Taken together these findings support future

Taken together, these findings support future trials to investigate the utility of alternative drug regimens in patients with severe forms of extra-pulmonary TB, in whom inadequate drug penetration may contribute to poor outcome. There is increasing concern that the conventionally prescribed dose of rifampicin (10mg/kg/day) is too low, both for treating pulmonary TB () and extra-pulmonary TB (e.g. TBM) (). Higher-than-normal doses of rifampicin (up to 35mg/kg/day), combined with the other standard-of-care drugs given for 7days, appear to be safe, result in increased rifampicin exposure and associate with a greater estimated fall in bacillary load compared to doses of 10mg/kg/day in pulmonary TB patients (). Furthermore, in a TBM trial rifampicin, administered intravenously at doses of ~13mg/kg/day compared to oral doses of ~10mg/kg/day, resulted in higher rifampicin exposure (as measured by plasma AUC, plasma C and the highest concentration measured in CSF) which was, in turn, associated with increased survival during the first 2weeks of TBM treatment (). Mortality was not the primary outcome and the sample size was small (n=60), but these results emphasize the need for bigger trials to assess the utility of higher doses of rifampicin given intravenously, in frequently lethal forms of TB. It further seems logical to consider alternative drugs with good drug penetration into the disease site (e.g. fluoroquinolones such as moxifloxacin and levofloxacin that show good penetration into CSF during TBM), for treating severe forms of TB. However, a recent study that investigated the spatial distribution of TB drugs in intact biopsied lung lesions from TB patients using a matrix-assisted laser desorption/ionization (MALDI) mass spectrometry suite reveals a caveat of such an approach (). This study found that moxifloxacin, although present at higher concentrations in lesions (as measured in homogenized lesions) than in plasma, was inhomogeneously distributed within the lesions with poor penetration into acellular caseum where bacilli may reside. Although the study by Shenje and colleagues () will undoubtedly advance knowledge in the field of TB drug PK/PD considerably, it is important to consider that drug concentrations in accessible fluid adjacent to primary disease sites, i.e. pericardial fluid, and CSF, may provide an incomplete picture of drug concentrations within affected tissue, i.e. pericardium and meninges, respectively. Optimistically we consider that technologies such as the MALDI mass spectrometry suite will be developed to assess TB drug distribution in tissues in vivo which will provide the next piece in the puzzle of TB drug PK/PD in all forms of TB. Conflicts of Interest
Atherosclerosis contributes to heart attack, stroke, and peripheral vascular disease and remains the leading cause of death in the U.S. (). Atherosclerotic plaques can be treated by revascularization procedures, including angioplasty, stenting, or bypass surgery, but microtrauma to the blood vessel during these procedures can lead to a complication called intimal hyperplasia, a hyper-proliferation of Deferoxamine mesylate in the vascular lumen (). Smooth muscle cells (SMC), which comprise the muscular layer of arteries, retain the remarkable ability to dedifferentiate in response to injury and assume a repair phenotype. These SMC downregulate expression of their characteristic contractile proteins and migrate from the vessel wall into the lumen where they proliferate and secrete matrix proteins, forming a fibrotic scar (). While local drug delivery with drug-eluting stents has been effective in reducing intimal hyperplasia in coronary arteries, intimal hyperplasia remains a major challenge in diabetic patients and in peripheral blood vessels (). In this issue, Wang et al. present exciting findings that targeting epigenetic “reader” proteins is a promising therapeutic strategy for preventing intimal hyperplasia. Our understanding of the smooth muscle phenotypic switching that underlies the intimal hyperplastic response has been largely at the transcriptional level, but recent studies revealed roles for epigenetic regulation, including DNA methylation and modifications of the histone proteins that organize DNA into chromatin. Collectively, these epigenetic modifications, made by proteins referred to as “writers” and “erasers”, govern chromatin accessibility to transcription factors (). The bromodomain and extraterminal domain (BET) family of reader proteins serve as critical adaptors, recognizing histone acetylated lysine residues and recruiting additional proteins to promote transcription elongation (). Wang et al. demonstrate that BET proteins play an important role in intimal hyperplasia. The authors found that the BET protein BRD4 was expressed at low levels in normal rat carotid artery but was highly induced in SMC following balloon angioplasty. BRD4 was also present in human vein and artery graft intimal hyperplastic lesions but not in normal vessels. The most exciting finding was that a BET-specific bromodomain inhibitor, JQ1, reduced intimal hyperplasia by 75% when applied to the vessel prior to angioplasty. Mechanistically, JQ1 treatment inhibited proliferation and migration in cultured aortic SMC in response to PDGF-BB, a growth factor that mediates much of the intimal hyperplastic response. While this inhibitor targets multiple BET proteins, knockdown experiments implicated BRD4, but not BRD2 or BRD3, in SMC proliferation. Their data support a model where BRD4 expression is induced by PDGF-BB, but also potentiates the signaling of its cognate receptor, PDGFRβ. An interesting finding was that PDGFRα was dramatically upregulated in the luminal hyperplastic SMC following angioplasty and its expression depended on BET protein function in cultured SMC. The role of PDGFRα and its ligands PDGF-AA or –CC in intimal hyperplasia is not well understood, but this work suggests that further investigation in this area is warranted. Other questions raised by this work include whether there may be roles for BRD2 or BRD3 (also inhibited by JQ1) in SMC biology, identifying the key target genes regulated by BRD4 in intimal hyperplasia, and determining the mechanisms that confer the specific interaction of BRD4 with target genes.