Risk of Cardiovascular Disease and Death in Individuals With Prediabetes Defined by Different Criteria: The Whitehall II Study

OBJECTIVE: We compared the risk of cardiovascular disease (CVD) and all-cause mortality in subgroups of prediabetes defined by fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), or HbA1c. RESEARCH DESIGN AND METHODS: In the Whitehall II cohort, 5,427 participants aged 50–79 years and without diabetes were followed for a median of 11.5 years. A total of 628 (11.6%) had prediabetes by the World Health Organization (WHO)/International Expert Committee (IEC) criteria (FPG 6.1–6.9 mmol/L and/or HbA1c 6.0–6.4%), and 1,996 (36.8%) by the American Diabetes Association (ADA) criteria (FPG 5.6–6.9 mmol/L and/or HbA1c 5.7–6.4%). In a subset of 4,730 individuals with additional measures of 2hPG, 663 (14.0%) had prediabetes by 2hPG. Incidence rates of a major event (nonfatal/fatal CVD or all-cause mortality) were compared for different definitions of prediabetes, with adjustment for relevant confounders. RESULTS: Compared with that for normoglycemia, incidence rate in the context of prediabetes was 54% higher with the WHO/IEC definition and 37% higher with the ADA definition (P < 0.001) but declining to 17% and 12% after confounder adjustment (P ≥ 0.111). Prediabetes by HbA1c was associated with a doubling in incidence rate for both the IEC and ADA criteria. However, upon adjustment, excess risk was reduced to 13% and 17% (P ≥ 0.055), respectively. Prediabetes by FPG or 2hPG was not associated with an excess risk in the adjusted analysis. CONCLUSIONS: Prediabetes defined by HbA1c was associated with a worse prognosis than prediabetes defined by FPG or 2hPG. However, the excess risk among individuals with prediabetes is mainly explained by the clustering of other cardiometabolic risk factors associated with hyperglycemia

Eradication of chronic myeloid leukemia stem cells: a novel mathematical model predicts no therapeutic benefit of adding G-CSF to imatinib

Imatinib mesylate induces complete cytogenetic responses in patients with chronic myeloid leukemia (CML), yet many patients have detectable BCR-ABL transcripts in peripheral blood even after prolonged therapy. Bone marrow studies have shown that this residual disease resides within the stem cell compartment. Quiescence of leukemic stem cells has been suggested as a mechanism conferring insensitivity to imatinib, and exposure to the Granulocyte-Colony Stimulating Factor (G-CSF), together with imatinib, has led to a significant reduction in leukemic stem cells in vitro. In this paper, we design a novel mathematical model of stem cell quiescence to investigate the treatment response to imatinib and G-CSF. We find that the addition of G-CSF to an imatinib treatment protocol leads to observable effects only if the majority of leukemic stem cells are quiescent; otherwise it does not modulate the leukemic cell burden. The latter scenario is in agreement with clinical findings in a pilot study administering imatinib continuously or intermittently, with or without G-CSF (GIMI trial). Furthermore, our model predicts that the addition of G-CSF leads to a higher risk of resistance since it increases the production of cycling leukemic stem cells. Although the pilot study did not include enough patients to draw any conclusion with statistical significance, there were more cases of progression in the experimental arms as compared to continuous imatinib. Our results suggest that the additional use of G-CSF may be detrimental to patients in the clinic

The impact of Cochrane Systematic Reviews : a mixed method evaluation of outputs from Cochrane Review Groups supported by the UK National Institute for Health Research

© 2014 Bunn et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: There has been a growing emphasis on evidence-informed decision making in health care. Systematic reviews, such as those produced by the Cochrane Collaboration, have been a key component of this movement. The UK National Institute for Health Research (NIHR) Systematic Review Programme currently supports 20 Cochrane Review Groups (CRGs). The aim of this study was to identify the impacts of Cochrane reviews published by NIHR funded CRGs during the years 2007-11. Methods: We sent questionnaires to CRGs and review authors, interviewed guideline developers and used bibliometrics and documentary review to get an overview of CRG impact and to evaluate the impact of a sample of 60 Cochrane reviews. We used a framework with four categories (knowledge production, research targeting, informing policy development, and impact on practice/services). Results: A total of 1502 new and updated reviews were produced by the 20 NIHR funded CRGs between 2007-11. The clearest impacts were on policy with a total of 483 systematic reviews cited in 247 sets of guidance; 62 were international, 175 national (87 from the UK) and 10 local. Review authors and CRGs provided some examples of impact on practice or services, for example safer use of medication, the identification of new effective drugs or treatments and potential economic benefits through the reduction in the use of unproven or unnecessary procedures. However, such impacts are difficult to objectively document and the majority of reviewers were unsure if their review had produced specific impacts. Qualitative data suggested that Cochrane reviews often play an instrumental role in informing guidance although a poor fit with guideline scope or methods, reviews being out of date and a lack of communication between CRGs and guideline developers were barriers to their use. Conclusions: Health and economic impacts of research are generally difficult to measure. We found that to be the case with this evaluation. Impacts on knowledge production and clinical guidance were easier to identify and substantiate than those on clinical practice. Questions remain about how we define and measure impact and more work is needed to develop suitable methods for impact analysis.Peer reviewe

Inhibition of E2-induced expression of BRCA1 by persistent organochlorines

BACKGROUND: Environmental persistent organochlorines (POCs) biomagnify in the food chain, and the chemicals are suspected of being involved in a broad range of human malignancies. It is speculated that some POCs that can interfere with estrogen receptor-mediated responses are involved in the initiation and progression of human breast cancer. The tumor suppressor gene BRCA1 plays a role in cell-cycle control, in DNA repair, and in genomic stability, and it is often downregulated in sporadic mammary cancers. The aim of the present study was to elucidate whether POCs have the potential to alter the expression of BRCA1. METHODS: Using human breast cancer cell lines MCF-7 and MDA-MB-231, the effect on BRCA1 expression of chemicals belonging to different classes of organochlorine chemicals (the pesticide toxaphene, 2,3,7,8-tetrachlorodibenzo-p-dioxin, and three polychlorinated biphenyls [PCB#138, PCB#153 and PCB#180]) was measured by a reporter gene construct carrying 267 bp of the BRCA1 promoter. A twofold concentration range was analyzed in MCF-7, and the results were supported by northern blot analysis of BRCA1 mRNA using the highest concentrations of the chemicals. RESULTS: All three polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin reduced 17β-estradiol (E2)-induced expression as well as basal reporter gene expression in both cell lines, whereas northern blot analysis only revealed a downregulation of E2-induced BRCA1 mRNA expression in MCF-7 cells. Toxaphene, like E2, induced BRCA1 expression in MCF-7. CONCLUSION: The present study shows that some POCs have the capability to alter the expression of the tumor suppressor gene BRCA1 without affecting the cell-cycle control protein p21(Waf/Cip1). Some POCs therefore have the potential to affect breast cancer risk

Large Scale Gene Expression Profiles of Regenerating Inner Ear Sensory Epithelia

Loss of inner ear sensory hair cells (HC) is a leading cause of human hearing loss and balance disorders. Unlike mammals, many lower vertebrates can regenerate these cells. We used cross-species microarrays to examine this process in the avian inner ear. Specifically, changes in expression of over 1700 transcription factor (TF) genes were investigated in hair cells of auditory and vestibular organs following treatment with two different damaging agents and regeneration in vitro. Multiple components of seven distinct known signaling pathways were clearly identifiable: TGFβ, PAX, NOTCH, WNT, NFKappaB, INSULIN/IGF1 and AP1. Numerous components of apoptotic and cell cycle control pathways were differentially expressed, including p27KIP and TFs that regulate its expression. A comparison of expression trends across tissues and treatments revealed identical patterns of expression that occurred at identical times during regenerative proliferation. Network analysis of the patterns of gene expression in this large dataset also revealed the additional presence of many components (and possible network interactions) of estrogen receptor signaling, circadian rhythm genes and parts of the polycomb complex (among others). Equal numbers of differentially expressed genes were identified that have not yet been placed into any known pathway. Specific time points and tissues also exhibited interesting differences: For example, 45 zinc finger genes were specifically up-regulated at later stages of cochlear regeneration. These results are the first of their kind and should provide the starting point for more detailed investigations of the role of these many pathways in HC recovery, and for a description of their possible interactions

Wellbeing of gay fathers with children born through surrogacy: a comparison with lesbian-mother families and heterosexual IVF parent families.

STUDY QUESTION: Are there differences in levels of parental wellbeing (parental stress, psychological adjustment and partner relationship satisfaction) between gay-father families with infants born through surrogacy, lesbian-mother families with infants born through donor insemination, and heterosexual-parent families with infants born through IVF? SUMMARY ANSWER: There were no differences in parental wellbeing. WHAT IS KNOWN ALREADY: The only other study of parental wellbeing in gay-father families formed through surrogacy (mean age children: 4 years old) found no difference in couple relationship satisfaction between these families and lesbian-mother families formed through donor insemination and heterosexual-parent families formed without assisted reproductive technologies. STUDY DESIGN, SIZE, DURATION: This cross-sectional study is part of an international research project involving 38 gay-father families, 61 lesbian-mother families and 41 heterosexual-parent families with 4-month-olds. In each country (the UK, the Netherlands and France), participants were recruited through several sources, such as specialist lawyers with expertise in surrogacy (for the recruitment of gay fathers), lesbian and gay parenting support groups, fertility clinics (for the recruitment of lesbian and heterosexual parents), and/or online forums and magazines. PARTICIPANTS/MATERIALS, SETTING, METHODS: During a home visit when their infants were between 3.5 and 4.5 months old, participants completed standardized measures of parental stress, parental psychological adjustment (anxiety and depression) and partner relationship satisfaction. MAIN RESULTS AND THE ROLE OF CHANCE: All parents reported relatively low levels of parental stress, anxiety and depression, and were all relatively satisfied with their intimate relationships. After controlling for caregiver role (primary or secondary caregiver role), there were no significant family type differences in parental stress, P = 0.949, depression, P = 0.089, anxiety, P = 0.117, or relationship satisfaction, P = 0.354. LIMITATIONS, REASONS FOR CAUTION: The findings cannot be generalized to all first-time ART parents with infants because only families from relatively privileged backgrounds participated. WIDER IMPLICATIONS OF THE FINDINGS: Our findings may have implications for the development of policy and legislation in relation to these new family forms, as well as the regulation of surrogacy in the Netherlands and France. In addition, our findings might encourage professional organizations of obstetricians and gynecologists in these countries to recommend that requests for assisted reproduction should be considered regardless of the applicants' sexual orientation. STUDY FUNDING/COMPETING INTEREST(S): This research was supported, under the auspices of the Open Research Area (Application BO 3973/1-1; Principal Investigator, Michael E Lamb), by grants from the UK Economic and Social Research Council (ESRC; Grant ES/K006150/1; Principal Investigator, Michael E. Lamb), The Netherlands Organisation for Scientific Research (NWO; Grant NWO 464-11-001, Principal Investigator, Henny W.M. Bos) and the French Agence Nationale de Recherche (ANR; Grant ANR-12-ORAR-00005-01, Principal Investigator, Olivier Vecho) whose support is gratefully acknowledged. There were no competing interests

SEQADAPT: an adaptable system for the tracking, storage and analysis of high throughput sequencing experiments

<p>Abstract</p> <p>Background</p> <p>High throughput sequencing has become an increasingly important tool for biological research. However, the existing software systems for managing and processing these data have not provided the flexible infrastructure that research requires.</p> <p>Results</p> <p>Existing software solutions provide static and well-established algorithms in a restrictive package. However as high throughput sequencing is a rapidly evolving field, such static approaches lack the ability to readily adopt the latest advances and techniques which are often required by researchers. We have used a loosely coupled, service-oriented infrastructure to develop SeqAdapt. This system streamlines data management and allows for rapid integration of novel algorithms. Our approach also allows computational biologists to focus on developing and applying new methods instead of writing boilerplate infrastructure code.</p> <p>Conclusion</p> <p>The system is based around the Addama service architecture and is available at our website as a demonstration web application, an installable single download and as a collection of individual customizable services.</p

Preventing Establishment: An Inventory of Introduced Plants in Puerto Villamil, Isabela Island, Galapagos

As part of an island-wide project to identify and eradicate potentially invasive plant species before they become established, a program of inventories is being carried out in the urban and agricultural zones of the four inhabited islands in Galapagos. This study reports the results of the inventory from Puerto Villamil, a coastal village representing the urban zone of Isabela Island. We visited all 1193 village properties to record the presence of the introduced plants. In addition, information was collected from half of the properties to determine evidence for potential invasiveness of the plant species. We recorded 261 vascular taxa, 13 of which were new records for Galapagos. Most of the species were intentionally grown (cultivated) (73.3%) and used principally as ornamentals. The most frequent taxa we encountered were Cocos nucifera (coconut tree) (22.1%) as a cultivated plant and Paspalum vaginatum (salt water couch) (13.2%) as a non cultivated plant. In addition 39 taxa were naturalized. On the basis of the invasiveness study, we recommend five species for eradication (Abutilon dianthum, Datura inoxia, Datura metel, Senna alata and Solanum capsicoides), one species for hybridization studies (Opuntia ficus-indica) and three species for control (Furcraea hexapetala, Leucaena leucocephala and Paspalum vaginatum)

Dipoid-Specific Genome Stability Genes of S. cerevisiae: Genomic Screen Reveals Haploidization as an Escape from Persisting DNA Rearrangement Stress

Maintaining a stable genome is one of the most important tasks of every living cell and the mechanisms ensuring it are similar in all of them. The events leading to changes in DNA sequence (mutations) in diploid cells occur one to two orders of magnitude more frequently than in haploid cells. The majority of those events lead to loss of heterozygosity at the mutagenesis marker, thus diploid-specific genome stability mechanisms can be anticipated. In a new global screen for spontaneous loss of function at heterozygous forward mutagenesis marker locus, employing three different mutagenesis markers, we selected genes whose deletion causes genetic instability in diploid Saccharomyces cerevisiae cells. We have found numerous genes connected with DNA replication and repair, remodeling of chromatin, cell cycle control, stress response, and in particular the structural maintenance of chromosome complexes. We have also identified 59 uncharacterized or dubious ORFs, which show the genome instability phenotype when deleted. For one of the strongest mutators revealed in our screen, ctf18Δ/ctf18Δ the genome instability manifests as a tendency to lose the whole set of chromosomes. We postulate that this phenomenon might diminish the devastating effects of DNA rearrangements, thereby increasing the cell's chances of surviving stressful conditions. We believe that numerous new genes implicated in genome maintenance, together with newly discovered phenomenon of ploidy reduction, will help revealing novel molecular processes involved in the genome stability of diploid cells. They also provide the clues in the quest for new therapeutic targets to cure human genome instability-related diseases