Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors

Traditional treatment of infectious diseases is based on compounds that kill or inhibit growth of bacteria. A major concern with this approach is the frequent development of resistance to antibiotics. The discovery of communication systems (quorum sensing systems) regulating bacterial virulence has afforded a novel opportunity to control infectious bacteria without interfering with growth. Compounds that can override communication signals have been found in the marine environment. Using Pseudomonas aeruginosa PAO1 as an example of an opportunistic human pathogen, we show that a synthetic derivate of natural furanone compounds can act as a potent antagonist of bacterial quorum sensing. We employed GeneChip((R)) microarray technology to identify furanone target genes and to map the quorum sensing regulon. The transcriptome analysis showed that the furanone drug specifically targeted quorum sensing systems and inhibited virulence factor expression. Application of the drug to P.aeruginosa biofilms increased bacterial susceptibility to tobramycin and SDS. In a mouse pulmonary infection model, the drug inhibited quorum sensing of the infecting bacteria and promoted their clearance by the mouse immune response.

Attenuation of perceptual asymmetries in patients with early-onset schizophrenia: Evidence in favour of reduced hemispheric differentiation in schizophrenia?

Lateral biases in visual perception have been demonstrated in normal individuals and in patients with unilateral brain lesions. It has been suggested that the absence of structural and functional asymmetries in schizophrenia could be due to a failure in lateralisation that may be most pronounced in those patients whose illness onset is at an early age. Here we examined lateral biases in patients with schizophrenia of an early onset (N = 21) and a late onset.(N = 19), and their respective age-matched control groups, using the greyscales task, a sensitive measure of asymmetries in visual processing. The stimuli consisted of two rectangles, one above the other, shaded in opposite directions and matched overall for darkness. Participants judged which of the two rectangles looked darker overall. Previous studies using this task in healthy participants have reported a reliable bias, such that the rectangle with the darker end on the left is selected preferentially. Whereas the late-onset patients in this study exhibited a perceptual bias of similar direction and magnitude to that of controls, this was not the case for the early-onset patients, who exhibited significantly less bias than their control group. The reduced perceptual bias seen in the early-onset group, but not the late-onset group, suggests an attenuation of right hemisphere mechanisms dedicated to processing vistiospatial information. The attenuated perceptual asymmetry in the early-onset group only may be consistent with the view that (i) an earlier illness onset reflects a greater loss of hemispheric differentiation and (ii) reduced functional asymmetries in the early-onset group are a manifestation of a failure to allocate functions to one or the other hemisphere.

Wolbachia density and virulence attenuation after transfer into a novel host

The factors that control replication rate of the intracellular bacterium Wolbachia pipientis in its insect hosts are unknown and difficult to explore, given the complex interaction of symbiont and host genotypes. Using a strain of Wolbachia that is known to over-replicate and shorten the lifespan of its Drosophila melanogaster host, we have tracked the evolution of replication control in both somatic and reproductive tissues in a novel host/Wolbachia association. After transinfection (the transfer of a Wolbachia strain into a different species) of the over-replicating Wolbachia popcorn strain from D. metanogaster to Drosophila simulans, we demonstrated that initial high densities in the ovaries were in excess of what was required for perfect maternal transmission, and were likely causing reductions in reproductive fitness. Both densities and fitness costs associated with ovary infection rapidly declined in the generations after transinfection. The early death effect in D. simulans attenuated only slightly and was comparable to that induced in D. metanogaster. This study reveals a strong host involvement in Wolbachia replication rates, the independence of density control responses in different tissues, and the strength of natural selection acting on reproductive fitness.

Attenuation of cardiac fibrosis by pirfenidone and amiloride in DOCA-salt hypertensive rats

1 This study has administered pirfenidone (5-methyl-l-phenyl-2-[1H]-pyridone) or amiloride to attenuate the remodelling and associated functional changes, especially an increased cardiac stiffness, in DOCA-salt hypertensive rats. 2 In control rats, the elimination half-life of pirfenidone following a single intravenous dose of 200 mg kg(-1) was 37 min while oral bioavailability at this dose was 25.7%. Plasma pirfenidone concentrations in control rats averaged 1.9 +/- 0.1 mug ml(-1) over 24 It after 14 days' administration as a 0.4% mixture in food. 3 Pirfenidone (approximately 250-300 mg kg(-1) day(-1) as 0.4% in food) and amiloride (I mg kg-1 day(-1) sc) were administered for 2 weeks starting 2 weeks post-surgery. Pirfenidone but not amiloride attenuated ventricular hypertrophy (2.69 +/- 0.09, UNX 2.01 +/- 0.05. DOCA-salt 3.11 +/- 0.09 mg kg(-1) body wt) without lowering systolic blood pressure. 4 Collagen deposition was significantly increased in the interstitium after 2 weeks and further increased with scarring of the left ventricle after 4 weeks; pirfenidone and amiloride reversed the increases and prevented further increases. This accumulation of collagen was accompanied by an increase in diastolic stiffness constant; both amiloride and pirfenidone, reversed this increase. 5 Noradrenaline potency (positive chronotropy) was decreased in right atria (neg log EC50: control 6.92 +/- 0.06; DOCA-salt 6.64 +/- 0.08); pirfenidone but not amiloride reversed this change. Noradrenaline was a more potent vasoconstrictor in thoracic aortic rings (neg log EC50: control 6.91 +/- 0.10; DOCA-salt 7.90 +/- 0.07); pirfenidone treatment did not change noradrenaline potency. 6 Thus, pirfenidone and amiloride reverse and prevent cardiac remodelling and the increased cardiac stiffness without reversing the increased vascular responses to noradrenaline.