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.

/pdf/gut-flora-metabolism-of-phosphatidylcholine-promotes-437q5mia6l.pdf

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

The in vitro activity of 15 penicillins and mecillinam against Neisseria gonorrhoeae

In-vitro antibacterial activity of cefoperazone, a piperazine cephalosporin

Purpuromycin and its semi-synthetic derivative MDL 63,604 had in-vitro activity similar to that of amphotericin B against isolates of Candida albicans. MDL 63,604 had activity similar to that of metronidazole against Trichomonas vaginalis. Both compounds were very active against most species of Gram-positive and Gram-negative anaerobes and against Gardnerella vaginalis. MDL 63,604 had significantly lower MICs than purpuromycin against T. vaginalis and most of the bacteria, probably due to antagonism of purpuromycin's activity by medium supplements (blood or serum). Purpuromycin or related compounds may have a potential role in the topical treatment of vaginitis and vaginosis.

In-vitro activity of purpuromycin and MDL 63, 604 against microorganisms that cause vaginitis and vaginosis

Sultamicillin is a covalent union of ampicillin and the beta lactamase inhibitor, sulbactam (CP-45,899). Two studies were conducted to assess its efficacy in treating uncomplicated gonorrhoea. In the first study treatment comprised sultamicillin 1.5 g and probenecid 1 g; 124 (89.2%) of 139 patients responded including seven of 11 patients harbouring beta lactamase (penicillinase) producing strains of Neisseria gonorrhoeae (PPNG). In the second study sultamicillin 2.25 g and probenecid 1 g were given; 122 (93.8%) of 130 patients responded. Only two of seven pharyngeal infections resolved, and if pharyngeal infections are excluded the overall cure rate rose to 95.3%. Thirteen of 14 patients infected with PPNG strains were cured by the larger dose. Side effects were mild and transitory. It may be concluded that sultamicillin 2.25 g plus probenecid 1 g is an effective regimen to treat uncomplicated rectal and genital gonorrhoea and is useful for treating infections with PPNG strains. Most beta lactamase resistant antimicrobials must be given parenterally; sultamicillin is given by mouth.

https://sti.bmj.com/content/sextrans/61/1/44.full.pdf

Ian Phillips

Papers

The in vitro activity of 15 penicillins and mecillinam against Neisseria gonorrhoeae

In-vitro antibacterial activity of cefoperazone, a piperazine cephalosporin

In-vitro activity of purpuromycin and MDL 63, 604 against microorganisms that cause vaginitis and vaginosis

Two regimens of sultamicillin in treating uncomplicated gonorrhoea.

The in vitro antibacterial activity of nine aminoglycosides and spectinomycin on clinical isolates of common Gram-negative bacteria