Statistical method for testing the neutral mutation hypothesis by DNA polymorphism.

Metabolomics studies hold promise for the discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. Here we used a metabolomics approach to generate unbiased small-molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine—choline, trimethylamine N-oxide (TMAO) and betaine—were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted upregulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary-choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases, an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidaemic mice. Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease.

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Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease

Extended-spectrum β-lactamases (ESBLs) are a rapidly evolving group of β-lactamases which share the ability to hydrolyze third-generation cephalosporins and aztreonam yet are inhibited by clavulanic acid. Typically, they derive from genes for TEM-1, TEM-2, or SHV-1 by mutations that alter the amino acid configuration around the active site of these β-lactamases. This extends the spectrum of β-lactam antibiotics susceptible to hydrolysis by these enzymes. An increasing number of ESBLs not of TEM or SHV lineage have recently been described. The presence of ESBLs carries tremendous clinical significance. The ESBLs are frequently plasmid encoded. Plasmids responsible for ESBL production frequently carry genes encoding resistance to other drug classes (for example, aminoglycosides). Therefore, antibiotic options in the treatment of ESBL-producing organisms are extremely limited. Carbapenems are the treatment of choice for serious infections due to ESBL-producing organisms, yet carbapenem-resistant isolates have recently been reported. ESBL-producing organisms may appear susceptible to some extended-spectrum cephalosporins. However, treatment with such antibiotics has been associated with high failure rates. There is substantial debate as to the optimal method to prevent this occurrence. It has been proposed that cephalosporin breakpoints for the Enterobacteriaceae should be altered so that the need for ESBL detection would be obviated. At present, however, organizations such as the Clinical and Laboratory Standards Institute (formerly the National Committee for Clinical Laboratory Standards) provide guidelines for the detection of ESBLs in klebsiellae and Escherichia coli. In common to all ESBL detection methods is the general principle that the activity of extended-spectrum cephalosporins against ESBL-producing organisms will be enhanced by the presence of clavulanic acid. ESBLs represent an impressive example of the ability of gram-negative bacteria to develop new antibiotic resistance mechanisms in the face of the introduction of new antimicrobial agents.

Extended-spectrum beta-lactamases: a clinical update.

https://stacks.cdc.gov/view/cdc/6674/cdc_6674_DS1.pdf

Guideline for Hand Hygiene in Health-Care Settings. Recommendations of the Healthcare Infection Control Practices Advisory Committee and the HIPAC/SHEA/APIC/IDSA Hand Hygiene Task Force.

Transcription of the c-fos proto-oncogene is greatly increased within minutes of administering purified growth factors to quiescent 3T3 cells. This stimulation is the most rapid transcriptional response to peptide growth factors yet described, and implies a role for c-fos in cell-cycle control. Transformation by c-fos may result from a temporal deregulation of this control.

Stimulation of 3T3 cells induces transcription of the c- fos proto-oncogene

Effect of Thyroid Hormones onFlavin-containing Monooxygenase Activity in Co-cultured Adult Rat Hepatocytes

The cytochrome P-450-mediated mixed-function monooxygenase system is one of the major enzyme systems involved in the detoxification of foreign compounds, including many drugs and carcinogens (Hietanen, 1982). In contrast, some xenobiotics can be activated by cytochrome P450 to compounds that can bind covalently to cellular macromolecules resulting in deleterious effects such as toxicity, mutation and neoplasia (Gelboin, 1980). Any one organism usually possesses a multiplicity of cytochromes P450, which differ from each other in molecular weight, amino acid composition, substrate and reaction specificity, and immunochemical properties (Nebert & Negishi, 1982). The cytochromes P-450 are inducible by a wide variety of foreign compounds, the specific variant induced depending on the compound. We have shown that PB induces a rat-liver cytochrome P450 variant (PB P-450) of M , 52000 by approximately 40fold (Phillips et al., 1981, 19830). The induction is mediated by a 20-fold increase in the translatable mRNA coding for PB P-450 (Shephard et al., 1982). In order to investigate further the mechanism of the induction process we have cloned cDNAs coding for PB P450 (Phillips et al . , 19836). A cDNA library representative of total liver polyribosomal poly(A)+ RNA isolated from PB-treated rats was established. The library was screened by differential colony hybridization to 32P-labelled cDNAs synthesized from poly(A)+ RNA extracted from the livers of PBor NF-treated or untreated rats. Colonies giving a stronger signal with 'PB cDNA' than with either 'NF cDNA' or 'control cDNA' were subjected to hybridselected translation and immunoprecipitational analysis with anti-(PB P-450) serum. A plasmid, pP-450(1), coding for PB P-450, was isolated and used as a molecular hybridization probe. Northern blot and solution hybridization analysis showed that PB P-450 is encoded by a single mRNA size-class of 2 I00 nucleotides that is induced 20-fold by phenobarbital treatment and decreased 3-fold by P-naphthoflavone (Phillips et al . , 19836,~).

Ian Phillips

Papers

Effect of Thyroid Hormones onFlavin-containing Monooxygenase Activity in Co-cultured Adult Rat Hepatocytes

Microheterogeneity in a cytochrome P-450 multigene family

Tissue-specific expression of cytochrome P-450 genes

Change of Editor

Structure and expression of human cytochrome P-450 genes