Showing papers by "Baylor College of Medicine published in 2009"
TL;DR: The guidelines reiterate the importance of nutrition assessment-particularly, the detection of malnourished patients who are most vulnerable and therefore may benefit from timely intervention and there is a need for renewed focus on accurate estimation of energy needs and attention to optimizing protein intake.
Abstract: This document represents the first collaboration between 2 organizations-the American Society for Parenteral and Enteral Nutrition and the Society of Critical Care Medicine-to describe best practices in nutrition therapy in critically ill children. The target of these guidelines is intended to be the pediatric critically ill patient (>1 month and 2-3 days in a PICU admitting medical, surgical, and cardiac patients. In total, 2032 citations were scanned for relevance. The PubMed/MEDLINE search resulted in 960 citations for clinical trials and 925 citations for cohort studies. The EMBASE search for clinical trials culled 1661 citations. In total, the search for clinical trials yielded 1107 citations, whereas the cohort search yielded 925. After careful review, 16 randomized controlled trials and 37 cohort studies appeared to answer 1 of the 8 preidentified question groups for this guideline. We used the GRADE criteria (Grading of Recommendations, Assessment, Development, and Evaluation) to adjust the evidence grade based on assessment of the quality of study design and execution. These guidelines are not intended for neonates or adult patients. The guidelines reiterate the importance of nutrition assessment-particularly, the detection of malnourished patients who are most vulnerable and therefore may benefit from timely intervention. There is a need for renewed focus on accurate estimation of energy needs and attention to optimizing protein intake. Indirect calorimetry, where feasible, and cautious use of estimating equations and increased surveillance for unintended caloric underfeeding and overfeeding are recommended. Optimal protein intake and its correlation with clinical outcomes are areas of great interest. The optimal route and timing of nutrient delivery are areas of intense debate and investigations. Enteral nutrition remains the preferred route for nutrient delivery. Several strategies to optimize enteral nutrition during critical illness have emerged. The role of supplemental parenteral nutrition has been highlighted, and a delayed approach appears to be beneficial. Immunonutrition cannot be currently recommended. Overall, the pediatric critical care population is heterogeneous, and a nuanced approach to individualizing nutrition support with the aim of improving clinical outcomes is necessary.
2,947 citations
Centers for Disease Control and Prevention1, University of Cambridge2, National Institutes of Health3, Erasmus University Rotterdam4, Naval Medical Center San Diego5, Arizona State University6, Colorado Department of Public Health and Environment7, Oklahoma State Department of Health8, Wadsworth Center9, Ohio Department of Health10, South Carolina Department of Health and Environmental Control11, Dallas County12, Baylor College of Medicine13, San Diego State University14, Centra15, California Health and Human Services Agency16, Marshfield Clinic17, Michigan Department of Community Health18
TL;DR: The lack of similarity between the 2009 A(H1N1) virus and its nearest relatives indicates that its gene segments have been circulating undetected for an extended period as mentioned in this paper.
Abstract: Since its identification in April 2009, an A(H1N1) virus containing a unique combination of gene segments from both North American and Eurasian swine lineages has continued to circulate in humans. The lack of similarity between the 2009 A(H1N1) virus and its nearest relatives indicates that its gene segments have been circulating undetected for an extended period. Its low genetic diversity suggests that the introduction into humans was a single event or multiple events of similar viruses. Molecular markers predictive of adaptation to humans are not currently present in 2009 A(H1N1) viruses, suggesting that previously unrecognized molecular determinants could be responsible for the transmission among humans. Antigenically the viruses are homogeneous and similar to North American swine A(H1N1) viruses but distinct from seasonal human A(H1N1).
2,393 citations
National Institutes of Health1, University of Tübingen2, University of Coimbra3, University College London4, University of Luxembourg5, University of Lübeck6, Washington University in St. Louis7, University of Bonn8, University of Florida9, University of Kiel10, Baylor College of Medicine11, Scripps Research Institute12, AARP13, Penn State Milton S. Hershey Medical Center14
TL;DR: It is demonstrated that an unequivocal role for common genetic variants in the etiology of typical PD and population-specific genetic heterogeneity in this disease is suggested, and supporting evidence that common variation around LRRK2 modulates risk for PD is provided.
Abstract: We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinson's disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we observed two strong association signals, one in the gene encoding a-synuclein (SNCA; rs2736990, OR = 1.23, P = 2.24 x 10(-16)) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 x 10(-16)). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS1, confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort (PARK16, rs823128, OR = 0.66, P = 7.29 x 10(-8)) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 x 10(-5)). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease.
1,793 citations
Dartmouth College1, Cedars-Sinai Medical Center2, HealthPartners3, University of Missouri4, Icahn School of Medicine at Mount Sinai5, Georgia Regents University6, Arizona State University7, Baylor College of Medicine8, University of Massachusetts Medical School9, University of California, San Francisco10, University of Pennsylvania11, University of Minnesota12
TL;DR: The USPSTF concludes that the current evidence is insufficient to assess additional benefits and harms of either digital mammography or magnetic resonance imaging instead of film mammography as screening modalities for breast cancer.
Abstract: Description: Update of the 2002 U. S. Preventive Services Task Force (USPSTF) recommendation statement on screening for breast cancer in the general population. Methods: The USPSTF examined the evidence on the efficacy of 5 screening modalities in reducing mortality from breast cancer: film mammography, clinical breast examination, breast self-examination, digital mammography, and magnetic resonance imaging in order to update the 2002 recommendation. To accomplish this update, the USPSTF commissioned 2 studies: 1) a targeted systematic evidence review of 6 selected questions relating to benefits and harms of screening, and 2) a decision analysis that used population modeling techniques to compare the expected health outcomes and resource requirements of starting and ending mammography screening at different ages and using annual versus biennial screening intervals. Recommendations: The USPSTF recommends against routine screening mammography in women aged 40 to 49 years. The decision to start regular, biennial screening mammography before the age of 50 years should be an individual one and take into account patient context, including the patient's values regarding specific benefits and harms. (Grade C recommendation) The USPSTF recommends biennial screening mammography for women between the ages of 50 and 74 years. (Grade B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the additional benefits and harms of screening mammography in women 75 years or older. (I statement) The USPSTF concludes that the current evidence is insufficient to assess the additional benefits and harms of clinical breast examination beyond screening mammography in women 40 years or older. (I statement) The USPSTF recommends against clinicians teaching women how to perform breast self-examination. (Grade D recommendation) The USPSTF concludes that the current evidence is insufficient to assess additional benefits and harms of either digital mammography or magnetic resonance imaging instead of film mammography as screening modalities for breast cancer. (I statement)
1,405 citations
TL;DR: Supporting evidence is provided that the residual breast tumor cell populations surviving after conventional treatment may be enriched for subpopulations of cells with both tumor-initiating and mesenchymal features.
Abstract: Some breast cancers have been shown to contain a small fraction of cells characterized by CD44+/CD24−/low cell-surface antigen profile that have high tumor-initiating potential. In addition, breast cancer cells propagated in vitro as mammospheres (MSs) have also been shown to be enriched for cells capable of self-renewal. In this study, we have defined a gene expression signature common to both CD44+/CD24−/low and MS-forming cells. To examine its clinical significance, we determined whether tumor cells surviving after conventional treatments were enriched for cells bearing this CD44+/CD24−/low-MS signature. The CD44+/CD24−/low-MS signature was found mainly in human breast tumors of the recently identified “claudin-low” molecular subtype, which is characterized by expression of many epithelial-mesenchymal-transition (EMT)-associated genes. Both CD44+/CD24−/low-MS and claudin-low signatures were more pronounced in tumor tissue remaining after either endocrine therapy (letrozole) or chemotherapy (docetaxel), consistent with the selective survival of tumor-initiating cells posttreatment. We confirmed an increased expression of mesenchymal markers, including vimentin (VIM) in cytokeratin-positive epithelial cells metalloproteinase 2 (MMP2), in two separate sets of postletrozole vs. pretreatment specimens. Taken together, these data provide supporting evidence that the residual breast tumor cell populations surviving after conventional treatment may be enriched for subpopulations of cells with both tumor-initiating and mesenchymal features. Targeting proteins involved in EMT may provide a therapeutic strategy for eliminating surviving cells to prevent recurrence and improve long-term survival in breast cancer patients.
1,337 citations
Veterans Health Administration1, Northwestern University2, University of Nebraska Omaha3, University of Pennsylvania4, University of California, San Francisco5, University of Michigan6, National Institutes of Health7, University of Kansas8, Oregon Health & Science University9, Portland VA Medical Center10, United States Department of Veterans Affairs11, Baylor College of Medicine12, Virginia Commonwealth University13, University of Iowa14
TL;DR: Deep brain stimulation was more effective than best medical therapy in improving on time without troubling dyskinesias, motor function, and quality of life at 6 months, but was associated with an increased risk of serious adverse events.
Abstract: Context Deep brain stimulation is an accepted treatment for advanced Parkinson disease (PD), although there are few randomized trials comparing treatments, and most studies exclude older patients. Objective To compare 6-month outcomes for patients with PD who received deep brain stimulation or best medical therapy. Design, Setting, and Patients Randomized controlled trial of patients who received either deep brain stimulation or best medical therapy, stratified by study site and patient age ( Intervention Bilateral deep brain stimulation of the subthalamic nucleus (n = 60) or globus pallidus (n = 61). Patients receiving best medical therapy (n = 134) were actively managed by movement disorder neurologists. Main Outcome Measures The primary outcome was time spent in the “on” state (good motor control with unimpeded motor function) without troubling dyskinesia, using motor diaries. Other outcomes included motor function, quality of life, neurocognitive function, and adverse events. Results Patients who received deep brain stimulation gained a mean of 4.6 h/d of on time without troubling dyskinesia compared with 0 h/d for patients who received best medical therapy (between group mean difference, 4.5 h/d [95% CI, 3.7-5.4 h/d]; P Conclusion In this randomized controlled trial of patients with advanced PD, deep brain stimulation was more effective than best medical therapy in improving on time without troubling dyskinesias, motor function, and quality of life at 6 months, but was associated with an increased risk of serious adverse events. Trial Registration clinicaltrials.gov Identifier: NCT00056563
1,218 citations
TL;DR: Current models of the mechanisms that cause copy number variation focus on perturbation of DNA replication and replication of non-contiguous DNA segments and cellular stress might induce repair of broken replication forks to switch from high-fidelity homologous recombination to non-homologous repair, thus promoting copy number change.
Abstract: Deletions and duplications of chromosomal segments (copy number variants, CNVs) are a major source of variation between individual humans and are an underlying factor in human evolution and in many diseases, including mental illness, developmental disorders and cancer CNVs form at a faster rate than other types of mutation, and seem to do so by similar mechanisms in bacteria, yeast and humans Here we review current models of the mechanisms that cause copy number variation Non-homologous end-joining mechanisms are well known, but recent models focus on perturbation of DNA replication and replication of non-contiguous DNA segments For example, cellular stress might induce repair of broken replication forks to switch from high-fidelity homologous recombination to non-homologous repair, thus promoting copy number change
1,169 citations
Christine G. Elsik1, Christine G. Elsik2, Christine G. Elsik3, Ross L. Tellam3 +325 more•Institutions (65)
TL;DR: To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage and provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.
Abstract: To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.
1,144 citations
TL;DR: The updated STAIR preclinical recommendations reinforce the previous suggestions that reproducibly defining dose response and time windows with both histological and functional outcomes in multiple animal species with appropriate physiological monitoring is appropriate.
Abstract: The initial Stroke Therapy Academic Industry Roundtable (STAIR) recommendations published in 1999 were intended to improve the quality of preclinical studies of purported acute stroke therapies Although recognized as reasonable, they have not been closely followed nor rigorously validated Substantial advances have occurred regarding the appropriate quality and breadth of preclinical testing for candidate acute stroke therapies for better clinical translation The updated STAIR preclinical recommendations reinforce the previous suggestions that reproducibly defining dose response and time windows with both histological and functional outcomes in multiple animal species with appropriate physiological monitoring is appropriate The updated STAIR recommendations include: the fundamentals of good scientific inquiry should be followed by eliminating randomization and assessment bias, a priori defining inclusion/exclusion criteria, performing appropriate power and sample size calculations, and disclosing potential conflicts of interest After initial evaluations in young, healthy male animals, further studies should be performed in females, aged animals, and animals with comorbid conditions such as hypertension, diabetes, and hypercholesterolemia Another consideration is the use of clinically relevant biomarkers in animal studies Although the recommendations cannot be validated until effective therapies based on them emerge from clinical trials, it is hoped that adherence to them might enhance the chances for success
1,127 citations
TL;DR: Copy number variation, especially gene duplication and exon shuffling, can be a predominant mechanism driving gene and genome evolution and appear much higher for CNVs than for SNPs.
Abstract: Copy number variation (CNV) is a source of genetic diversity in humans. Numerous CNVs are being identified with various genome analysis platforms, including array comparative genomic hybridization (aCGH), single nucleotide polymorphism (SNP) genotyping platforms, and next-generation sequencing. CNV formation occurs by both recombination-based and replication-based mechanisms and de novo locus-specific mutation rates appear much higher for CNVs than for SNPs. By various molecular mechanisms, including gene dosage, gene disruption, gene fusion, position effects, etc., CNVs can cause Mendelian or sporadic traits, or be associated with complex diseases. However, CNV can also represent benign polymorphic variants. CNVs, especially gene duplication and exon shuffling, can be a predominant mechanism driving gene and genome evolution.
1,100 citations
Colorado Department of Public Health and Environment1, Agency for Healthcare Research and Quality2, Arizona State University3, Cincinnati Children's Hospital Medical Center4, Dartmouth College5, Cedars-Sinai Medical Center6, Group Health Cooperative7, Regions Hospital8, University of Missouri9, Icahn School of Medicine at Mount Sinai10, Georgia Regents University11, Baylor College of Medicine12, University of Massachusetts Medical School13, University of California, San Francisco14, University of Pennsylvania15, University of Minnesota16
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TL;DR: The discovery of disease-causing mutations in RNAs is yielding a wealth of new therapeutic targets, and the growing understanding of RNA biology and chemistry is providing new RNA-based tools for developing therapeutics.
TL;DR: The results of both experimental and clinical studies indicate that Arg is a nutritionally essential amino acid (AA) for spermatogenesis, embryonic survival, fetal and neonatal growth, as well as maintenance of vascular tone and hemodynamics and novel and effective therapies for obesity, diabetes, and the metabolic syndrome.
Abstract: l-Arginine (Arg) is synthesised from glutamine, glutamate, and proline via the intestinal-renal axis in humans and most other mammals (including pigs, sheep and rats). Arg degradation occurs via multiple pathways that are initiated by arginase, nitric-oxide synthase, Arg:glycine amidinotransferase, and Arg decarboxylase. These pathways produce nitric oxide, polyamines, proline, glutamate, creatine, and agmatine with each having enormous biological importance. Arg is also required for the detoxification of ammonia, which is an extremely toxic substance for the central nervous system. There is compelling evidence that Arg regulates interorgan metabolism of energy substrates and the function of multiple organs. The results of both experimental and clinical studies indicate that Arg is a nutritionally essential amino acid (AA) for spermatogenesis, embryonic survival, fetal and neonatal growth, as well as maintenance of vascular tone and hemodynamics. Moreover, a growing body of evidence clearly indicates that dietary supplementation or intravenous administration of Arg is beneficial in improving reproductive, cardiovascular, pulmonary, renal, gastrointestinal, liver and immune functions, as well as facilitating wound healing, enhancing insulin sensitivity, and maintaining tissue integrity. Additionally, Arg or l-citrulline may provide novel and effective therapies for obesity, diabetes, and the metabolic syndrome. The effect of Arg in treating many developmental and health problems is unique among AAs, and offers great promise for improved health and wellbeing of humans and animals.
TL;DR: Liraglutide is safe and effective as initial pharmacological therapy for type 2 diabetes mellitus and leads to greater reductions in HbA(1c), weight, hypoglycaemia, and blood pressure than does glimepiride.
TL;DR: A pathway involving the mitotic kinase PLK1, the anaphase-promoting complex/cyclosome, and the proteasome that, when inhibited, results in prometaphase accumulation and the subsequent death of Ras mutant cells is described.
TL;DR: This work has developed an efficient bisulfite reads mapping algorithm BSMAP, which is able to map high-throughput bisulfITE reads at whole genome level with feasible memory and CPU usage.
Abstract: Bisulfite sequencing is a powerful technique to study DNA cytosine methylation. Bisulfite treatment followed by PCR amplification specifically converts unmethylated cytosines to thymine. Coupled with next generation sequencing technology, it is able to detect the methylation status of every cytosine in the genome. However, mapping high-throughput bisulfite reads to the reference genome remains a great challenge due to the increased searching space, reduced complexity of bisulfite sequence, asymmetric cytosine to thymine alignments, and multiple CpG heterogeneous methylation. We developed an efficient bisulfite reads mapping algorithm BSMAP to address the above issues. BSMAP combines genome hashing and bitwise masking to achieve fast and accurate bisulfite mapping. Compared with existing bisulfite mapping approaches, BSMAP is faster, more sensitive and more flexible. BSMAP is the first general-purpose bisulfite mapping software. It is able to map high-throughput bisulfite reads at whole genome level with feasible memory and CPU usage. It is freely available under GPL v3 license at http://code.google.com/p/bsmap/
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TL;DR: Cleveland Clinic, Department of Cardiovascular Medicine, Cleveland, OH, Ohio State University, Division of ardiovascular Medicine, Columbus, Ohio, Broward General Medical Center, Fort Lauderdale, FL, University Hospital, ivision of cardiovascular medicine, Pisa, Italy, University of Miami, Cardiothoracic Surgery, Miami, FL as discussed by the authors, St. Thomas esearch Institute and Providence St. Joseph Medical enter, Burbank, CA, American Heart Association Representative.
TL;DR: The role of AR in androgen-independent cancer cells is not to direct the androgen -dependent gene expression program without androgen, but rather to execute a distinct program resulting in androgens-independent growth.
TL;DR: A clear definition of PNI is laid out to highlight its significance in those malignancies in which it has been studied best and current research models that are leading to advancements in the understanding of this metastatic process are introduced.
Abstract: Perineural invasion (PNI) is the process of neoplastic invasion of nerves and is an under-recognized route of metastatic spread. It is emerging as an important pathologic feature of many malignancies, including those of the pancreas, colon and rectum, prostate, head and neck, biliary tract, and stomach. For many of these malignancies, PNI is a marker of poor outcome and a harbinger of decreased survival. PNI is a distinct pathologic entity that can be observed in the absence of lymphatic or vascular invasion. It can be a source of distant tumor spread well beyond the extent of any local invasion; and, for some tumors, PNI may be the sole route of metastatic spread. Despite increasing recognition of this metastatic process, there has been little progress in the understanding of molecular mechanisms behind PNI and, to date, no targeted treatment modalities aimed at this pathologic entity. The objectives of this review were to lay out a clear definition of PNI to highlight its significance in those malignancies in which it has been studied best. The authors also summarized current theories on the molecular mediators and pathogenesis of PNI and introduced current research models that are leading to advancements in the understanding of this metastatic process.
TL;DR: An algorithm (mrFAST) is presented to comprehensively map next-generation sequence reads, which allows for the prediction of absolute copy-number variation of duplicated segments and genes, and can distinguish between different copies of highly identical genes.
Abstract: Despite their importance in gene innovation and phenotypic variation, duplicated regions have remained largely intractable owing to difficulties in accurately resolving their structure, copy number and sequence content. We present an algorithm (mrFAST) to comprehensively map next-generation sequence reads, which allows for the prediction of absolute copy-number variation of duplicated segments and genes. We examine three human genomes and experimentally validate genome-wide copy number differences. We estimate that, on average, 73-87 genes vary in copy number between any two individuals and find that these genic differences overwhelmingly correspond to segmental duplications (odds ratio = 135; P < 2.2 x 10(-16)). Our method can distinguish between different copies of highly identical genes, providing a more accurate assessment of gene content and insight into functional constraint without the limitations of array-based technology.
TL;DR: The results show that maintenance of the ovarian phenotype is an active process throughout life and might have important medical implications for the understanding and treatment of some disorders of sexual development in children and premature menopause in women.
Baylor College of Medicine1, University of Missouri2, United States Department of Agriculture3, University of New England (United States)4, Commonwealth Scientific and Industrial Research Organisation5, Texas A&M University6, Norwegian University of Life Sciences7, George Mason University8, AgResearch9, Catholic University of the Sacred Heart10, International Atomic Energy Agency11, Empresa Brasileira de Pesquisa Agropecuária12, Sao Paulo State University13, International Livestock Research Institute14, Parco Tecnologico Padano15, University of Edinburgh16, Ethiopian Institute of Agricultural Research17, Livestock Improvement Corporation18, Cornell University19, University of Alberta20, Tuscia University21, Wellcome Trust Sanger Institute22, Government of Victoria23, University of Melbourne24, Trinity College, Dublin25, Simon Fraser University26
TL;DR: Data show that cattle have undergone a rapid recent decrease in effective population size from a very large ancestral population, possibly due to bottlenecks associated with domestication, selection, and breed formation.
Abstract: The imprints of domestication and breed development on the genomes of livestock likely differ from those of companion animals. A deep draft sequence assembly of shotgun reads from a single Hereford female and comparative sequences sampled from six additional breeds were used to develop probes to interrogate 37,470 single-nucleotide polymorphisms (SNPs) in 497 cattle from 19 geographically and biologically diverse breeds. These data show that cattle have undergone a rapid recent decrease in effective population size from a very large ancestral population, possibly due to bottlenecks associated with domestication, selection, and breed formation. Domestication and artificial selection appear to have left detectable signatures of selection within the cattle genome, yet the current levels of diversity within breeds are at least as great as exists within humans.
University of Texas MD Anderson Cancer Center1, French Institute of Health and Medical Research2, Umeå University3, University of Bonn4, Karolinska Institutet5, University of Zurich6, German Cancer Research Center7, University of Leeds8, Baylor College of Medicine9, University of Nottingham10, Council on Education for Public Health11
TL;DR: Meta-analysis of two genome-wide association studies by genotyping 550K tagging SNPs shows that common low-penetrance susceptibility alleles contribute to the risk of developing glioma and provide insight into disease causation of this primary brain tumor.
Abstract: To identify risk variants for glioma, we conducted a meta-analysis of two genome-wide association studies by genotyping 550K tagging SNPs in a total of 1,878 cases and 3,670 controls, with validation in three additional independent series totaling 2,545 cases and 2,953 controls. We identified five risk loci for glioma at 5p15.33 (rs2736100, TERT; P = 1.50 x 10(-17)), 8q24.21 (rs4295627, CCDC26; P = 2.34 x 10(-18)), 9p21.3 (rs4977756, CDKN2A-CDKN2B; P = 7.24 x 10(-15)), 20q13.33 (rs6010620, RTEL1; P = 2.52 x 10(-12)) and 11q23.3 (rs498872, PHLDB1; P = 1.07 x 10(-8)). These data show that common low-penetrance susceptibility alleles contribute to the risk of developing glioma and provide insight into disease causation of this primary brain tumor.
TL;DR: It is proposed that breakage of replication forks in stressed cells that are deficient in homologous recombination induces an aberrant repair process with features of break-induced replication (BIR) that will anneal with microhomology on any single-stranded DNA nearby, priming low-processivity polymerization with multiple template switches generating complex rearrangements, and eventual re-establishment of processive replication.
Abstract: Chromosome structural changes with nonrecurrent endpoints associated with genomic disorders offer windows into the mechanism of origin of copy number variation (CNV). A recent report of nonrecurrent duplications associated with Pelizaeus-Merzbacher disease identified three distinctive characteristics. First, the majority of events can be seen to be complex, showing discontinuous duplications mixed with deletions, inverted duplications, and triplications. Second, junctions at endpoints show microhomology of 2–5 base pairs (bp). Third, endpoints occur near pre-existing low copy repeats (LCRs). Using these observations and evidence from DNA repair in other organisms, we derive a model of microhomology-mediated break-induced replication (MMBIR) for the origin of CNV and, ultimately, of LCRs. We propose that breakage of replication forks in stressed cells that are deficient in homologous recombination induces an aberrant repair process with features of break-induced replication (BIR). Under these circumstances, single-strand 3′ tails from broken replication forks will anneal with microhomology on any single-stranded DNA nearby, priming low-processivity polymerization with multiple template switches generating complex rearrangements, and eventual re-establishment of processive replication.
TL;DR: Early treatment with rasagiline at a dose of 1 mg per day provided benefits that were consistent with a possible disease-modifying effect, but early treatment with the two doses were associated with different outcomes, the study results must be interpreted with caution.
Abstract: In this double-blind trial, we examined the possibility that rasagiline has diseasemodifying effects in Parkinson’s disease. A total of 1176 subjects with untreated Parkinson’s disease were randomly assigned to receive rasagiline (at a dose of either 1 mg or 2 mg per day) for 72 weeks (the early-start group) or placebo for 36 weeks followed by rasagiline (at a dose of either 1 mg or 2 mg per day) for 36 weeks (the delayed-start group). To determine a positive result with either dose, the early-start treatment group had to meet each of three hierarchical end points of the primary analysis based on the Unified Parkinson’s Disease Rating Scale (UPDRS, a 176-point scale, with higher numbers indicating more severe disease): superiority to placebo in the rate of change in the UPDRS score between weeks 12 and 36, superiority to delayed-start treatment in the change in the score between baseline and week 72, and noninferiority to delayed-start treatment in the rate of change in the score between weeks 48 and 72. Results Early-start treatment with rasagiline at a dose of 1 mg per day met all end points in the primary analysis: a smaller mean (±SE) increase (rate of worsening) in the UPDRS score between weeks 12 and 36 (0.09±0.02 points per week in the early-start group vs. 0.14±0.01 points per week in the placebo group, P = 0.01), less worsening in the score between baseline and week 72 (2.82±0.53 points in the early-start group vs. 4.52±0.56 points in the delayed-start group, P = 0.02), and noninferiority between the two groups with respect to the rate of change in the UPDRS score between weeks 48 and 72 (0.085±0.02 points per week in the early-start group vs. 0.085±0.02 points per week in the delayed-start group, P<0.001). All three end points were not met with rasagiline at a dose of 2 mg per day, since the change in the UPDRS score between baseline and week 72 was not significantly different in the two groups (3.47±0.50 points in the earlystart group and 3.11±0.50 points in the delayed-start group, P = 0.60). Conclusions Early treatment with rasagiline at a dose of 1 mg per day provided benefits that were consistent with a possible disease-modifying effect, but early treatment with rasagiline at a dose of 2 mg per day did not. Because the two doses were associated with different outcomes, the study results must be interpreted with caution. (ClinicalTrials. gov number, NCT00256204.)
TL;DR: More recent successes of applying PLGA-based nanotechnologies and tools in medicine-related applications are presented and the possible mechanisms, diagnosis and treatment effects of PLGA preparations and devices are focused on.
Abstract: Co-polymer poly(lactic-co-glycolic acid) (PLGA) nanotechnology has been developed for many years and has been approved by the US FDA for the use of drug delivery, diagnostics and other applications of clinical and basic science research, including cardiovascular disease, cancer, vaccine and tissue engineering. This article presents the more recent successes of applying PLGA-based nanotechnologies and tools in these medicine-related applications. It focuses on the possible mechanisms, diagnosis and treatment effects of PLGA preparations and devices. This updated information will benefit to both new and established research scientists and clinical physicians who are interested in the development and application of PLGA nanotechnology as new therapeutic and diagnostic strategies for many diseases.
TL;DR: These guidelines were developed under the auspices of the American College of Gastroenterology by a committee of experts in the field, reviewed by its Practice Parameters Committee, and approved by the Board of Trustees to be considered valid at the time of production based on the data available.
TL;DR: Bone regions measured were the lumbar spine, hip, tibia, forearm, calcaneus, total body, and segmental regions from the total‐body scan, and potential redistribution of bone mineral was observed: during bed rest the bone mineral increased in the skull of all subjects.
Abstract: The purpose of this work was to determine the rate and extent of bone loss and recovery from long-term disuse and in particular from disuse after exposure to weightlessness. For this purpose, bed rest is used to simulate the reduced stress and strain on the skeleton. This study reports on the bone loss and recovery after 17 weeks of continuous bed rest and 6 months of reambulation in six normal male volunteers. Bone regions measured were the lumbar spine, hip, tibia, forearm, calcaneus, total body, and segmental regions from the total-body scan. The total body, lumbar spine, femoral neck, trochanter, tibia, and calcaneus demonstrated significant loss, p less than 0.05. Expressed as the percentage change from baseline, these were 1.4, 3.9, 3.6, 4.6, 2.2, and 10.4, respectively. Although several areas showed positive slopes during reambulation, only the calcaneus was significant (p less than 0.05), with nearly 100% recovery. Segmental analysis of the total-body scans showed significant loss (p less than 0.05) in the lumbar spine, total spine, pelvis, trunk, and legs. During reambulation, the majority of the regions demonstrated positive slopes, although only the pelvis and trunk were significant (p less than 0.05). Potential redistribution of bone mineral was observed: during bed rest the bone mineral increased in the skull of all subjects. The change in total BMD and calcium from calcium balance were significantly (p less than 0.05) correlated, R = 0.88.
Queen Mary University of London1, University Medical Center Freiburg2, University of St. Gallen3, Dartmouth College4, Baylor College of Medicine5, Newcastle University6, National Institutes of Health7, Queen Mary's College8, University of Oxford9, Mario Negri Institute for Pharmacological Research10, University of California, Irvine11, American Cancer Society12
TL;DR: Aspirin has emerged as the most likely NSAID for use in chemoprevention because of its known cardiovascular benefit and available safety and efficacy data, and coadministration of aspirin with a proton-pump inhibitor is an attractive option.
Abstract: Evidence clearly shows a chemopreventive effect for aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) on colorectal cancer and probably other cancer types; however, data on the risk-benefit profile for cancer prevention are insufficient and no definitive recommendations can be made. Aspirin has emerged as the most likely NSAID for use in chemoprevention because of its known cardiovascular benefit and available safety and efficacy data. Other traditional NSAIDs, particularly sulindac, and selective COX-2 inhibitors are now given to patients at high risk of colorectal cancer, although these drugs do not provide cardioprotection. More studies of aspirin and cancer prevention are needed to define the lowest effective dose, the age at which to initiate therapy, the optimum treatment duration, and the subpopulations for which the benefits of chemoprevention outweigh the risks of adverse side-effects. Although it might be possible to answer some of these questions with longer follow-up of existing clinical trials, randomised controlled trials with new study designs will be needed. Future projects should investigate the effects of aspirin treatment on multiple organ systems. Cancers of interest are colorectal, breast, prostate, lung, stomach, and oesophageal. The main side-effect of aspirin is peptic ulcers; therefore coadministration of aspirin with a proton-pump inhibitor is an attractive option and is under investigation in the AspECT trial.
Pennsylvania State University1, Otto-von-Guericke University Magdeburg2, University of Ferrara3, Johns Hopkins University4, University of Pennsylvania5, SUNY Downstate Medical Center6, Cornell University7, Cardiff University8, University of Chile9, University of Buenos Aires10, Kyoto University11, Federal University of Rio de Janeiro12, Women's College, Kolkata13, Baylor College of Medicine14
TL;DR: This update reviews new information about acne pathophysiology and treatment-such as lasers and light therapy-and relevant topics where published data were sparse in 2003 but are now available including combination therapy, revision of acne scarring, and maintenance therapy.
Abstract: The Global Alliance to Improve Outcomes in Acne published recommendations for the management of acne as a supplement to the Journal of the American Academy of Dermatology in 2003. The recommendations incorporated evidence-based strategies when possible and the collective clinical experience of the group when evidence was lacking. This update reviews new information about acne pathophysiology and treatment–such as lasers and light therapy–and relevant topics where published data were sparse in 2003 but are now available including combination therapy, revision of acne scarring, and maintenance therapy. The update also includes a new way of looking at acne as a chronic disease, a discussion of the changing role of antibiotics in acne management as a result of concerns about microbial resistance, and factors that affect adherence to acne treatments. Summary statements and recommendations are provided throughout the update along with an indication of the level of evidence that currently supports each finding. As in the original supplement, the authors have based recommendations on published evidence as much as possible.