Multidrug-Resistant Tuberculosis in Panama Is Driven by Clonal Expansion of an MDR-TB Strain Related to the KZN XDR-TB Strain From South Africa.

Multidrug-resistant tuberculosis in Panama is driven by clonal expansion of an MDR-TB strain related to the KZN XDR-TB strain from South Africa.

J Clin Microbiol. 2013 Jul 24;
Lanzas F, Karakousis PC, Sacchettini JC, Ioerger TR

Multidrug-resistant tuberculosis (MDR-TB) is a significant health problem in Panama. The extent to which these cases are the result of primary or acquired resistance and the strain families involved are unknown. We performed whole-genome sequencing on a collection of 66 MDR clinical isolates, along with 31 drug-susceptible isolates, that were isolated from Panama during 2001-2010. 78% of the MDR isolates belong to the LAM family. Drug resistance mutations correlated well with drug susceptibility profiles. To determine the relationships among these strains and better understand the acquisition of resistance mutations, a phylogenetic tree was constructed based on a genome-wide SNP analysis. The phylogenetic tree shows that the isolates are highly clustered, with a single strain (LAM9-c1) accounting for nearly half of the MDR isolates (29/66). The LAM9-c1 strain is most prevalent among males of productive age, and was associated with high mortality. Members of this cluster all share identical mutations conferring resistance to isoniazid (KatG:S315T), rifampicin (RpoB:S531L), and streptomycin (rrs:c517t). This evidence of primary resistance supports a model in which MDR-TB in Panama is driven by clonal expansion and on-going transmission of several strains in the LAM family, including the highly successful MDR strain LAM9-c1. The phylogenetic analysis also shows that the LAM9-c1 strain is closely related to the KZN XDR-TB strain identified in KwaZulu-Natal, South Africa. The LAM9-c1 and KZN strains likely arose from a recent common ancestor that was transmitted between Panama and South Africa, which had the capacity to tolerate an accumulation of multiple resistance mutations. HubMed – drug

Loss of d2 dopamine receptor function modulates cocaine-induced glutamatergic synaptic potentiation in the ventral tegmental area.

J Neurosci. 2013 Jul 24; 33(30): 12329-36
Madhavan A, Argilli E, Bonci A, Whistler JL

Potentiation of glutamate responses is a critical synaptic response to cocaine exposure in ventral tegmental area (VTA) neurons. However, the mechanism by which cocaine exposure promotes potentiation of NMDA receptors (NMDARs) and subsequently AMPA receptors (AMPARs) is not fully understood. In this study we demonstrate that repeated cocaine treatment causes loss of D2 dopamine receptor functional responses via interaction with lysosome-targeting G-protein-associated sorting protein1 (GASP1). We also show that the absence of D2 downregulation in GASP1-KO mice prevents cocaine-induced potentiation of NMDAR currents, elevation of the AMPA/NMDA ratio, and redistribution of NMDAR and AMPAR subunits to the membrane. As a pharmacological parallel, coadministration of the high-affinity D2 agonist, aripiprazole, reduces not only functional downregulation of D2s in response to cocaine but also potentiation of NMDAR and AMPAR responses in wild-type mice. Together these data suggest that functional loss of D2 receptors is a critical mechanism mediating cocaine-induced glutamate plasticity in VTA neurons. HubMed – drug

Nicotine-Modulated Subunit Stoichiometry Affects Stability and Trafficking of ?3?4 Nicotinic Receptor.

J Neurosci. 2013 Jul 24; 33(30): 12316-28
Mazzo F, Pistillo F, Grazioso G, Clementi F, Borgese N, Gotti C, Colombo SF

Heteromeric nAChRs are pentameric cation channels, composed of combinations of two or three ? and three or two ? subunits, which play key physiological roles in the central and peripheral nervous systems. The prototypical agonist nicotine acts intracellularly to upregulate many nAChR subtypes, a phenomenon that is thought to contribute to the nicotine dependence of cigarette smokers. The ?3?4 subtype has recently been genetically linked to nicotine dependence and lung cancer; however, the mode of action of nicotine on this receptor subtype has been incompletely investigated. Here, using transfected mammalian cells as model system, we characterized the response of the human ?3?4 receptor subtype to nicotine and the mechanism of action of the drug. Nicotine, when present at 1 mm concentration, elicited a ?5-fold increase of cell surface ?3?4 and showed a more modest upregulatory effect also at concentrations as low as 10 ?M. Upregulation was obtained if nicotine was present during, but not after, pentamer assembly and was caused by increased stability and trafficking of receptors assembled in the presence of the drug. Experimental determinations as well as computational studies of subunit stoichiometry showed that nicotine favors assembly of pentamers with (?3)2(?4)3 stoichiometry; these are less prone than (?3)3(?4)2 receptors to proteasomal degradation and, because of the presence in the ? subunit of an endoplasmic reticulum export motif, more efficiently transported to the plasma membrane. Our findings uncover a novel mechanism of nicotine-induced ?3?4 nAChR upregulation that may be relevant also for other nAChR subtypes. HubMed – drug

Oral and intravenous thyroxine (T4) achieve comparable serum levels for hormonal resuscitation protocol in organ donors: a randomized double-blinded study.

Can J Anaesth. 2013 Jul 25;
Sharpe MD, van Rassel B, Haddara W

Thyroxine (T4) administration is advocated in the management of organ donors; however, the bioavailability of oral thyroxine is unknown in this patient population.The primary objective of this study was to compare the percentage of the study time (from study drug administration to organ procurement) that patients in the oral vs the intravenous group required inotropic support. Secondary objectives included plasma levels of T3 and T4 and number of organs donated following oral vs intravenous T4 administration.Randomized double-blinded study.Adult medical-surgical intensive care unit.Thirty-two adult solid organ donors.Patients were randomized to receive either an oral or intravenous dose of T4 (2 ?g·kg(-1)). All patients received an oral and intravenous study drug preparation, one of which was a placebo. The study was double-blinded, and randomization occurred in blocks of four and six.The number and duration of inotropic/vasopressor therapies and free serum levels of T3 and T4 were determined hourly until procurement.Following T4 administration, all patients remained on inotropic/vasopressor therapy for the same mean (SD) duration [93 (3)%] of the study period. There was a similar and gradual decrease in the number and dosages of inotropes/vasopressors required in both groups. There was no difference in T3 or T4 levels between groups. Oral bioavailability of T4 was 93% of the intravenous group at six hours and 91% overall. At six hours, the mean area under the curve for T4 was similar between the intravenous group [92.2 (33); 95% confidence interval (CI) 76 to 108.4] and the oral group [86.1 (14); 95% CI 79.4 to 92.8].Orally administered T4 is well absorbed and achieves a bioavailability of approximately 91-93% of intravenous T4 in organ donors. Inotropic/vasopressor requirements and hemodynamic responses following oral or intravenous thyroxine administration were comparable. Oral T4 is suitable for hormonal therapy for organ donors. This trial was registered at : NCT00238030. HubMed – drug

C-peptide activates AMPK? and prevents ROS-mediated mitochondrial fission and endothelial apoptosis in diabetes mellitus.

Diabetes. 2013 Jul 24;
Bhatt MP, Lim YC, Kim YM, Ha KS

Vasculopathy is a major complication of diabetes mellitus; however, molecular mechanisms mediating the development of vasculopathy and potential strategies for prevention have not been identified. We have previously reported that C-peptide prevents diabetic vasculopathy by inhibiting reactive oxygen species (ROS)-mediated endothelial apoptosis. To gain further insight into ROS-dependent mechanism of diabetic vasculopathy and its prevention, we studied high glucose-induced cytosolic and mitochondrial ROS production and its effect on altered mitochondrial dynamics and apoptosis. For the therapeutic strategy, we investigated the vasoprotective mechanism of C-peptide against hyperglycemia-induced endothelial damage through the AMP-activated protein kinase ? (AMPK?) pathway using human umbilical vein endothelial cells and aorta of diabetic mice. High glucose (33 mM) increased intracellular ROS through a mechanism involving inter-regulation between cytosolic and mitochondrial ROS generation. C-peptide (1 nM) activation of AMPK? inhibited high glucose-induced ROS generation, mitochondrial fission, mitochondrial membrane potential collapse, and endothelial cell apoptosis. Additionally, the AMPK activator 5-aminoimidazole-4-carboxamide 1-?-D-ribofuranoside and the anti-hyperglycemic drug metformin mimicked protective effects of C-peptide. C-peptide replacement therapy normalized hyperglycemia-induced AMPK? dephosphorylation, ROS generation, and mitochondrial disorganization in aorta of diabetic mice. These findings highlight a novel mechanism by which C-peptide activates AMPK? and protects against hyperglycemia-induced vasculopathy. HubMed – drug