Metformin pretreatment ameliorates busulfan-induced liver endothelial toxicity during haematopoietic stem cell transplantation.

The success of Haematopoietic cell transplantation (HCT) is often limited by regimen-related toxicity (RRT) caused by conditioning regimen drugs. Among different conditioning drugs, busulfan (Bu) and treosulfan (Treo), although widely used in HCT, exhibit different toxicity profiles, the mechanism of which is still unclear. Here we investigated the effects of Bu and Treo in endothelial cells. While both Bu and Treo induced DNA damage in endothelial cells, we observed Bu alone to induce oxidative stress and sustained activation of phospho-ERK1/2, leading to apoptosis. However, Treo-treated cells exhibited no oxidative stress/apoptosis of endothelial cells. Screening of pharmacological inhibitors of both ROS and p-ERK revealed that metformin effectively ameliorates Bu-mediated toxicity in endothelial cells. In Balb/c mice, we observed a significant reduction in bone marrow endothelial cells in Bu-treated mice compared to Treo-treated mice. Further, liver sinusoidal endothelial cells (LSEC) was damaged by Bu, which is implicated in liver vasculature and their functional capacity to uptake FITC-albumin. However, Treo-treated mice liver vasculature was morphologically and functionally normal. When mice were pretreated with metformin followed by Bu, LSECs damage was ameliorated morphologically and functionally. Bone marrow transplants done on these mice did not affect the engraftment of donor cells

Distribution and association of the study ST’s with the ST’s from Southeast Asian region retrieved from the PubMLST database (10).

<p>Light Green–ST1364 (Kerala & Sri Lanka); Dark Green ST375 (Tamilnadu & Thailand); Black—ST1552 (Tamilnadu and Pondicherry); Red—ST51 (Tamilnadu, Singapore, China, Thailand, Malaysia and Burma); Purple—ST228 (West Bengal, Thailand &Vietnam); Blue–ST1099 (Jharkhand & China); Brown–ST56 (West Bengal Bangladesh, Cambodia & Vietnam); Orange—ST300 (West Bengal and Thailand); Yellow–ST99 (Bangladesh, Philippines, Thailand and Malaysia). The figure was recreated using open source-<a href="https://commons.wikimedia.org/wiki/Atlas_of_the_world" target="_blank">https://commons.wikimedia.org/wiki/Atlas_of_the_world</a>.</p

Epidemiological year of isolation of the STs identified in the study isolates from different South Asian countries.

<p>Epidemiological year of isolation of the STs identified in the study isolates from different South Asian countries.</p

Populations structure analysis.

<p><b>(A)</b> goeBURST analysis of 1643 STs present in the PubMLST database. Each dot represents the single ST. Groups are formed by linking the STs that are double locus variants (DLV) and called as clonal complex (CC). The largest clonal complex 300 has the other STs leaving 1634, 1632, 1636, 1639 as singletons (<b>B</b>) Snapshot of the clonal complex 300.</p

Details of the study isolates identifiers and corresponding year of isolation, type of infection, geographical location, and the sequence type information.

<p>Details of the study isolates identifiers and corresponding year of isolation, type of infection, geographical location, and the sequence type information.</p

Comparison between the nucleotide diversity of MLST housekeeping genes of the study isolates.

<p>Comparison between the nucleotide diversity of MLST housekeeping genes of the study isolates.</p

Epidemiological investigation and successful management of a Burkholderia cepacia outbreak in a neurotrauma intensive care unit

Objective: The detailed epidemiological and molecular characterization of an outbreak of Burkholderia cepacia at a neurotrauma intensive care unit of a level 1 trauma centre is described. The stringent infection control interventions taken to successfully curb this outbreak are emphasized. Methods: The clinical and microbiological data for those patients who had more than one blood culture that grew B. cepacia were reviewed. Bacterial identification and antimicrobial susceptibility testing was done using automated Vitek 2 systems. Prospective surveillance, environmental sampling, and multilocus sequence typing (MLST) were performed for extensive source tracking. Intensive infection control measures were taken to further control the hospital spread. Results: Out of a total 48 patients with B. cepacia bacteraemia, 15 (31%) had central line-associated blood stream infections. Two hundred and thirty-one environmental samples were collected and screened, and only two water samples grew B. cepacia with similar phenotypic characteristics. The clinical strains characterized by MLST typing were clonal. However, isolates from the water represented a novel strain type (ST-1289). Intensive terminal cleaning, disinfection of the water supply, and the augmentation of infection control activities were done to curb the outbreak. A subsequent reduction in bacteraemia cases was observed. Conclusion: Early diagnosis and appropriate therapy, along with the rigorous implementation of essential hospital infection control practices is required for successful containment of this pathogen and to curb such an outbreak. Keywords: Burkholderia cepacia, Outbreak, Neurotrauma unit, MLST typing, Novel ST typ