Hypoglycemia with insulin and sulfonylureas

Clinical Inquiries question: In patients with type 2 diabetes mellitus (T2DM), does the combination of insulin and sulfonylurea (SU) increase the risk of hypoglycemia? Evidence-based answer: The incidence of severe hypoglycemia in patients with T2DM taking insulin alone, SU alone, or the combination of insulin and SU is low (strength of recommendation [SOR] A based on a systematic review of randomized controlled trials). The combination of insulin and SU in patients with T2DM does increase the risk of hypoglycemia; however, the clinical significance of this risk is small (SOR B based on 4 large retrospective cohort studies). Of note, patients 65 years and older are at an increased risk of hypoglycemia compared with younger patients, although the clinical significance has not been specified (SOR B based on 2 large retrospective cohort studies).Karyn B. Kolman, MD; Joshua Freeman, MD; Carol L. Howe, MD, MLSDr Kolman is Assistant Professor and Dr Freeman is Clinical Professor in the Department of Family and Community Medicine at the University of Arizona in Tucson. Dr Howe is a librarian in the Health Sciences Library at the University of Arizona.Includes bibliographical reference

Initiation of DNA replication at the human β-globin 3′ enhancer

The origin of DNA replication in the human β-globin gene contains an initiation region (IR) and two flanking auxiliary elements. Two replicator modules are located within the upstream auxiliary sequence and the IR core, but the functional sequences in the downstream auxiliary element are unknown. Here, we use a combination of benzoylated-naphthoylated DEAE (BND) cellulose purification and nascent strand abundance assays to show that replication initiation occurs at the β-globin 3′ enhancer on human chromosome 11 in the Hu11 hybrid murine erythroleukemia (MEL) cell line. To examine replicator function, 3′ enhancer fragments were inserted into an ectopic site in MEL cells via an optimized FRT/EGFP-FLP integration system. These experiments demonstrate that the 1.6 kb downstream auxiliary element is a third replicator module called bGRep-E in erythroid cells. The minimal 260 bp 3′ enhancer is required but not sufficient to initiate efficient replication, suggesting cooperation with adjacent sequences. The minimal 3′ enhancer also cooperates with elements in an expressing HS3β/γ-globin construct to initiate replication. These data indicate that the β-globin replicator has multiple initiation sites in three closely spaced replicator modules. We conclude that a mammalian enhancer can cooperate with adjacent sequences to create an efficient replicator module

Reproducible doxycycline-inducible transgene expression at specific loci generated by Cre-recombinase mediated cassette exchange

Comparative analysis of mutants using transfection is complicated by clones exhibiting variable levels of gene expression due to copy number differences and genomic position effects. Recombinase-mediated cassette exchange (RMCE) can overcome these problems by introducing the target gene into pre-determined chromosomal loci, but recombination between the available recombinase targeting sites can reduce the efficiency of targeted integration. We developed a new LoxP site (designated L3), which when used with the original LoxP site (designated L2), allows highly efficient and directional replacement of chromosomal DNA with incoming DNA. A total of six independent LoxP integration sites introduced either by homologous recombination or retroviral delivery were analyzed; 70–80% of the clones analyzed in hamster and human cells were correct recombinants. We combined the RMCE strategy with a new, tightly regulated tetracycline induction system to produce a robust, highly reliable system for inducible transgene expression. We observed stable inducible expression for over 1 month, with uniform expression in the cell population and between clones derived from the same integration site. This system described should find significant applications for studies requiring high level and regulated transgene expression and for determining the effects of various stresses or oncogenic conditions in vivo and in vitro

Dynamics of a cantilever beam with piezoelectric sensor: Parameter identification

This work has been supported by the grant 23-06220S of the Czech Science Foundation within institutional support RVO:61388998

Computation of Invariants of Lie Algebras by Means of Moving Frames

A new purely algebraic algorithm is presented for computation of invariants (generalized Casimir operators) of Lie algebras. It uses the Cartan's method of moving frames and the knowledge of the group of inner automorphisms of each Lie algebra. The algorithm is applied, in particular, to computation of invariants of real low-dimensional Lie algebras. A number of examples are calculated to illustrate its effectiveness and to make a comparison with the same cases in the literature. Bases of invariants of the real solvable Lie algebras up to dimension five, the real six-dimensional nilpotent Lie algebras and the real six-dimensional solvable Lie algebras with four-dimensional nilradicals are newly calculated and listed in tables.Comment: 17 pages, extended versio

Mitochondrial echoes of first settlement and genetic continuity in El Salvador

Background: From Paleo-Indian times to recent historical episodes, the Mesoamerican isthmus played an important role in the distribution and patterns of variability all around the double American continent. However, the amount of genetic information currently available on Central American continental populations is very scarce. In order to shed light on the role of Mesoamerica in the peopling of the New World, the present study focuses on the analysis of the mtDNA variation in a population sample from El Salvador. Methodology/Principal Findings: We have carried out DNA sequencing of the entire control region of the mitochondrial DNA (mtDNA) genome in 90 individuals from El Salvador. We have also compiled more than 3,985 control region profiles from the public domain and the literature in order to carry out inter-population comparisons. The results reveal a predominant Native American component in this region: by far, the most prevalent mtDNA haplogroup in this country (at ~90%) is A2, in contrast with other North, Meso- and South American populations. Haplogroup A2 shows a star-like phylogeny and is very diverse with a substantial proportion of mtDNAs (45%; sequence range 16090–16365) still unobserved in other American populations. Two different Bayesian approaches used to estimate admixture proportions in El Salvador shows that the majority of the mtDNAs observed come from North America. A preliminary founder analysis indicates that the settlement of El Salvador occurred about 13,400±5,200 Y.B.P.. The founder age of A2 in El Salvador is close to the overall age of A2 in America, which suggests that the colonization of this region occurred within a few thousand years of the initial expansion into the Americas. Conclusions/Significance: As a whole, the results are compatible with the hypothesis that today's A2 variability in El Salvador represents to a large extent the indigenous component of the region. Concordant with this hypothesis is also the observation of a very limited contribution from European and African women (~5%). This implies that the Atlantic slave trade had a very small demographic impact in El Salvador in contrast to its transformation of the gene pool in neighbouring populations from the Caribbean facade