BackgroundCorynebacterium pseudotuberculosis is generally regarded as an important animal pathogen that rarely infects humans. Clinical strains are occasionally recovered from human cases of lymphadenitis, such as C. pseudotuberculosis FRC41 that was isolated from the inguinal lymph node of a 12-year-old girl with necrotizing lymphadenitis. To detect potential virulence factors and corresponding gene-regulatory networks in this human isolate, the genome sequence of C. pseudotuberculosis FCR41 was determined by pyrosequencing and functionally annotated.ResultsSequencing and assembly of the C. pseudotuberculosis FRC41 genome yielded a circular chromosome with a size of 2,337,913 bp and a mean G+C content of 52.2%. Specific gene sets associated with iron and zinc homeostasis were detected among the 2,110 predicted protein-coding regions and integrated into a gene-regulatory network that is linked with both the central metabolism and the oxidative stress response of FRC41. Two gene clusters encode proteins involved in the sortase-mediated polymerization of adhesive pili that can probably mediate the adherence to host tissue to facilitate additional ligand-receptor interactions and the delivery of virulence factors. The prominent virulence factors phospholipase D (Pld) and corynebacterial protease CP40 are encoded in the genome of this human isolate. The genome annotation revealed additional serine proteases, neuraminidase H, nitric oxide reductase, an invasion-associated protein, and acyl-CoA carboxylase subunits involved in mycolic acid biosynthesis as potential virulence factors. The cAMP-sensing transcription regulator GlxR plays a key role in controlling the expression of several genes contributing to virulence.ConclusionThe functional data deduced from the genome sequencing and the extended knowledge of virulence factors indicate that the human isolate C. pseudotuberculosis FRC41 is equipped with a distinct gene set promoting its survival under unfavorable environmental conditions encountered in the mammalian host.

The objective of this international, 8-week, randomized, double-blind study was to show the superiority of the antidepressant efficacy of agomelatine, the first MT1/MT2 receptor agonist and 5-HT2C receptor antagonist antidepressant, versus fluoxetine in outpatients fulfilling Diagnostic and Statistical Manual of Mental Disorders-volume IV-TR criteria for major depressive disorder of severe intensity, defined by a baseline Hamilton Depression Rating Scale (HAM-D17) total score of at least 25 and CGI severity of illness score of at least 4. Patients received agomelatine 25-50 mg/day (n=252) or fluoxetine 20-40 mg/day (n=263) for 8 weeks. The main efficacy outcome measure was HAM-D17 total score (change from baseline to last post-baseline assessment). Secondary outcome measures were Clinical Global Impressions-improvement (CGI), severity (CGI-S), anxiety (HAM-A), and sleep (HAM-D sleep items) scores. The mean decrease in HAM-D17 total score over 8 weeks was significantly greater with agomelatine than fluoxetine with a between-group difference of 1.49 (95% confidence interval, 0.20-2.77; P=0.024). The percentage of responders at last post-baseline assessment was higher with agomelatine on both HAM-D17 (decrease in total score from baseline ≥50%; 71.7% agomelatine vs. 63.8% fluoxetine; P=0.060) and CGI-improvement (score 1 or 2; 77.7 vs. 68.8%; P=0.023). There was a significant between-group difference of 0.37 (95% confidence interval, 0.06-0.68) in HAM-D sleep subscore in favor of agomelatine (P=0.018). Similar improvements were observed on HAM-A with agomelatine and fluoxetine. Both treatments were safe and well tolerated. In conclusion, in this study, agomelatine showed superior antidepressant efficacy over fluoxetine in treating patients with a severe episode of major depressive disorder after 8 weeks of treatment with a good tolerability profile.

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