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

Humans can metabolize an extremely wide range of potentially harmful foreign hydrophobic compounds including many drugs, environmental pollutants and chemical carcinogens. This ability is mainly due to the action of cytochromes 1’-450. These proteins constitute a large superfamily that has been classified into several families, the largest of which (P45011) has been further divided into seven subfamilies

Quantification of cytochrome P-450 gene expression in human tissues.

Rapid compound pattern classification by recursive partitioning of feature space. An application in flow cytometry

Chromosomal localization of a cytochrome b5 gene to human chromosome 18 and a cytochrome b5 pseudogene to the X chromosome.

Beta-lactamase induction and derepression.

The in-vitro activity of the penem Sch 34343 was assessed in comparison with third-generation cephalosporins, aztreonam and imipenem. Sch 34343 was active, with MICs generally 2 mg/1 or less, against a broad spectrum of organisms amongst which were staphylococci (including methicillin-resistant strains), streptococci (though enterococci were less susceptible with Sch 34343 MICs mostly 4-8 mg/1), anaerobes (including the Bacteroides fragilis group), Haemophilus influenzae and Neisseria gonorrhoeae. It was also active against the Enterobacteriaceae though Enterobacter cloacae and Serratia spp. were somewhat less susceptible than other members of this group. Sch 34343 lacked useful activity against most species of Pseudomonas (including Ps. aeruginosa) but was active against Ps. acidovorans and some isolates of Ps. cepacia. Sch 34343 showed a high degree of resistance to plasmid-determined and most chromosomally-determined beta-lactamases; however, it was hydrolysed rapidly by enzymes from some isolates of Aeromonas hydrophila and more slowly by enzymes from Ps. maltophilia and Bact. melaninogenicus subspecies intermedius. We did not observe any reduction in sensitivity to Sch 34343 for most beta-lactamase-producing organisms, including strains of Enterobacter spp. and Citrobacter freundii that were resistant to most other beta-lactams.

Ian Phillips

Papers

Quantification of cytochrome P-450 gene expression in human tissues.

Rapid compound pattern classification by recursive partitioning of feature space. An application in flow cytometry

Chromosomal localization of a cytochrome b5 gene to human chromosome 18 and a cytochrome b5 pseudogene to the X chromosome.

Beta-lactamase induction and derepression.

Sch 34343: in-vitro antibacterial activity and susceptibility to β-lactamases