained 36.9% (p\u2009=\u20090.001) of caudate Glx. There was no significant relationship in EPMC. The EPC vs EPMC interaction was significant (p\u2009=\u20090.042). There was no such relationship in control regions. These results are the first to demonstrate association of grey matter volume and striatal glutamate in the EPC group. This may suggest a history of cannabis use leads to a conformational change in distal CB1 rich grey matter regions to influence striatal glutamatergic levels or that such connectivity predisposes to heavy cannabis use

Association of cannabis with glutamatergic levels in patients with early psychosis: Evidence for altered volume striatal glutamate relationships in patients with a history of cannabis use in early psychosis

he associative striatum, an established substrate in psychosis, receives widespread glutamatergic projections. We sought to see if glutamatergic indices are altered between early psychosis patients with and without a history of cannabis use and characterise the relationship to grey matter. 92 participants were scanned: Early Psychosis with a history of cannabis use (EPC = 29); Early Psychosis with minimal cannabis use (EPMC = 25); Controls with a history of cannabis use (HCC = 16) and Controls with minimal use (HCMC = 22). Whole brain T1 weighted MR images and localised proton MR spectra were acquired from head of caudate, anterior cingulate and hippocampus. We examined relationships in regions with known high cannabinoid 1 receptor (CB1R) expression (grey matter, cortex, hippocampus, amygdala) and low expression (white matter, ventricles, brainstem) to caudate Glutamine+Glutamate (Glx). Patients were well matched in symptoms, function and medication. There was no significant group difference in Glx in any region. In EPC grey matter volume explained 31.9% of the variance of caudate Glx (p = 0.003) and amygdala volume explained 36.9% (p = 0.001) of caudate Glx. There was no significant relationship in EPMC. The EPC vs EPMC interaction was significant (p = 0.042). There was no such relationship in control regions. These results are the first to demonstrate association of grey matter volume and striatal glutamate in the EPC group. This may suggest a history of cannabis use leads to a conformational change in distal CB1 rich grey matter regions to influence striatal glutamatergic levels or that such connectivity predisposes to heavy cannabis use

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

The Back Pain Consortium (BACPAC) Research Program Data Harmonization: Rationale for Data Elements and Standards

ObjectiveOne aim of the Back Pain Consortium (BACPAC) Research Program is to develop an integrated model of chronic low back pain that is informed by combined data from translational research and clinical trials. We describe efforts to maximize data harmonization and accessibility to facilitate Consortium-wide analyses.MethodsConsortium-wide working groups established harmonized data elements to be collected in all studies and developed standards for tabular and nontabular data (eg, imaging and omics). The BACPAC Data Portal was developed to facilitate research collaboration across the Consortium.ResultsClinical experts developed the BACPAC Minimum Dataset with required domains and outcome measures to be collected by use of questionnaires across projects. Other nonrequired domain-specific measures are collected by multiple studies. To optimize cross-study analyses, a modified data standard was developed on the basis of the Clinical Data Interchange Standards Consortium Study Data Tabulation Model to harmonize data structures and facilitate integration of baseline characteristics, participant-reported outcomes, chronic low back pain treatments, clinical exam, functional performance, psychosocial characteristics, quantitative sensory testing, imaging, and biomechanical data. Standards to accommodate the unique features of chronic low back pain data were adopted. Research units submit standardized study data to the BACPAC Data Portal, developed as a secure cloud-based central data repository and computing infrastructure for researchers to access and conduct analyses on data collected by or acquired for BACPAC.ConclusionsBACPAC harmonization efforts and data standards serve as an innovative model for data integration that could be used as a framework for other consortia with multiple, decentralized research programs

The Surgical Infection Society revised guidelines on the management of intra-abdominal infection

Background: Previous evidence-based guidelines on the management of intra-abdominal infection (IAI) were published by the Surgical Infection Society (SIS) in 1992, 2002, and 2010. At the time the most recent guideline was released, the plan was to update the guideline every five years to ensure the timeliness and appropriateness of the recommendations. Methods: Based on the previous guidelines, the task force outlined a number of topics related to the treatment of patients with IAI and then developed key questions on these various topics. All questions were approached using general and specific literature searches, focusing on articles and other information published since 2008. These publications and additional materials published before 2008 were reviewed by the task force as a whole or by individual subgroups as to relevance to individual questions. Recommendations were developed by a process of iterative consensus, with all task force members voting to accept or reject each recommendation. Grading was based on the GRADE (Grades of Recommendation Assessment, Development, and Evaluation) system; the quality of the evidence was graded as high, moderate, or weak, and the strength of the recommendation was graded as strong or weak. Review of the document was performed by members of the SIS who were not on the task force. After responses were made to all critiques, the document was approved as an official guideline of the SIS by the Executive Council. Results: This guideline summarizes the current recommendations developed by the task force on the treatment of patients who have IAI. Evidence-based recommendations have been made regarding risk assessment in individual patients; source control; the timing, selection, and duration of antimicrobial therapy; and suggested approaches to patients who fail initial therapy. Additional recommendations related to the treatment of pediatric patients with IAI have been included. Summary: The current recommendations of the SIS regarding the treatment of patients with IAI are provided in this guideline

Effect of Advanced Glycation End‐Products (AGE) Lowering Drug ALT‐711 on Biochemical, Vascular, and Bone Parameters in a Rat Model of CKD‐MBD

Chronic kidney disease–mineral bone disorder (CKD‐MBD) is a systemic disorder that affects blood measures of bone and mineral homeostasis, vascular calcification, and bone. We hypothesized that the accumulation of advanced glycation end‐products (AGEs) in CKD may be responsible for the vascular and bone pathologies via alteration of collagen. We treated a naturally occurring model of CKD‐MBD, the Cy/+ rat, with a normal and high dose of the AGE crosslink breaker alagebrium (ALT‐711), or with calcium in the drinking water to mimic calcium phosphate binders for 10 weeks. These animals were compared to normal (NL) untreated animals. The results showed that CKD animals, compared to normal animals, had elevated blood urea nitrogen (BUN), PTH, FGF23 and phosphorus. Treatment with ALT‐711 had no effect on kidney function or PTH, but 3 mg/kg lowered FGF23 whereas calcium lowered PTH. Vascular calcification of the aorta assessed biochemically was increased in CKD animals compared to NL, and decreased by the normal, but not high dose of ALT‐711, with parallel decreases in left ventricular hypertrophy. ALT‐711 (3 mg/kg) did not alter aorta AGE content, but reduced aorta expression of receptor for advanced glycation end products (RAGE) and NADPH oxidase 2 (NOX2), suggesting effects related to decreased oxidative stress at the cellular level. The elevated total bone AGE was decreased by 3 mg/kg ALT‐711 and both bone AGE and cortical porosity were decreased by calcium treatment, but only calcium improved bone properties. In summary, treatment of CKD‐MBD with an AGE breaker ALT‐711, decreased FGF23, reduced aorta calcification, and reduced total bone AGE without improvement of bone mechanics. These results suggest little effect of ALT‐711 on collagen, but potential cellular effects. The data also highlights the need to better measure specific types of AGE proteins at the tissue level in order to fully elucidate the impact of AGEs on CKD‐MBD. © 2019 American Society for Bone and Mineral Research

Modulation of Drosophila Retinal Epithelial Integrity by the Adhesion Proteins Capricious and Tartan

Background The development of the Drosophila eye imaginal disc requires complex epithelial rearrangements. Cells of the morphogenetic furrow are apically constricted and this leads to a physical indentation in the epithelium. Posterior to the furrow, cells start to rearrange into distinct clusters and eventually form a precisely patterned array of ommatidia. These morphogenetic processes include regulated changes of adhesion between cells. Methodology/Principal Findings Here, we show that two transmembrane adhesion proteins, Capricious and Tartan, have dynamic and complementary expression patterns in the eye imaginal disc. We also describe novel null mutations in capricious and double null mutations in capricious and tartan. We report that they have redundant functions in regulating the architecture of the morphogenetic furrow and ommatidial spacing. Conclusions/Significance We conclude that Capricious and Tartan contribute to the adhesive properties of the cells in the morphogenetic furrow and that this regulated adhesion participates in the control of spacing ommatidial clusters